diff --git "a/SETH-train.iob" "b/SETH-train.iob"
new file mode 100644--- /dev/null
+++ "b/SETH-train.iob"
@@ -0,0 +1,111610 @@
+Word,Tag
+#10790217
+Detection,O
+of,O
+point,O
+mutations,O
+of,O
+BCL10,B-Gene
+gene,O
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+hepatocellular,O
+carcinoma,O
+tissues,O
+:,O
+report,O
+of,O
+46,O
+cases,O
+.,O
+ , 
+BCL10,B-Gene
+was,O
+found,O
+to,O
+have,O
+truncated,O
+mutations,O
+at,O
+a,O
+high,O
+frequency,O
+in,O
+MALT,O
+(,O
+mucosa,O
+-,O
+associated,O
+lymphoid,O
+tissue,O
+),O
+B,O
+cell,O
+lymphomas,O
+.,O
+ , 
+We,O
+examined,O
+the,O
+mutations,O
+of,O
+BCL10,B-Gene
+gene,O
+in,O
+human,O
+primary,O
+liver,O
+cancer,O
+using,O
+non,O
+-,O
+isotopic,O
+PCR,O
+-,O
+SSCP,O
+.,O
+ , 
+Three,O
+exons,O
+were,O
+examined,O
+in,O
+both,O
+cancer,O
+and,O
+non,O
+-,O
+HCC,O
+adjacent,O
+liver,O
+tissues,O
+.,O
+ , 
+For,O
+each,O
+exon,O
+,,O
+six,O
+PCR,O
+products,O
+with,O
+abnormal,O
+bands,O
+were,O
+sequenced,O
+to,O
+verify,O
+those,O
+mutations,O
+.,O
+ , 
+56.5,O
+%,O
+samples,O
+were,O
+revealed,O
+a,O
+C,B-SNP
+to,I-SNP
+G,I-SNP
+mutation,I-SNP
+at,I-SNP
+position,I-SNP
+5744,I-SNP
+(,B-SNP
+g5744C,I-SNP
+>,I-SNP
+G,I-SNP
+),I-SNP
+of,O
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+first,O
+exon,O
+of,O
+BCL10,B-Gene
+gene,O
+;,O
+54.3,O
+%,O
+samples,O
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+revealed,O
+a,O
+T,B-SNP
+deletion,I-SNP
+mutation,I-SNP
+at,I-SNP
+position,I-SNP
+11311,I-SNP
+(,B-SNP
+g11311delT,I-SNP
+),I-SNP
+of,O
+the,O
+second,O
+exon,O
+of,O
+BCL10,B-Gene
+gene,O
+;,O
+45.7,O
+%,O
+samples,O
+were,O
+revealed,O
+a,O
+C,B-SNP
+to,I-SNP
+T,I-SNP
+mutation,I-SNP
+at,I-SNP
+position,I-SNP
+14116,I-SNP
+(,B-SNP
+g14116C,I-SNP
+>,I-SNP
+T,I-SNP
+),I-SNP
+of,O
+the,O
+third,O
+exon,O
+of,O
+BCL10,B-Gene
+gene,O
+.,O
+ , 
+Similar,O
+mutation,O
+types,O
+were,O
+found,O
+in,O
+tumor,O
+-,O
+adjacent,O
+tissues,O
+at,O
+a,O
+lower,O
+frequency,O
+.,O
+ , 
+The,O
+single,O
+base,O
+changes,O
+result,O
+in,O
+a,O
+truncated,O
+BCL10,B-Gene
+protein,O
+expression,O
+.,O
+ , 
+Serum,O
+alpha,O
+-,O
+fetoprotein,O
+(,O
+AFP,O
+),O
+level,O
+,,O
+the,O
+tumor,O
+size,O
+had,O
+no,O
+significant,O
+relationship,O
+with,O
+BCL10,B-Gene
+mutation,O
+.,O
+ , 
+#20537299
+Principal,O
+-,O
+component,O
+analysis,O
+for,O
+assessment,O
+of,O
+population,O
+stratification,O
+in,O
+mitochondrial,O
+medical,O
+genetics,O
+.,O
+ , 
+Although,O
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+mitochondrial,O
+genetic,O
+variation,O
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+cause,O
+human,O
+disease,O
+,,O
+no,O
+validated,O
+methods,O
+exist,O
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+control,O
+of,O
+confounding,O
+due,O
+to,O
+mitochondrial,O
+population,O
+stratification,O
+(,O
+PS,O
+),O
+.,O
+ , 
+We,O
+sought,O
+to,O
+identify,O
+a,O
+reliable,O
+method,O
+for,O
+PS,O
+assessment,O
+in,O
+mitochondrial,O
+medical,O
+genetics,O
+.,O
+ , 
+We,O
+analyzed,O
+mitochondrial,O
+SNP,O
+data,O
+from,O
+1513,O
+European,O
+American,O
+individuals,O
+concomitantly,O
+genotyped,O
+with,O
+the,O
+use,O
+of,O
+a,O
+previously,O
+validated,O
+panel,O
+of,O
+144,O
+mitochondrial,O
+markers,O
+as,O
+well,O
+as,O
+the,O
+Affymetrix,O
+6.0,O
+(,O
+n,O
+=,O
+432,O
+),O
+,,O
+Illumina,O
+610,O
+-,O
+Quad,O
+(,O
+n,O
+=,O
+458,O
+),O
+,,O
+or,O
+Illumina,O
+660,O
+(,O
+n,O
+=,O
+623,O
+),O
+platforms,O
+.,O
+ , 
+Additional,O
+analyses,O
+were,O
+performed,O
+in,O
+938,O
+participants,O
+in,O
+the,O
+Human,O
+Genome,O
+Diversity,O
+Panel,O
+(,O
+HGDP,O
+),O
+(,O
+Illumina,O
+650,O
+),O
+.,O
+ , 
+We,O
+compared,O
+the,O
+following,O
+methods,O
+for,O
+controlling,O
+for,O
+PS,O
+:,O
+haplogroup,O
+-,O
+stratified,O
+analyses,O
+,,O
+mitochondrial,O
+principal,O
+-,O
+component,O
+analysis,O
+(,O
+PCA,O
+),O
+,,O
+and,O
+combined,O
+autosomal,O
+-,O
+mitochondrial,O
+PCA,O
+.,O
+ , 
+We,O
+computed,O
+mitochondrial,O
+genomic,O
+inflation,O
+factors,O
+(,O
+mtGIFs,O
+),O
+and,O
+test,O
+statistics,O
+for,O
+simulated,O
+case,O
+-,O
+control,O
+and,O
+continuous,O
+phenotypes,O
+(,O
+10,000,O
+simulations,O
+each,O
+),O
+with,O
+varying,O
+degrees,O
+of,O
+correlation,O
+with,O
+mitochondrial,O
+ancestry,O
+.,O
+ , 
+Results,O
+were,O
+then,O
+compared,O
+across,O
+adjustment,O
+methods,O
+.,O
+ , 
+We,O
+also,O
+calculated,O
+power,O
+for,O
+discovery,O
+of,O
+true,O
+associations,O
+under,O
+each,O
+method,O
+,,O
+using,O
+a,O
+simulation,O
+approach,O
+.,O
+ , 
+Mitochondrial,O
+PCA,O
+recapitulated,O
+haplogroup,O
+information,O
+,,O
+but,O
+haplogroup,O
+-,O
+stratified,O
+analyses,O
+were,O
+inferior,O
+to,O
+mitochondrial,O
+PCA,O
+in,O
+controlling,O
+for,O
+PS,O
+.,O
+ , 
+Correlation,O
+between,O
+nuclear,O
+and,O
+mitochondrial,O
+principal,O
+components,O
+(,O
+PCs,O
+),O
+was,O
+very,O
+limited,O
+.,O
+ , 
+Adjustment,O
+for,O
+nuclear,O
+PCs,O
+had,O
+no,O
+effect,O
+on,O
+mitochondrial,O
+analysis,O
+of,O
+simulated,O
+phenotypes,O
+.,O
+ , 
+Mitochondrial,O
+PCA,O
+performed,O
+with,O
+the,O
+use,O
+of,O
+data,O
+from,O
+commercially,O
+available,O
+genome,O
+-,O
+wide,O
+arrays,O
+correlated,O
+strongly,O
+with,O
+PCA,O
+performed,O
+with,O
+the,O
+use,O
+of,O
+an,O
+exhaustive,O
+mitochondrial,O
+marker,O
+panel,O
+.,O
+ , 
+Finally,O
+,,O
+we,O
+demonstrate,O
+,,O
+through,O
+simulation,O
+,,O
+no,O
+loss,O
+in,O
+power,O
+for,O
+detection,O
+of,O
+true,O
+associations,O
+with,O
+the,O
+use,O
+of,O
+mitochondrial,O
+PCA,O
+.,O
+ , 
+#1363805
+Mutations,O
+in,O
+the,O
+medium,B-Gene
+chain,I-Gene
+acyl,I-Gene
+-,I-Gene
+CoA,I-Gene
+dehydrogenase,I-Gene
+(,B-Gene
+MCAD,I-Gene
+),I-Gene
+gene,O
+.,O
+ , 
+Medium,B-Gene
+chain,I-Gene
+acyl,I-Gene
+-,I-Gene
+CoA,I-Gene
+dehydrogenase,I-Gene
+(,B-Gene
+MCAD,I-Gene
+),I-Gene
+catalyzes,O
+the,O
+first,O
+reaction,O
+of,O
+the,O
+beta,O
+-,O
+oxidation,O
+cycle,O
+for,O
+4,O
+-,O
+10,O
+-,O
+carbon,O
+fatty,O
+acids,O
+.,O
+ , 
+MCAD,B-Gene
+deficiency,O
+is,O
+one,O
+of,O
+the,O
+most,O
+frequent,O
+inborn,O
+metabolic,O
+disorders,O
+in,O
+populations,O
+of,O
+northwestern,O
+European,O
+origin,O
+.,O
+ , 
+In,O
+the,O
+compilation,O
+of,O
+data,O
+from,O
+a,O
+worldwide,O
+study,O
+of,O
+172,O
+unrelated,O
+patients,O
+each,O
+representing,O
+an,O
+independent,O
+pedigree,O
+,,O
+a,O
+total,O
+of,O
+8,O
+different,O
+mutations,O
+have,O
+been,O
+identified,O
+.,O
+ , 
+Among,O
+them,O
+,,O
+a,O
+single,O
+prevalent,O
+mutation,O
+,,O
+985A-->G,B-SNP
+,,I-SNP
+was,O
+found,O
+in,O
+90,O
+%,O
+of,O
+344,O
+variant,O
+alleles,O
+.,O
+ , 
+985A-->G,B-SNP
+causes,O
+glutamate,B-SNP
+substitution,I-SNP
+for,I-SNP
+lysine-304,I-SNP
+in,O
+the,O
+mature,O
+MCAD,O
+subunit,O
+,,O
+which,O
+causes,O
+impairment,O
+of,O
+tetramer,O
+assembly,O
+and,O
+instability,O
+of,O
+the,O
+protein,O
+.,O
+ , 
+Three,O
+of,O
+7,O
+rarer,O
+mutations,O
+have,O
+been,O
+identified,O
+in,O
+a,O
+few,O
+unrelated,O
+patients,O
+,,O
+while,O
+the,O
+remaining,O
+4,O
+have,O
+each,O
+been,O
+found,O
+in,O
+only,O
+a,O
+single,O
+pedigree,O
+.,O
+ , 
+In,O
+addition,O
+to,O
+tabulating,O
+the,O
+mutations,O
+,,O
+the,O
+acyl,B-Gene
+-,I-Gene
+CoA,I-Gene
+dehydrogenase,I-Gene
+gene,O
+family,O
+,,O
+the,O
+structure,O
+of,O
+the,O
+MCAD,B-Gene
+gene,O
+and,O
+the,O
+evolution,O
+of,O
+985A-->G,B-SNP
+mutation,O
+are,O
+briefly,O
+discussed,O
+.,O
+ , 
+#9718360
+",O
+Well,O
+-,O
+bear,O
+and,O
+well,O
+-,O
+rear,O
+",O
+in,O
+China,O
+?,O
+ , 
+#8751870
+Family,O
+study,O
+and,O
+segregation,O
+analysis,O
+of,O
+Tourette,O
+syndrome,O
+:,O
+evidence,O
+for,O
+a,O
+mixed,O
+model,O
+of,O
+inheritance,O
+.,O
+ , 
+To,O
+investigate,O
+the,O
+transmission,O
+of,O
+Tourette,O
+syndrome,O
+(,O
+TS,O
+),O
+and,O
+associated,O
+disorders,O
+within,O
+families,O
+,,O
+complex,O
+segregation,O
+analysis,O
+was,O
+performed,O
+on,O
+family,O
+study,O
+data,O
+obtained,O
+from,O
+53,O
+independently,O
+ascertained,O
+children,O
+and,O
+adolescents,O
+with,O
+TS,O
+and,O
+their,O
+154,O
+first,O
+-,O
+degree,O
+relatives,O
+.,O
+ , 
+The,O
+results,O
+suggest,O
+that,O
+the,O
+susceptibility,O
+for,O
+TS,O
+is,O
+conveyed,O
+by,O
+a,O
+major,O
+locus,O
+in,O
+combination,O
+with,O
+a,O
+multifactorial,O
+background,O
+.,O
+ , 
+Other,O
+models,O
+of,O
+inheritance,O
+were,O
+definitively,O
+rejected,O
+,,O
+including,O
+strictly,O
+polygenic,O
+models,O
+,,O
+all,O
+single,O
+major,O
+locus,O
+models,O
+,,O
+and,O
+mixed,O
+models,O
+with,O
+dominant,O
+and,O
+recessive,O
+major,O
+loci,O
+.,O
+ , 
+The,O
+frequency,O
+of,O
+the,O
+TS,O
+susceptibility,O
+allele,O
+was,O
+estimated,O
+to,O
+be,O
+.01,O
+.,O
+ , 
+The,O
+major,O
+locus,O
+accounts,O
+for,O
+over,O
+half,O
+of,O
+the,O
+phenotypic,O
+variance,O
+for,O
+TS,O
+,,O
+whereas,O
+the,O
+multifactorial,O
+background,O
+accounts,O
+for,O
+approximately,O
+40,O
+%,O
+of,O
+phenotypic,O
+variance,O
+.,O
+ , 
+Penetrance,O
+estimates,O
+suggest,O
+that,O
+all,O
+individuals,O
+homozygous,O
+for,O
+the,O
+susceptibility,O
+allele,O
+at,O
+the,O
+major,O
+locus,O
+are,O
+affected,O
+,,O
+whereas,O
+only,O
+2.2,O
+%,O
+of,O
+males,O
+and,O
+0.3,O
+%,O
+of,O
+females,O
+heterozygous,O
+at,O
+the,O
+major,O
+locus,O
+are,O
+affected,O
+.,O
+ , 
+Of,O
+individuals,O
+affected,O
+with,O
+TS,O
+,,O
+approximately,O
+62,O
+%,O
+are,O
+heterozygous,O
+and,O
+approximately,O
+38,O
+%,O
+are,O
+homozygous,O
+at,O
+the,O
+major,O
+locus,O
+.,O
+ , 
+While,O
+none,O
+of,O
+the,O
+families,O
+had,O
+two,O
+parents,O
+affected,O
+with,O
+TS,O
+,,O
+19,O
+%,O
+of,O
+families,O
+had,O
+two,O
+parents,O
+affected,O
+with,O
+the,O
+broader,O
+,,O
+phenotype,O
+,,O
+which,O
+includes,O
+TS,O
+,,O
+chronic,O
+tic,O
+disorder,O
+,,O
+or,O
+obsessive,O
+-,O
+compulsive,O
+disorder,O
+.,O
+ , 
+#23122587
+Mutations,O
+of,O
+the,O
+gene,O
+encoding,O
+otogelin,B-Gene
+are,O
+a,O
+cause,O
+of,O
+autosomal,O
+-,O
+recessive,O
+nonsyndromic,O
+moderate,O
+hearing,O
+impairment,O
+.,O
+ , 
+Already,O
+40,O
+genes,O
+have,O
+been,O
+identified,O
+for,O
+autosomal,O
+-,O
+recessive,O
+nonsyndromic,O
+hearing,O
+impairment,O
+(,O
+arNSHI,O
+),O
+;,O
+however,O
+,,O
+many,O
+more,O
+genes,O
+are,O
+still,O
+to,O
+be,O
+identified,O
+.,O
+ , 
+In,O
+a,O
+Dutch,O
+family,O
+segregating,O
+arNSHI,O
+,,O
+homozygosity,O
+mapping,O
+revealed,O
+a,O
+2.4,O
+Mb,O
+homozygous,O
+region,O
+on,O
+chromosome,O
+11,O
+in,O
+p15.1,O
+-,O
+15.2,O
+,,O
+which,O
+partially,O
+overlapped,O
+with,O
+the,O
+previously,O
+described,O
+DFNB18,B-Gene
+locus,O
+.,O
+ , 
+However,O
+,,O
+no,O
+putative,O
+pathogenic,O
+variants,O
+were,O
+found,O
+in,O
+USH1C,B-Gene
+,,I-Gene
+the,O
+gene,O
+mutated,O
+in,O
+DFNB18,O
+hearing,O
+impairment,O
+.,O
+ , 
+The,O
+homozygous,O
+region,O
+contained,O
+12,O
+additional,O
+annotated,O
+genes,O
+including,O
+OTOG,B-Gene
+,,I-Gene
+the,O
+gene,O
+encoding,O
+otogelin,B-Gene
+,,I-Gene
+a,O
+component,O
+of,O
+the,O
+tectorial,O
+membrane,O
+.,O
+ , 
+It,O
+is,O
+thought,O
+that,O
+otogelin,O
+contributes,O
+to,O
+the,O
+stability,O
+and,O
+strength,O
+of,O
+this,O
+membrane,O
+through,O
+interaction,O
+or,O
+stabilization,O
+of,O
+its,O
+constituent,O
+fibers,O
+.,O
+ , 
+The,O
+murine,B-Gene
+orthologous,O
+gene,O
+was,O
+already,O
+known,O
+to,O
+cause,O
+hearing,O
+loss,O
+when,O
+defective,O
+.,O
+ , 
+Analysis,O
+of,O
+OTOG,B-Gene
+in,O
+the,O
+Dutch,O
+family,O
+revealed,O
+a,O
+homozygous,O
+1,O
+ ,O
+bp,O
+deletion,O
+,,O
+c.5508delC,B-SNP
+,,I-SNP
+which,O
+leads,O
+to,O
+a,O
+shift,O
+in,O
+the,O
+reading,O
+frame,O
+and,O
+a,O
+premature,O
+stop,O
+codon,O
+,,O
+p.,B-SNP
+Ala1838ProfsX31,I-SNP
+.,I-SNP
+ , 
+Further,O
+screening,O
+ ,O
+of,O
+60,O
+unrelated,O
+probands,O
+from,O
+Spanish,O
+arNSHI,O
+families,O
+detected,O
+compound,O
+heterozygous,O
+OTOG,B-Gene
+mutations,O
+in,O
+one,O
+family,O
+,,O
+c.6347C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+Pro2116Leu,I-SNP
+),I-SNP
+and,O
+c.,O
+6559C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+Arg2187X,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+missense,O
+mutation,O
+p.,B-SNP
+Pro2116Leu,I-SNP
+affects,O
+a,O
+highly,O
+conserved,O
+residue,O
+in,O
+the,O
+fourth,O
+von,O
+Willebrand,O
+factor,O
+type,O
+D,O
+domain,O
+of,O
+otogelin,O
+.,O
+ , 
+The,O
+subjects,O
+with,O
+OTOG,B-Gene
+mutations,O
+have,O
+a,O
+moderate,O
+hearing,O
+impairment,O
+,,O
+which,O
+can,O
+be,O
+associated,O
+with,O
+vestibular,O
+dysfunction,O
+.,O
+ , 
+The,O
+flat,O
+to,O
+shallow,O
+",O
+U,O
+",O
+or,O
+slightly,O
+downsloping,O
+shaped,O
+audiograms,O
+closely,O
+resembled,O
+audiograms,O
+of,O
+individuals,O
+with,O
+recessive,O
+mutations,O
+in,O
+the,O
+gene,O
+encoding,O
+α,B-Gene
+-,I-Gene
+tectorin,I-Gene
+,,I-Gene
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+component,O
+of,O
+the,O
+tectorial,O
+membrane,O
+.,O
+ , 
+This,O
+distinctive,O
+phenotype,O
+may,O
+represent,O
+a,O
+clue,O
+to,O
+orientate,O
+the,O
+molecular,O
+diagnosis,O
+.,O
+ , 
+#21565292
+Random,O
+-,O
+effects,O
+model,O
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+in,O
+meta,O
+-,O
+analysis,O
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+genome,O
+-,O
+wide,O
+association,O
+studies,O
+.,O
+ , 
+Meta,O
+-,O
+analysis,O
+is,O
+an,O
+increasingly,O
+popular,O
+tool,O
+for,O
+combining,O
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+different,O
+genome,O
+-,O
+wide,O
+association,O
+studies,O
+(,O
+GWASs,O
+),O
+in,O
+a,O
+single,O
+aggregate,O
+analysis,O
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+order,O
+to,O
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+with,O
+very,O
+small,O
+effect,O
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+.,O
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+Because,O
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+data,O
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+a,O
+meta,O
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+,,O
+referring,O
+to,O
+the,O
+differences,O
+in,O
+effect,O
+sizes,O
+between,O
+the,O
+collected,O
+studies,O
+,,O
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+often,O
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+in,O
+the,O
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+to,O
+apply,O
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+the,O
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+-,O
+effects,O
+model,O
+(,O
+FE,O
+),O
+under,O
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+assumption,O
+of,O
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+same,O
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+between,O
+studies,O
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+the,O
+random,O
+-,O
+effects,O
+model,O
+(,O
+RE,O
+),O
+under,O
+an,O
+assumption,O
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+between,O
+studies,O
+.,O
+ , 
+However,O
+,,O
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+,,O
+RE,O
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+less,O
+significant,O
+p,O
+values,O
+than,O
+FE,O
+at,O
+variants,O
+that,O
+actually,O
+show,O
+varying,O
+effect,O
+sizes,O
+between,O
+studies,O
+.,O
+ , 
+This,O
+is,O
+ironic,O
+because,O
+RE,O
+is,O
+designed,O
+specifically,O
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+the,O
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+in,O
+which,O
+there,O
+is,O
+heterogeneity,O
+.,O
+ , 
+As,O
+a,O
+result,O
+,,O
+usually,O
+,,O
+RE,O
+does,O
+not,O
+discover,O
+any,O
+associations,O
+that,O
+FE,O
+did,O
+not,O
+discover,O
+.,O
+ , 
+In,O
+this,O
+paper,O
+,,O
+we,O
+show,O
+that,O
+the,O
+underlying,O
+reason,O
+for,O
+this,O
+phenomenon,O
+is,O
+that,O
+RE,O
+implicitly,O
+assumes,O
+a,O
+markedly,O
+conservative,O
+null,O
+-,O
+hypothesis,O
+model,O
+,,O
+and,O
+we,O
+present,O
+a,O
+new,O
+random,O
+-,O
+effects,O
+model,O
+that,O
+relaxes,O
+the,O
+conservative,O
+assumption,O
+.,O
+ , 
+Unlike,O
+the,O
+traditional,O
+RE,O
+,,O
+the,O
+new,O
+method,O
+is,O
+shown,O
+to,O
+achieve,O
+higher,O
+statistical,O
+power,O
+than,O
+FE,O
+when,O
+there,O
+is,O
+heterogeneity,O
+,,O
+indicating,O
+that,O
+the,O
+new,O
+method,O
+has,O
+practical,O
+utility,O
+for,O
+discovering,O
+associations,O
+in,O
+the,O
+meta,O
+-,O
+analysis,O
+of,O
+GWASs,O
+.,O
+ , 
+#16411177
+Masking,O
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+sequence,O
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+incorporating,O
+mismatches,O
+into,O
+melting,O
+analysis,O
+probes,O
+.,O
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+Hybridization,O
+probe,O
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+analysis,O
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+be,O
+complicated,O
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+sequence,O
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+(,O
+benign,O
+polymorphisms,O
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+other,O
+mutations,O
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+near,O
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+targeted,O
+mutation,O
+.,O
+ , 
+We,O
+investigated,O
+the,O
+use,O
+of,O
+",O
+masking,O
+",O
+probes,O
+to,O
+differentiate,O
+alleles,O
+with,O
+similar,O
+probe,O
+melting,O
+temperatures,O
+.,O
+ , 
+Selected,O
+sequence,O
+variation,O
+was,O
+masked,O
+by,O
+incorporating,O
+mismatches,O
+(,O
+deletion,O
+,,O
+unmatched,O
+nucleotide,O
+,,O
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+universal,O
+base,O
+),O
+into,O
+hybridization,O
+probes,O
+at,O
+the,O
+polymorphic,O
+location,O
+.,O
+ , 
+Such,O
+masking,O
+probes,O
+create,O
+a,O
+probe,O
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+target,O
+mismatch,O
+with,O
+all,O
+possible,O
+alleles,O
+at,O
+the,O
+selected,O
+polymorphic,O
+location,O
+.,O
+ , 
+Any,O
+allele,O
+with,O
+additional,O
+variation,O
+at,O
+another,O
+site,O
+is,O
+identified,O
+by,O
+a,O
+lower,O
+probe,O
+melting,O
+temperature,O
+than,O
+alleles,O
+that,O
+vary,O
+only,O
+at,O
+the,O
+masked,O
+position,O
+.,O
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+This,O
+",O
+masking,O
+technique,O
+",O
+was,O
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+to,O
+RET,B-Gene
+protooncogene,O
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+HPA6,B-Gene
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+saturating,O
+dsDNA,O
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+,,O
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+high,O
+-,O
+resolution,O
+melting,O
+analysis,O
+.,O
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+Masking,O
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+from,O
+polymorphisms,O
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+at,O
+least,O
+1,O
+base,O
+pair,O
+(,O
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+variation,O
+.,O
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+We,O
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+able,O
+to,O
+mask,O
+polymorphisms,O
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+adjacent,O
+to,O
+mutations,O
+,,O
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+certain,O
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+,,O
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+as,O
+those,O
+involving,O
+single,O
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+both,O
+adjacent,O
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+the,O
+same,O
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+nucleotides,O
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+The,O
+masking,O
+probes,O
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+specific,O
+codons,O
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+nucleotide,O
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+.,O
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+Masking,O
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+simplify,O
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+for,O
+sequencing,O
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+#16252233
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+Mutation,O
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+human,O
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+single,O
+base,O
+-,O
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+to,O
+whole,O
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+Karyotyping,O
+,,O
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+in,O
+situ,O
+hybridization,O
+,,O
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+comparative,O
+genome,O
+hybridization,O
+are,O
+currently,O
+used,O
+to,O
+detect,O
+chromosome,O
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+of,O
+clinical,O
+significance,O
+.,O
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+These,O
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+,,O
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+from,O
+limitations,O
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+resolution,O
+,,O
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+they,O
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+detect,O
+copy,O
+-,O
+neutral,O
+chromosomal,O
+aberrations,O
+--,O
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+example,O
+,,O
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+(,O
+UPD,O
+),O
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+We,O
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+developed,O
+a,O
+high,O
+-,O
+throughput,O
+approach,O
+for,O
+assessment,O
+of,O
+DNA,O
+copy,O
+-,O
+number,O
+changes,O
+,,O
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+use,O
+of,O
+high,O
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+synthetic,O
+oligonucleotide,O
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+116,204,O
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+Using,O
+this,O
+approach,O
+,,O
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+that,O
+failed,O
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+analysis,O
+,,O
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+we,O
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+amplifications,O
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+deletions,O
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+a,O
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+(,O
+1.3,O
+-,O
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+,,O
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+genotype,O
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+determine,O
+the,O
+molecular,O
+origin,O
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+two,O
+cases,O
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+UPD,O
+.,O
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+Furthermore,O
+,,O
+our,O
+data,O
+provided,O
+independent,O
+confirmation,O
+for,O
+a,O
+case,O
+that,O
+had,O
+been,O
+misinterpreted,O
+by,O
+karyotype,O
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+.,O
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+The,O
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+our,O
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+,,O
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+allows,O
+subtle,O
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+The,O
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+need,O
+for,O
+cell,O
+culture,O
+.,O
+ , 
+This,O
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+in,O
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+accurate,O
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+#18179886
+Oncostatin,B-Gene
+M,I-Gene
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+Familial,O
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+chronic,O
+skin,O
+itching,O
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+deposition,O
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+epidermal,O
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+-,O
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+dermis,O
+.,O
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+FPLCA,O
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+,,O
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+OSMRbeta,B-Gene
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+oncostatin,B-Gene
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+OSM,I-Gene
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+PI3K,O
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+OSM,B-Gene
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+IL-31,B-Gene
+cytokine,O
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+The,O
+pathogenic,O
+amino,O
+acid,O
+substitutions,O
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+located,O
+within,O
+the,O
+extracellular,O
+fibronectin,O
+type,O
+III,O
+-,O
+like,O
+(,O
+FNIII,O
+),O
+domains,O
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+function,O
+.,O
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+OSM,B-Gene
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+,,O
+but,O
+our,O
+OSMR,O
+data,O
+in,O
+individuals,O
+with,O
+FPLCA,O
+represent,O
+the,O
+first,O
+human,O
+germline,O
+mutations,O
+in,O
+this,O
+cytokine,O
+receptor,O
+complex,O
+and,O
+provide,O
+new,O
+insight,O
+into,O
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+skin,O
+itching,O
+.,O
+ , 
+#22521416
+A,O
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+CEP135,B-Gene
+causes,O
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+disturbed,O
+centrosomal,O
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+Autosomal,O
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+(,O
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+disorder,O
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+intellectual,O
+disability,O
+,,O
+reduced,O
+brain,O
+and,O
+head,O
+size,O
+,,O
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+usually,O
+without,O
+defects,O
+in,O
+cerebral,O
+cortical,O
+architecture,O
+,,O
+and,O
+other,O
+syndromic,O
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+.,O
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+MCPH,O
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+.,O
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+The,O
+underlying,O
+genes,O
+of,O
+the,O
+seven,O
+known,O
+loci,O
+code,O
+for,O
+centrosomal,O
+proteins,O
+.,O
+ , 
+We,O
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+a,O
+family,O
+from,O
+northern,O
+Pakistan,O
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+two,O
+microcephalic,O
+children,O
+using,O
+homozygosity,O
+mapping,O
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+found,O
+suggestive,O
+linkage,O
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+regions,O
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+chromosomes,O
+2,O
+,,O
+4,O
+,,O
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+9,O
+.,O
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+We,O
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+positional,O
+candidate,O
+genes,O
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+identified,O
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+frameshift,O
+mutation,O
+in,O
+the,O
+gene,O
+encoding,O
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+135,O
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+kDa,O
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+protein,O
+(,B-Gene
+CEP135,I-Gene
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+,,O
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+in,O
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+linkage,O
+interval,O
+on,O
+chromosome,O
+4,O
+,,O
+in,O
+both,O
+affected,O
+children,O
+.,O
+ , 
+Post,O
+hoc,O
+whole,O
+-,O
+exome,O
+sequencing,O
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+mutation,O
+'s,O
+identification,O
+as,O
+the,O
+causal,O
+variant,O
+.,O
+ , 
+Fibroblasts,O
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+from,O
+one,O
+of,O
+the,O
+patients,O
+showed,O
+multiple,O
+and,O
+fragmented,O
+centrosomes,O
+,,O
+disorganized,O
+microtubules,O
+,,O
+and,O
+reduced,O
+growth,O
+rate,O
+.,O
+ , 
+Similar,O
+effects,O
+were,O
+reported,O
+after,O
+knockdown,O
+of,O
+CEP135,B-Gene
+through,O
+RNA,O
+interference,O
+;,O
+we,O
+could,O
+provoke,O
+them,O
+also,O
+by,O
+ectopic,O
+overexpression,O
+of,O
+the,O
+mutant,O
+protein,O
+.,O
+ , 
+Our,O
+findings,O
+suggest,O
+an,O
+additional,O
+locus,O
+for,O
+MCPH,O
+at,O
+HSA,O
+4q12,O
+(,B-Gene
+MCPH8,I-Gene
+),I-Gene
+,,O
+further,O
+strengthen,O
+the,O
+role,O
+of,O
+centrosomes,O
+in,O
+the,O
+development,O
+of,O
+MCPH,O
+,,O
+and,O
+place,O
+CEP135,B-Gene
+among,O
+the,O
+essential,O
+components,O
+of,O
+this,O
+important,O
+organelle,O
+in,O
+particular,O
+for,O
+a,O
+normal,O
+neurogenesis,O
+.,O
+ , 
+#8956037
+A,O
+novel,O
+deletion,O
+/,O
+inversion,O
+mutation,O
+in,O
+the,O
+low,B-Gene
+-,I-Gene
+density,I-Gene
+lipoprotein,I-Gene
+receptor,I-Gene
+gene,O
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+a,O
+cause,O
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+heterozygous,O
+familial,O
+hypercholesterolemia,O
+.,O
+ , 
+A,O
+combined,O
+deletion,O
+/,O
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+rearrangement,O
+of,O
+the,O
+LDL,B-Gene
+receptor,O
+gene,O
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+in,O
+a,O
+Finnish,O
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+familial,O
+hypercholesterolemia,O
+(,O
+FH,O
+),O
+.,O
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+Sequence,O
+analysis,O
+of,O
+the,O
+mutated,O
+allele,O
+revealed,O
+an,O
+insertion,O
+of,O
+4,O
+nucleotides,O
+in,O
+exon,O
+11,O
+,,O
+caused,O
+by,O
+a,O
+combined,O
+deletion,O
+and,O
+insertion,O
+event,O
+replacing,O
+a,O
+13,O
+-,O
+bp,O
+segment,O
+of,O
+the,O
+normal,O
+exon,O
+11,O
+sequence,O
+of,O
+the,O
+LDL,O
+receptor,O
+gene,O
+by,O
+a,O
+17,O
+-,O
+bp,O
+stretch,O
+of,O
+new,O
+sequence,O
+at,O
+the,O
+deletion,O
+breakpoint,O
+.,O
+ , 
+The,O
+inserted,O
+sequence,O
+was,O
+identical,O
+to,O
+the,O
+normal,O
+exon,O
+9,O
+sequence,O
+of,O
+the,O
+LDL,B-Gene
+receptor,O
+gene,O
+from,O
+nt1225,O
+to,O
+nt1241,O
+inserted,O
+in,O
+an,O
+inverted,O
+orientation,O
+.,O
+ , 
+This,O
+defect,O
+causes,O
+a,O
+translational,O
+frameshift,B-SNP
+after,I-SNP
+amino,I-SNP
+acid,I-SNP
+525,I-SNP
+(,I-SNP
+glycine,I-SNP
+),I-SNP
+and,I-SNP
+leads,I-SNP
+to,I-SNP
+a,I-SNP
+premature,I-SNP
+termination,I-SNP
+codon,I-SNP
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+amino,I-SNP
+acid,I-SNP
+position,I-SNP
+538,I-SNP
+.,I-SNP
+ , 
+Analysis,O
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+transcriptase,O
+-,O
+PCR,O
+products,O
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+total,O
+RNA,O
+extracted,O
+from,O
+cultured,O
+fibroblasts,O
+revealed,O
+only,O
+transcripts,O
+encoded,O
+by,O
+the,O
+normal,O
+allele,O
+.,O
+ , 
+This,O
+finding,O
+was,O
+consistent,O
+with,O
+the,O
+reduced,O
+functional,O
+activity,O
+of,O
+the,O
+LDL,B-Gene
+receptor,O
+found,O
+in,O
+the,O
+fibroblasts,O
+of,O
+the,O
+patient,O
+to,O
+levels,O
+less,O
+than,O
+50,O
+%,O
+of,O
+those,O
+in,O
+normal,O
+cells,O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+we,O
+have,O
+identified,O
+a,O
+complex,O
+and,O
+hitherto,O
+unreported,O
+type,O
+of,O
+rearrangement,O
+of,O
+the,O
+human,O
+LDL,B-Gene
+receptor,O
+gene,O
+.,O
+ , 
+The,O
+precise,O
+mechanism,O
+of,O
+this,O
+mutation,O
+(,O
+designated,O
+as,O
+FH,O
+-,O
+Jalasjärvi,O
+),O
+remains,O
+obscure,O
+,,O
+although,O
+it,O
+may,O
+involve,O
+complex,O
+loop,O
+formation,O
+by,O
+interaction,O
+of,O
+complementary,O
+sequences,O
+present,O
+in,O
+the,O
+mutation,O
+breakpoints,O
+and,O
+their,O
+immediate,O
+flanking,O
+regions,O
+.,O
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+#11359216
+Mitochondria,O
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+quality,O
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+human,O
+gametes,O
+.,O
+ , 
+#20052763
+Ex,O
+vivo,O
+splicing,O
+assays,O
+of,O
+mutations,O
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+noncanonical,O
+positions,O
+of,O
+splice,O
+sites,O
+in,O
+USHER,B-Gene
+genes,O
+.,O
+ , 
+Molecular,O
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+Usher,O
+syndrome,O
+type,O
+1,O
+and,O
+2,O
+patients,O
+led,O
+to,O
+the,O
+identification,O
+of,O
+21,O
+sequence,O
+variations,O
+located,O
+in,O
+noncanonical,O
+positions,O
+of,O
+splice,O
+sites,O
+in,O
+MYO7A,B-Gene
+,,I-Gene
+CDH23,B-Gene
+,,I-Gene
+USH1C,B-Gene
+,,I-Gene
+and,O
+USH2A,B-Gene
+genes,O
+.,O
+ , 
+To,O
+establish,O
+experimentally,O
+the,O
+splicing,O
+pattern,O
+of,O
+these,O
+substitutions,O
+,,O
+whose,O
+impact,O
+on,O
+splicing,O
+is,O
+not,O
+always,O
+predictable,O
+by,O
+available,O
+softwares,O
+,,O
+ex,O
+vivo,O
+splicing,O
+assays,O
+were,O
+performed,O
+.,O
+ , 
+The,O
+branch,O
+-,O
+point,O
+mapping,O
+strategy,O
+was,O
+also,O
+used,O
+to,O
+investigate,O
+further,O
+a,O
+putative,O
+branch,O
+-,O
+point,O
+mutation,O
+in,O
+USH2A,O
+intron,O
+43,O
+.,O
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+Aberrant,O
+splicing,O
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+16,O
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+the,O
+21,O
+(,O
+76.2,O
+%,O
+),O
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+sequence,O
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+.,O
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+The,O
+mutations,O
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+more,O
+frequently,O
+in,O
+activation,O
+of,O
+a,O
+nearby,O
+cryptic,O
+splice,O
+site,O
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+use,O
+of,O
+a,O
+de,O
+novo,O
+splice,O
+site,O
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+exon,O
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+(,O
+37.5,O
+%,O
+),O
+.,O
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+This,O
+study,O
+allowed,O
+the,O
+reclassification,O
+as,O
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+mutations,O
+of,O
+one,O
+silent,O
+(,B-SNP
+c.7872G,I-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+Glu2624Glu,I-SNP
+),I-SNP
+in,O
+CDH23,B-Gene
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+and,O
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+missense,O
+mutations,O
+(,B-SNP
+c.2993G,I-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+Arg998Lys,I-SNP
+),I-SNP
+in,O
+USH2A,B-Gene
+,,I-Gene
+c.592G,B-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+Ala198Thr,I-SNP
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+,,O
+c.3503G,B-SNP
+>,I-SNP
+C,I-SNP
+ , 
+[,B-SNP
+p.,I-SNP
+Arg1168Pro,I-SNP
+],I-SNP
+,,O
+c.5944G,B-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+Gly1982Arg,I-SNP
+),I-SNP
+in,O
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+clues,O
+about,O
+a,O
+role,O
+in,O
+structure,O
+/,O
+function,O
+in,O
+four,O
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+cases,O
+:,O
+c.802G,B-SNP
+>,I-SNP
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+A,B-SNP
+(,B-SNP
+p.,I-SNP
+Gly268Arg,I-SNP
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+Val218Glu,I-SNP
+),I-SNP
+(,B-Gene
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+T,I-SNP
+(,B-SNP
+p.,I-SNP
+His133Tyr,I-SNP
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+,,O
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+Arg1168Trp,I-SNP
+),I-SNP
+ , 
+(,B-Gene
+MYO7A,I-Gene
+),I-Gene
+.,O
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+Our,O
+data,O
+provide,O
+insights,O
+into,O
+the,O
+contribution,O
+of,O
+splicing,O
+mutations,O
+in,O
+Usher,O
+genes,O
+and,O
+illustrate,O
+the,O
+need,O
+to,O
+define,O
+accurately,O
+their,O
+splicing,O
+outcome,O
+for,O
+diagnostic,O
+purposes,O
+.,O
+ , 
+#1301930
+A,O
+comprehensive,O
+scanning,O
+method,O
+for,O
+rapid,O
+detection,O
+of,O
+beta,B-Gene
+-,I-Gene
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+gene,O
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+We,O
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+a,O
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+for,O
+the,O
+detection,O
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+the,O
+prenatal,O
+diagnosis,O
+of,O
+beta,O
+-,O
+thalassemias,O
+.,O
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+The,O
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+the,O
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+use,O
+of,O
+PCR,O
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+denaturing,O
+gradient,O
+gel,O
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+(,O
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+,,O
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+3,O
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+The,O
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+-,I-Gene
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+presence,O
+of,O
+deleterious,O
+mutations,O
+.,O
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+The,O
+proposed,O
+diagnostic,O
+strategy,O
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+major,O
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+over,O
+current,O
+approaches,O
+to,O
+beta,B-Gene
+-,I-Gene
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+gene,O
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+in,O
+both,O
+research,O
+and,O
+clinical,O
+laboratories,O
+,,O
+especially,O
+those,O
+which,O
+analyse,O
+DNA,O
+samples,O
+from,O
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+various,O
+ethnic,O
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+population,O
+groups,O
+.,O
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+The,O
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+this,O
+procedure,O
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+us,O
+to,O
+detect,O
+six,O
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+sequence,O
+changes,O
+in,O
+the,O
+beta,O
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+#21565291
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+.,O
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+Regulation,O
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+essential,O
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+normal,O
+development,O
+.,O
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+The,O
+Rho,O
+family,O
+of,O
+GTPases,O
+plays,O
+a,O
+critical,O
+role,O
+in,O
+the,O
+control,O
+of,O
+cell,O
+polarity,O
+and,O
+migration,O
+by,O
+effecting,O
+the,O
+cytoskeleton,O
+,,O
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+,,O
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+.,O
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+We,O
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+recognized,O
+developmental,O
+disorder,O
+,,O
+Adams,O
+-,O
+Oliver,O
+syndrome,O
+(,O
+AOS,O
+),O
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+by,O
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+combination,O
+of,O
+aplasia,O
+cutis,O
+congenita,O
+(,O
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+transverse,O
+limb,O
+defects,O
+(,O
+TTLD,O
+),O
+.,O
+ , 
+Through,O
+a,O
+genome,O
+-,O
+wide,O
+linkage,O
+analysis,O
+,,O
+we,O
+detected,O
+a,O
+locus,O
+for,O
+autosomal,O
+-,O
+dominant,O
+ACC,O
+-,O
+TTLD,O
+on,O
+3q,O
+generating,O
+a,O
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+LOD,O
+score,O
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+4.93,O
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+marker,O
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+.,O
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+Candidate,O
+-,O
+gene-,O
+and,O
+exome,O
+-,O
+based,O
+sequencing,O
+led,O
+to,O
+the,O
+identification,O
+of,O
+independent,O
+premature,O
+truncating,O
+mutations,O
+in,O
+the,O
+terminal,O
+exon,O
+of,O
+the,O
+Rho,B-Gene
+GTPase,I-Gene
+-,I-Gene
+activating,I-Gene
+protein,I-Gene
+31,I-Gene
+gene,O
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+ARHGAP31,B-Gene
+,,I-Gene
+which,O
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+a,O
+Cdc42,B-Gene
+/,I-Gene
+Rac1,I-Gene
+regulatory,O
+protein,O
+.,O
+ , 
+Mutant,O
+transcripts,O
+are,O
+stable,O
+and,O
+increase,O
+ARHGAP31,B-Gene
+activity,O
+in,O
+ ,O
+vitro,O
+through,O
+a,O
+gain,O
+-,O
+of,O
+-,O
+function,O
+mechanism,O
+.,O
+ , 
+Constitutively,O
+active,O
+ARHGAP31,B-Gene
+mutations,O
+result,O
+in,O
+a,O
+loss,O
+of,O
+available,O
+active,O
+Cdc42,B-Gene
+and,O
+consequently,O
+disrupt,O
+actin,O
+cytoskeletal,O
+structures,O
+.,O
+ , 
+Arhgap31,B-Gene
+expression,O
+in,O
+the,O
+mouse,O
+is,O
+substantially,O
+restricted,O
+to,O
+the,O
+terminal,O
+limb,O
+buds,O
+and,O
+craniofacial,O
+processes,O
+during,O
+early,O
+development,O
+;,O
+these,O
+locations,O
+closely,O
+mirror,O
+the,O
+sites,O
+of,O
+impaired,O
+organogenesis,O
+that,O
+characterize,O
+this,O
+syndrome,O
+.,O
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+These,O
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+requirement,O
+for,O
+regulated,O
+Cdc42,B-Gene
+and/or,O
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+signaling,O
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+during,O
+early,O
+human,O
+development,O
+.,O
+ , 
+#19370757
+An,O
+update,O
+on,O
+mutations,O
+of,O
+the,O
+SLC39A4,B-Gene
+gene,O
+in,O
+acrodermatitis,O
+enteropathica,O
+.,O
+ , 
+Acrodermatitis,O
+enteropathica,O
+(,O
+AE,O
+),O
+is,O
+a,O
+very,O
+rare,O
+inherited,O
+recessive,O
+disease,O
+caused,O
+by,O
+severe,O
+zinc,O
+deficiency,O
+.,O
+ , 
+It,O
+typically,O
+occurs,O
+in,O
+early,O
+infancy,O
+and,O
+is,O
+characterized,O
+by,O
+periorificial,O
+and,O
+acral,O
+dermatitis,O
+,,O
+alopecia,O
+,,O
+and,O
+diarrhea,O
+.,O
+ , 
+In,O
+2002,O
+,,O
+both,O
+we,O
+and,O
+others,O
+identified,O
+the,O
+AE,O
+SLC39A4,B-Gene
+gene,O
+located,O
+at,O
+8q24.3,O
+,,O
+and,O
+described,O
+the,O
+first,O
+causative,O
+mutations,O
+for,O
+the,O
+disease,O
+.,O
+ , 
+The,O
+SLC39A4,B-Gene
+gene,O
+encodes,O
+a,O
+zinc,O
+-,O
+specific,O
+transporter,O
+belonging,O
+to,O
+the,O
+Zinc,O
+/,O
+Iron,O
+-,O
+regulated,O
+transporter,O
+-,O
+like,O
+family,O
+,,O
+which,O
+is,O
+highly,O
+expressed,O
+in,O
+the,O
+duodenum,O
+and,O
+jejunum,O
+.,O
+ , 
+The,O
+SLC39A4,B-Gene
+mutations,O
+are,O
+spread,O
+over,O
+the,O
+entire,O
+gene,O
+and,O
+include,O
+many,O
+different,O
+types,O
+of,O
+mutations,O
+.,O
+ , 
+We,O
+report,O
+here,O
+the,O
+identification,O
+of,O
+five,O
+novel,O
+variants,O
+,,O
+including,O
+three,O
+likely,O
+pathogenic,O
+mutations,O
+.,O
+ , 
+Since,O
+the,O
+first,O
+description,O
+,,O
+31,O
+mutations,O
+or,O
+unclassified,O
+variants,O
+of,O
+SLC39A4,B-Gene
+have,O
+been,O
+reported,O
+in,O
+this,O
+gene,O
+.,O
+ , 
+Although,O
+most,O
+of,O
+the,O
+patients,O
+with,O
+AE,O
+carry,O
+homozygous,O
+or,O
+compound,O
+heterozygous,O
+mutations,O
+,,O
+some,O
+of,O
+them,O
+have,O
+either,O
+no,O
+SLC39A4,B-Gene
+mutation,O
+or,O
+only,O
+a,O
+monoallelic,O
+mutation,O
+.,O
+ , 
+Thus,O
+,,O
+a,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+is,O
+not,O
+easily,O
+defined,O
+for,O
+all,O
+AE,O
+patients,O
+,,O
+and,O
+the,O
+molecular,O
+basis,O
+of,O
+the,O
+disease,O
+could,O
+be,O
+more,O
+complex,O
+than,O
+previously,O
+described,O
+.,O
+ , 
+In,O
+cases,O
+unexplained,O
+by,O
+current,O
+genetic,O
+analyses,O
+,,O
+the,O
+most,O
+plausible,O
+molecular,O
+causes,O
+could,O
+be,O
+a,O
+dysregulation,O
+of,O
+the,O
+SLC39A4,B-Gene
+gene,O
+transcription,O
+--,O
+involving,O
+either,O
+metal,O
+response,O
+elements,O
+(,O
+MREs,O
+),O
+or,O
+a,O
+modifier,O
+gene,O
+--,O
+or,O
+the,O
+existence,O
+of,O
+another,O
+putative,O
+AE,O
+gene,O
+.,O
+ , 
+In,O
+this,O
+review,O
+,,O
+we,O
+summarize,O
+the,O
+current,O
+knowledge,O
+of,O
+SLC39A4,B-Gene
+mutations,O
+,,O
+as,O
+well,O
+as,O
+the,O
+future,O
+prospects,O
+to,O
+fully,O
+unravel,O
+the,O
+pathogenesis,O
+of,O
+AE,O
+.,O
+ , 
+#15952089
+Dysregulation,O
+of,O
+chondrogenesis,O
+in,O
+human,O
+cleidocranial,O
+dysplasia,O
+.,O
+ , 
+Cleidocranial,O
+dysplasia,O
+(,O
+CCD,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+skeletal,O
+dysplasia,O
+caused,O
+by,O
+heterozygosity,O
+of,O
+mutations,O
+in,O
+human,O
+RUNX2,B-Gene
+.,I-Gene
+ , 
+The,O
+disorder,O
+is,O
+characterized,O
+by,O
+delayed,O
+closure,O
+of,O
+the,O
+fontanel,O
+and,O
+hypoplastic,O
+clavicles,O
+that,O
+result,O
+from,O
+defective,O
+intramembranous,O
+ossification,O
+.,O
+ , 
+However,O
+,,O
+additional,O
+features,O
+,,O
+such,O
+as,O
+short,O
+stature,O
+and,O
+cone,O
+epiphyses,O
+,,O
+also,O
+suggest,O
+an,O
+underlying,O
+defect,O
+in,O
+endochondral,O
+ossification,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+observations,O
+of,O
+growth,O
+-,O
+plate,O
+abnormalities,O
+in,O
+a,O
+patient,O
+with,O
+a,O
+novel,O
+RUNX2,B-Gene
+gene,O
+mutation,O
+,,O
+a,O
+single,O
+C,O
+insertion,O
+(,B-SNP
+1228insC,I-SNP
+),I-SNP
+,,O
+which,O
+is,O
+predicted,O
+to,O
+lead,O
+to,O
+a,O
+premature,O
+termination,O
+codon,O
+and,O
+thus,O
+to,O
+haploinsufficiency,O
+of,O
+RUNX2,B-Gene
+and,O
+the,O
+CCD,O
+phenotype,O
+.,O
+ , 
+Histological,O
+analysis,O
+of,O
+the,O
+rib,O
+and,O
+long,O
+-,O
+bone,O
+cartilages,O
+showed,O
+a,O
+markedly,O
+diminished,O
+zone,O
+of,O
+hypertrophy,O
+.,O
+ , 
+Quantitative,O
+real,O
+-,O
+time,O
+reverse,O
+transcription,O
+-,O
+polymerase,O
+chain,O
+reaction,O
+analysis,O
+of,O
+limb,O
+cartilage,O
+RNA,O
+showed,O
+a,O
+5,O
+-,O
+10,O
+-,O
+fold,O
+decrease,O
+in,O
+the,O
+hypertrophic,O
+chondrocyte,O
+molecular,O
+markers,O
+VEGF,B-Gene
+,,I-Gene
+MMP13,B-Gene
+,,I-Gene
+and,O
+COL10A1,B-Gene
+.,I-Gene
+ , 
+Together,O
+,,O
+these,O
+data,O
+show,O
+that,O
+humans,O
+with,O
+CCD,O
+have,O
+altered,O
+endochondral,O
+ossification,O
+due,O
+to,O
+altered,O
+RUNX2,B-Gene
+regulation,O
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+hypertrophic,O
+chondrocyte,O
+-,O
+specific,O
+genes,O
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+chondrocyte,O
+maturation,O
+.,O
+ , 
+#10915611
+Rare,O
+etiology,O
+of,O
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+disease,O
+in,O
+a,O
+child,O
+with,O
+noncarrier,O
+parents,O
+.,O
+ , 
+A,O
+child,O
+with,O
+maple,O
+syrup,O
+urine,O
+disease,O
+type,O
+2,O
+(,O
+MSUD2,O
+),O
+was,O
+found,O
+to,O
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+a,O
+10,O
+-,O
+bp,O
+MSUD2,B-Gene
+-,I-Gene
+gene,O
+deletion,O
+on,O
+chromosome,O
+1,O
+.,O
+ , 
+Both,O
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+parents,O
+were,O
+tested,O
+,,O
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+neither,O
+carries,O
+the,O
+gene,O
+deletion,O
+.,O
+ , 
+Polymorphic,O
+simple,O
+-,O
+sequence,O
+repeat,O
+analyses,O
+at,O
+15,O
+loci,O
+on,O
+chromosome,O
+1,O
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+at,O
+16,O
+loci,O
+on,O
+other,O
+chromosomes,O
+confirmed,O
+parentage,O
+and,O
+revealed,O
+that,O
+a,O
+de,O
+novo,O
+mutation,O
+prior,O
+to,O
+maternal,O
+meiosis,O
+I,O
+,,O
+followed,O
+by,O
+nondisjunction,O
+in,O
+maternal,O
+meiosis,O
+II,O
+,,O
+resulted,O
+in,O
+an,O
+oocyte,O
+with,O
+two,O
+copies,O
+of,O
+the,O
+de,O
+novo,O
+mutant,O
+allele,O
+.,O
+ , 
+Fertilization,O
+by,O
+a,O
+sperm,O
+that,O
+did,O
+not,O
+carry,O
+a,O
+paternal,O
+chromosome,O
+1,O
+or,O
+subsequent,O
+mitotic,O
+loss,O
+of,O
+the,O
+paternal,O
+chromosome,O
+1,O
+resulted,O
+in,O
+the,O
+propositus,O
+inheriting,O
+two,O
+mutant,O
+MSUD2,B-Gene
+alleles,O
+on,O
+two,O
+maternal,O
+number,O
+1,O
+chromosomes,O
+.,O
+ , 
+#9042937
+HLA,O
+sharing,O
+and,O
+history,O
+of,O
+miscarriage,O
+among,O
+women,O
+with,O
+rheumatoid,O
+arthritis,O
+.,O
+ , 
+#15580547
+Identification,O
+of,O
+a,O
+3.0,O
+-,O
+kb,O
+major,O
+recombination,O
+hotspot,O
+in,O
+patients,O
+with,O
+Sotos,O
+syndrome,O
+who,O
+carry,O
+a,O
+common,O
+1.9,O
+-,O
+Mb,O
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+.,O
+ , 
+Sotos,O
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+(,O
+SoS,O
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+a,O
+congenital,O
+dysmorphic,O
+disorder,O
+characterized,O
+by,O
+overgrowth,O
+in,O
+childhood,O
+,,O
+distinctive,O
+craniofacial,O
+features,O
+,,O
+and,O
+mental,O
+retardation,O
+.,O
+ , 
+Haploinsufficiency,O
+of,O
+the,O
+NSD1,B-Gene
+gene,O
+owing,O
+to,O
+either,O
+intragenic,O
+mutations,O
+or,O
+microdeletions,O
+is,O
+known,O
+to,O
+be,O
+the,O
+major,O
+cause,O
+of,O
+SoS.,O
+The,O
+common,O
+approximately,O
+2.2,O
+-,O
+Mb,O
+microdeletion,O
+encompasses,O
+the,O
+whole,O
+NSD1,B-Gene
+gene,O
+and,O
+neighboring,O
+genes,O
+and,O
+is,O
+flanked,O
+by,O
+low,O
+-,O
+copy,O
+repeats,O
+(,O
+LCRs,O
+),O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+the,O
+identification,O
+of,O
+a,O
+3.0,O
+-,O
+kb,O
+major,O
+recombination,O
+hotspot,O
+within,O
+these,O
+LCRs,O
+,,O
+in,O
+which,O
+we,O
+mapped,O
+deletion,O
+breakpoints,O
+in,O
+78.7,O
+%,O
+(,O
+37/47,O
+),O
+of,O
+patients,O
+with,O
+SoS,O
+who,O
+carry,O
+the,O
+common,O
+microdeletion,O
+.,O
+ , 
+The,O
+deletion,O
+size,O
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+subsequently,O
+refined,O
+to,O
+1.9,O
+Mb,O
+.,O
+ , 
+Sequencing,O
+of,O
+breakpoint,O
+fragments,O
+from,O
+all,O
+37,O
+patients,O
+revealed,O
+junctions,O
+between,O
+a,O
+segment,O
+of,O
+the,O
+proximal,O
+LCR,O
+(,O
+PLCR,O
+-,O
+B,O
+),O
+and,O
+the,O
+corresponding,O
+region,O
+of,O
+the,O
+distal,O
+LCR,O
+(,O
+DLCR-2B,O
+),O
+.,O
+ , 
+PLCR,O
+-,O
+B,O
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+DLCR-2B,O
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+the,O
+only,O
+directly,O
+oriented,O
+regions,O
+,,O
+whereas,O
+the,O
+remaining,O
+regions,O
+of,O
+the,O
+PLCR,O
+and,O
+DLCR,O
+are,O
+in,O
+inverted,O
+orientation,O
+.,O
+ , 
+The,O
+PLCR,O
+,,O
+with,O
+a,O
+size,O
+of,O
+394.0,O
+kb,O
+,,O
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+the,O
+DLCR,O
+,,O
+with,O
+a,O
+size,O
+of,O
+of,O
+429.8,O
+kb,O
+,,O
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+high,O
+overall,O
+homology,O
+(,O
+approximately,O
+98.5,O
+%,O
+),O
+,,O
+with,O
+an,O
+increased,O
+sequence,O
+similarity,O
+(,O
+approximately,O
+99.4,O
+%,O
+),O
+within,O
+the,O
+3.0,O
+-,O
+kb,O
+breakpoint,O
+cluster,O
+.,O
+ , 
+Several,O
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+-,O
+associated,O
+motifs,O
+were,O
+identified,O
+in,O
+the,O
+hotspot,O
+and/or,O
+its,O
+vicinity,O
+.,O
+ , 
+Interestingly,O
+,,O
+a,O
+10,O
+-,O
+fold,O
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+increase,O
+of,O
+a,O
+translin,O
+motif,O
+,,O
+as,O
+compared,O
+with,O
+the,O
+normal,O
+distribution,O
+within,O
+the,O
+LCRs,O
+,,O
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+recognized,O
+.,O
+ , 
+Furthermore,O
+,,O
+a,O
+heterozygous,O
+inversion,O
+of,O
+the,O
+interval,O
+between,O
+the,O
+LCRs,O
+was,O
+detected,O
+in,O
+all,O
+fathers,O
+of,O
+the,O
+children,O
+carrying,O
+a,O
+deletion,O
+in,O
+the,O
+paternally,O
+derived,O
+chromosome,O
+.,O
+ , 
+The,O
+functional,O
+significance,O
+of,O
+these,O
+findings,O
+remains,O
+to,O
+be,O
+elucidated,O
+.,O
+ , 
+Segmental,O
+duplications,O
+of,O
+the,O
+primate,O
+genome,O
+play,O
+a,O
+major,O
+role,O
+in,O
+chromosomal,O
+evolution,O
+.,O
+ , 
+Evolutionary,O
+study,O
+showed,O
+that,O
+the,O
+duplication,O
+of,O
+the,O
+SoS,O
+LCRs,O
+occurred,O
+23.3,O
+-,O
+47.6,O
+million,O
+years,O
+ago,O
+,,O
+before,O
+the,O
+divergence,O
+of,O
+Old,O
+World,O
+monkeys,O
+.,O
+ , 
+#11083946
+The,O
+28,O
+-,O
+kb,O
+deletion,O
+spanning,O
+D15S63,O
+is,O
+a,O
+polymorphic,O
+variant,O
+in,O
+the,O
+Ashkenazi,O
+Jewish,O
+population,O
+.,O
+ , 
+D15S63,O
+is,O
+one,O
+of,O
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+loci,O
+,,O
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+chromosome,O
+15q11,O
+-,O
+q13,O
+,,O
+that,O
+exhibit,O
+parent,O
+-,O
+of,O
+-,O
+origin,O
+dependent,O
+methylation,O
+and,O
+that,O
+is,O
+commonly,O
+used,O
+in,O
+the,O
+diagnosis,O
+of,O
+Prader,O
+-,O
+Willi,O
+or,O
+Angelman,O
+syndromes,O
+(,O
+PWS,O
+/,O
+AS,O
+),O
+.,O
+ , 
+A,O
+28,O
+-,O
+kb,O
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+D15S63,O
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+identified,O
+in,O
+five,O
+unrelated,O
+patients,O
+;,O
+in,O
+each,O
+of,O
+them,O
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+deletion,O
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+inherited,O
+from,O
+a,O
+normal,O
+parent,O
+.,O
+ , 
+Three,O
+of,O
+the,O
+five,O
+families,O
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+the,O
+deletion,O
+were,O
+reported,O
+to,O
+be,O
+of,O
+Jewish,O
+Ashkenazi,O
+ancestry,O
+,,O
+and,O
+in,O
+the,O
+other,O
+two,O
+families,O
+the,O
+ancestral,O
+origin,O
+was,O
+unknown,O
+.,O
+ , 
+To,O
+determine,O
+whether,O
+the,O
+28,O
+-,O
+kb,O
+deletion,O
+is,O
+a,O
+benign,O
+variant,O
+,,O
+we,O
+screened,O
+for,O
+the,O
+deletion,O
+in,O
+137,O
+unselected,O
+Ashkenazi,O
+individuals,O
+and,O
+in,O
+268,O
+patients,O
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+referred,O
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+molecular,O
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+of,O
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+/,O
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+89,O
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+47,O
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+mixed,O
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+(,O
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+-,O
+Ashkenazi,O
+Jews,O
+),O
+.,O
+ , 
+In,O
+the,O
+control,O
+group,O
+,,O
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+individuals,O
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+carriers,O
+of,O
+the,O
+deletion,O
+;,O
+among,O
+the,O
+patients,O
+,,O
+three,O
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+,,O
+all,O
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+whom,O
+were,O
+Ashkenazi,O
+Jews,O
+.,O
+ , 
+There,O
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+no,O
+significant,O
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+the,O
+control,O
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+Ashkenazi,O
+patients,O
+,,O
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+that,O
+the,O
+deletion,O
+is,O
+not,O
+a,O
+cause,O
+of,O
+PWS-,O
+and,O
+AS,O
+-,O
+like,O
+syndromes,O
+.,O
+ , 
+The,O
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+of,O
+the,O
+28,O
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+the,O
+Ashkenazi,O
+population,O
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+1/75,O
+.,O
+ , 
+Since,O
+methylation,O
+analysis,O
+at,O
+the,O
+D15S63,O
+locus,O
+may,O
+lead,O
+to,O
+misdiagnosis,O
+,,O
+we,O
+suggest,O
+the,O
+use,O
+of,O
+SNRPN,O
+,,O
+either,O
+in,O
+a,O
+PCR,O
+-,O
+based,O
+assay,O
+or,O
+as,O
+a,O
+probe,O
+in,O
+Southern,O
+hybridization,O
+,,O
+as,O
+the,O
+method,O
+of,O
+choice,O
+in,O
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+diagnosis,O
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+PWS,O
+/,O
+AS,O
+.,O
+ , 
+#12428213
+myotilin,B-Gene
+Mutation,O
+found,O
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+second,O
+pedigree,O
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+LGMD1A.,B-Gene
+Limb,B-Gene
+-,I-Gene
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+dystrophy,I-Gene
+1A,I-Gene
+(,B-Gene
+LGMD1A,I-Gene
+[,O
+MIM,O
+159000,O
+],O
+),O
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+an,O
+autosomal,O
+dominant,O
+form,O
+of,O
+muscular,O
+dystrophy,O
+characterized,O
+by,O
+adult,O
+onset,O
+of,O
+proximal,O
+weakness,O
+progressing,O
+to,O
+distal,O
+muscle,O
+weakness,O
+.,O
+ , 
+We,O
+have,O
+reported,O
+elsewhere,O
+a,O
+mutation,O
+in,O
+the,O
+myotilin,O
+gene,O
+in,O
+a,O
+large,O
+,,O
+North,O
+American,O
+family,O
+of,O
+German,O
+descent,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+the,O
+mutation,O
+screening,O
+of,O
+an,O
+additional,O
+86,O
+families,O
+with,O
+a,O
+variety,O
+of,O
+neuromuscular,O
+pathologies,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+a,O
+new,O
+myotilin,O
+mutation,O
+in,O
+an,O
+Argentinian,O
+pedigree,O
+with,O
+LGMD1,B-Gene
+that,O
+is,O
+predicted,O
+to,O
+result,O
+in,O
+the,O
+conversion,O
+of,O
+serine,B-SNP
+55,I-SNP
+to,I-SNP
+phenylalanine,I-SNP
+(,B-SNP
+S55F,I-SNP
+),I-SNP
+.,O
+ , 
+This,O
+mutation,O
+has,O
+not,O
+been,O
+found,O
+in,O
+392,O
+control,O
+chromosomes,O
+and,O
+is,O
+located,O
+in,O
+the,O
+unique,O
+N,O
+-,O
+terminal,O
+domain,O
+of,O
+myotilin,B-Gene
+,,I-Gene
+only,O
+two,O
+residues,O
+from,O
+the,O
+T57I,B-SNP
+mutation,O
+reported,O
+elsewhere,O
+.,O
+ , 
+Both,O
+T57I,B-SNP
+and,O
+S55F,B-SNP
+are,O
+located,O
+outside,O
+the,O
+alpha,O
+-,O
+actinin,O
+and,O
+gamma,O
+-,O
+filamin,O
+binding,O
+sites,O
+within,O
+myotilin,B-Gene
+.,I-Gene
+ , 
+The,O
+identification,O
+of,O
+two,O
+independent,O
+pedigrees,O
+with,O
+the,O
+same,O
+disease,O
+,,O
+each,O
+bearing,O
+a,O
+different,O
+mutation,O
+in,O
+the,O
+same,O
+gene,O
+,,O
+has,O
+long,O
+been,O
+the,O
+gold,O
+standard,O
+for,O
+establishing,O
+a,O
+causal,O
+relationship,O
+between,O
+defects,O
+in,O
+a,O
+gene,O
+and,O
+the,O
+resultant,O
+disease,O
+.,O
+ , 
+As,O
+a,O
+description,O
+of,O
+the,O
+second,O
+known,O
+pedigree,O
+with,O
+LGMD1A,B-Gene
+,,I-Gene
+this,O
+finding,O
+constitutes,O
+that,O
+gold,O
+standard,O
+of,O
+proof,O
+that,O
+mutations,O
+in,O
+the,O
+myotilin,B-Gene
+gene,O
+cause,O
+LGMD1A.,B-Gene
+ , 
+#8037214
+A,O
+YAC,O
+contig,O
+encompassing,O
+the,O
+Treacher,O
+Collins,O
+syndrome,O
+critical,O
+region,O
+at,O
+5q31.3,O
+-,O
+32,O
+.,O
+ , 
+Treacher,O
+Collins,O
+syndrome,O
+(,O
+TCOF1,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+disorder,O
+of,O
+craniofacial,O
+development,O
+the,O
+features,O
+of,O
+which,O
+include,O
+conductive,O
+hearing,O
+loss,O
+and,O
+cleft,O
+palate,O
+.,O
+ , 
+Previous,O
+studies,O
+have,O
+localized,O
+the,O
+TCOF1,B-Gene
+locus,O
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+D5S519,O
+(,O
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+),O
+and,O
+SPARC,B-Gene
+(,O
+distal,O
+),O
+,,O
+a,O
+region,O
+of,O
+22,O
+centirays,O
+as,O
+estimated,O
+by,O
+radiation,O
+hybrid,O
+mapping,O
+.,O
+ , 
+In,O
+the,O
+current,O
+investigation,O
+we,O
+have,O
+created,O
+a,O
+contig,O
+across,O
+the,O
+TCOF1,B-Gene
+critical,O
+region,O
+,,O
+using,O
+YAC,O
+clones,O
+.,O
+ , 
+Isolation,O
+of,O
+a,O
+novel,O
+short,O
+tandem,O
+repeat,O
+polymorphism,O
+corresponding,O
+to,O
+the,O
+end,O
+of,O
+one,O
+of,O
+the,O
+YACs,O
+has,O
+allowed,O
+us,O
+to,O
+reduce,O
+the,O
+size,O
+of,O
+the,O
+critical,O
+region,O
+to,O
+approximately,O
+840,O
+kb,O
+,,O
+which,O
+has,O
+been,O
+covered,O
+with,O
+three,O
+nonchimeric,O
+YACs,O
+.,O
+ , 
+Restriction,O
+mapping,O
+has,O
+revealed,O
+that,O
+the,O
+region,O
+contains,O
+a,O
+high,O
+density,O
+of,O
+clustered,O
+rare,O
+-,O
+cutter,O
+restriction,O
+sites,O
+,,O
+suggesting,O
+that,O
+it,O
+may,O
+contain,O
+a,O
+number,O
+of,O
+different,O
+genes,O
+.,O
+ , 
+The,O
+results,O
+of,O
+the,O
+present,O
+investigation,O
+have,O
+further,O
+allowed,O
+us,O
+to,O
+confirm,O
+that,O
+the,O
+RPS14,B-Gene
+locus,O
+lies,O
+proximal,O
+to,O
+the,O
+critical,O
+region,O
+and,O
+can,O
+thereby,O
+be,O
+excluded,O
+from,O
+a,O
+role,O
+in,O
+the,O
+pathogenesis,O
+of,O
+TCOF1,B-Gene
+,,I-Gene
+while,O
+ANX6,B-Gene
+lies,O
+within,O
+the,O
+TCOF1,B-Gene
+critical,O
+region,O
+and,O
+remains,O
+a,O
+potential,O
+candidate,O
+for,O
+the,O
+mutated,O
+gene,O
+.,O
+ , 
+#16642433
+Polymorphism,O
+in,O
+maternal,O
+LRP8,B-Gene
+gene,O
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+.,O
+ , 
+Fetal,O
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+(,O
+FGR,O
+),O
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+>,O
+200,000,O
+pregnancies,O
+in,O
+the,O
+United,O
+States,O
+annually,O
+and,O
+is,O
+associated,O
+with,O
+increased,O
+perinatal,O
+mortality,O
+and,O
+morbidity,O
+,,O
+as,O
+well,O
+as,O
+poorer,O
+long,O
+-,O
+term,O
+health,O
+for,O
+infants,O
+with,O
+FGR,O
+compared,O
+with,O
+infants,O
+without,O
+FGR,O
+.,O
+ , 
+FGR,O
+appears,O
+to,O
+be,O
+a,O
+complex,O
+trait,O
+,,O
+but,O
+the,O
+role,O
+of,O
+genetic,O
+factors,O
+in,O
+the,O
+development,O
+of,O
+FGR,O
+is,O
+largely,O
+unknown,O
+.,O
+ , 
+We,O
+conducted,O
+a,O
+candidate,O
+-,O
+gene,O
+association,O
+study,O
+of,O
+birth,O
+weight,O
+and,O
+FGR,O
+in,O
+two,O
+independent,O
+study,O
+samples,O
+obtained,O
+at,O
+the,O
+Boston,O
+Medical,O
+Center,O
+.,O
+ , 
+We,O
+first,O
+investigated,O
+the,O
+association,O
+between,O
+maternal,O
+genotypes,O
+of,O
+68,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+(,O
+SNPs,O
+),O
+from,O
+41,O
+candidate,O
+genes,O
+and,O
+fetal,O
+growth,O
+in,O
+a,O
+sample,O
+of,O
+204,O
+black,O
+women,O
+selected,O
+for,O
+a,O
+previous,O
+study,O
+of,O
+preeclampsia,O
+,,O
+92,O
+of,O
+whom,O
+had,O
+preeclampsia,O
+(,O
+characterized,O
+by,O
+high,O
+blood,O
+pressure,O
+and,O
+the,O
+presence,O
+of,O
+protein,O
+in,O
+the,O
+urine,O
+),O
+.,O
+ , 
+We,O
+found,O
+significant,O
+association,O
+between,O
+SNP,O
+rs2297660,O
+in,O
+the,O
+LRP8,B-Gene
+gene,O
+and,O
+birth,O
+weight,O
+.,O
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+Subsequently,O
+,,O
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+replicated,O
+the,O
+association,O
+in,O
+a,O
+larger,O
+independent,O
+sample,O
+of,O
+1,094,O
+black,O
+women,O
+;,O
+similar,O
+association,O
+between,O
+LRP8,B-Gene
+and,O
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+observed,O
+in,O
+this,O
+sample,O
+.,O
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+The,O
+",O
+A,O
+",O
+allele,O
+at,O
+rs2297660,O
+was,O
+associated,O
+with,O
+a,O
+higher,O
+standardized,O
+birth,O
+weight,O
+and,O
+a,O
+lower,O
+risk,O
+of,O
+FGR,O
+.,O
+ , 
+Under,O
+the,O
+additive,O
+genetic,O
+model,O
+,,O
+each,O
+additional,O
+copy,O
+of,O
+the,O
+",O
+A,O
+",O
+allele,O
+reduced,O
+the,O
+risk,O
+of,O
+FGR,O
+by,O
+33,O
+%,O
+(,O
+P<.05,O
+),O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+results,O
+from,O
+the,O
+two,O
+independent,O
+samples,O
+of,O
+black,O
+women,O
+provide,O
+consistent,O
+evidence,O
+that,O
+SNP,O
+rs2297660,O
+in,O
+LRP8,B-Gene
+is,O
+associated,O
+with,O
+fetal,O
+growth,O
+.,O
+ , 
+#8328452
+Molecular,O
+analysis,O
+of,O
+Hurler,O
+syndrome,O
+in,O
+Druze,O
+and,O
+Muslim,O
+Arab,O
+patients,O
+in,O
+Israel,O
+:,O
+multiple,O
+allelic,O
+mutations,O
+of,O
+the,O
+IDUA,B-Gene
+gene,O
+in,O
+a,O
+small,O
+geographic,O
+area,O
+.,O
+ , 
+The,O
+mutations,O
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+Hurler,O
+syndrome,O
+(,O
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+IH,O
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+Four,O
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+(,O
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+PCR,O
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+reverse,O
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+DNA,O
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+(,O
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+),O
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+One,O
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+-,I-SNP
+->Arg,I-SNP
+in,O
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+exon,O
+14,O
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+The,O
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+(,B-SNP
+Tyr64,I-SNP
+-,I-SNP
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+),I-SNP
+,,O
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+Gln310,I-SNP
+-,I-SNP
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+),I-SNP
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+Transfection,O
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+Cos-1,O
+cells,O
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+two,O
+missense,O
+mutations,O
+,,O
+Thr366,B-SNP
+-,I-SNP
+->Pro,I-SNP
+and,O
+Ter-->Cys,O
+,,O
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+the,O
+expression,O
+of,O
+only,O
+trace,O
+amounts,O
+of,O
+alpha,O
+-,O
+L,O
+-,O
+iduronidase,O
+activity,O
+,,O
+whereas,O
+Gly409,B-SNP
+-,I-SNP
+->Arg,I-SNP
+permitted,O
+the,O
+expression,O
+of,O
+60,O
+%,O
+as,O
+much,O
+enzyme,O
+as,O
+did,O
+the,O
+normal,O
+cDNA,O
+.,O
+ , 
+The,O
+nonsense,O
+mutations,O
+were,O
+associated,O
+with,O
+abnormalities,O
+of,O
+RNA,O
+processing,O
+:,O
+(,O
+1,O
+),O
+both,O
+a,O
+very,O
+low,O
+level,O
+of,O
+mRNA,O
+and,O
+skipping,O
+of,O
+exon,O
+2,O
+for,O
+Tyr64,B-SNP
+-,I-SNP
+->Ter,I-SNP
+and,O
+(,O
+2,O
+),O
+utilization,O
+of,O
+a,O
+cryptic,O
+splice,O
+site,O
+for,O
+Gln310,B-SNP
+-,I-SNP
+->Ter,I-SNP
+.,I-SNP
+ , 
+In,O
+all,O
+instances,O
+,,O
+the,O
+probands,O
+were,O
+found,O
+homozygous,O
+,,O
+and,O
+the,O
+parents,O
+heterozygous,O
+,,O
+for,O
+the,O
+mutant,O
+alleles,O
+,,O
+as,O
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+the,O
+consanguinity,O
+in,O
+each,O
+family,O
+.,O
+ , 
+The,O
+two,O
+-,O
+mutation,O
+allele,O
+was,O
+identified,O
+in,O
+a,O
+family,O
+from,O
+Gaza,O
+;,O
+the,O
+other,O
+three,O
+alleles,O
+were,O
+found,O
+in,O
+seven,O
+families,O
+,,O
+five,O
+of,O
+them,O
+Druze,O
+,,O
+residing,O
+in,O
+a,O
+very,O
+small,O
+area,O
+of,O
+northern,O
+Israel,O
+.,O
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+Since,O
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+clustering,O
+suggests,O
+a,O
+classic,O
+founder,O
+effect,O
+,,O
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+presence,O
+of,O
+three,O
+mutant,O
+alleles,O
+of,O
+the,O
+IDUA,B-Gene
+gene,O
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+unexpected,O
+.,O
+ , 
+#10762557
+Complement,B-Gene
+factor,I-Gene
+H,I-Gene
+gene,O
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+with,O
+autosomal,O
+recessive,O
+atypical,O
+hemolytic,O
+uremic,O
+syndrome,O
+.,O
+ , 
+#17571465
+Arthur,O
+G.,O
+Steinberg,O
+,,O
+1912,O
+-,O
+2006,O
+.,O
+ , 
+#12402345
+Molecular,O
+studies,O
+in,O
+mutase,O
+-,O
+deficient,O
+(,O
+MUT,O
+),O
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+:,O
+identification,O
+of,O
+five,O
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+mutations,O
+.,O
+ , 
+Mutase,O
+-,O
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+(,O
+MUT,O
+),O
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+(,O
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+),O
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+autosomal,O
+recessive,O
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+error,O
+of,O
+organic,O
+acid,O
+metabolism,O
+,,O
+resulting,O
+from,O
+a,O
+functional,O
+defect,O
+in,O
+the,O
+nuclear,O
+encoded,O
+mitochondrial,O
+enzyme,O
+methylmalonyl,O
+-,O
+CoA,O
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+(,O
+MCM,O
+),O
+(,O
+EC.5.4.99.2,O
+),O
+.,O
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+The,O
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+as,O
+a,O
+cofactor,O
+.,O
+ , 
+Isolated,O
+MMA,O
+results,O
+from,O
+either,O
+apoenzyme,O
+or,O
+cofactor,O
+defects,O
+,,O
+and,O
+is,O
+classified,O
+into,O
+several,O
+genotypic,O
+classes,O
+and,O
+complementation,O
+groups,O
+.,O
+ , 
+These,O
+are,O
+designated,O
+mut(-,O
+),O
+or,O
+mut(0,O
+),O
+(,O
+together,O
+termed,O
+mut,O
+),O
+,,O
+depending,O
+on,O
+minimal,O
+or,O
+no,O
+apoenzyme,O
+activity,O
+respectively,O
+and,O
+cobalamin,O
+A,O
+or,O
+B,O
+(,O
+cbl,O
+A,O
+/,O
+B,O
+),O
+for,O
+cofactor,O
+defects,O
+.,O
+ , 
+To,O
+date,O
+various,O
+studies,O
+have,O
+identified,O
+over,O
+53,O
+disease,O
+-,O
+causing,O
+mutations,O
+from,O
+patients,O
+with,O
+mut(0/-,O
+),O
+MMA,O
+.,O
+ , 
+These,O
+are,O
+predominantly,O
+missense,O
+/,O
+nonsense,O
+nucleotide,O
+substitutions,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+report,O
+the,O
+genotype,O
+analysis,O
+on,O
+7,O
+patients,O
+diagnosed,O
+with,O
+mut,O
+MMA,O
+.,O
+ , 
+Five,O
+novel,O
+mutations,O
+were,O
+identified,O
+(,B-SNP
+R403stop,I-SNP
+,,I-SNP
+497delG,B-SNP
+,,I-SNP
+P615,B-SNP
+T,I-SNP
+,,I-SNP
+208delG,B-SNP
+and,O
+R467stop,B-SNP
+),I-SNP
+and,O
+one,O
+novel,O
+polymorphism,O
+(,B-SNP
+c712A->G,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+previously,O
+reported,O
+R228Q,B-SNP
+mutation,O
+was,O
+found,O
+in,O
+one,O
+patient,O
+,,O
+who,O
+is,O
+a,O
+compound,O
+heterozygote,O
+for,O
+this,O
+mutation,O
+and,O
+the,O
+R467stop,B-SNP
+mutation,O
+.,O
+ , 
+A,O
+recently,O
+reported,O
+N219Y,B-SNP
+mutation,O
+was,O
+found,O
+in,O
+one,O
+patient,O
+.,O
+ , 
+The,O
+497delG,B-SNP
+mutation,O
+was,O
+detected,O
+as,O
+a,O
+homozygous,O
+deletion,O
+.,O
+ , 
+The,O
+remaining,O
+mutations,O
+were,O
+observed,O
+in,O
+compound,O
+heterozygotes,O
+,,O
+with,O
+the,O
+second,O
+mutation,O
+yet,O
+to,O
+be,O
+identified,O
+.,O
+ , 
+Many,O
+of,O
+the,O
+unidentified,O
+mutations,O
+may,O
+occur,O
+within,O
+the,O
+promotor,O
+or,O
+intronic,O
+regions,O
+.,O
+ , 
+#16906510
+Visualization,O
+of,O
+MAPT,B-Gene
+inversion,O
+on,O
+stretched,O
+chromosomes,O
+of,O
+tau,O
+-,O
+negative,O
+frontotemporal,O
+dementia,O
+patients,O
+.,O
+ , 
+#7728155
+Mitochondrial,O
+acetoacetyl,B-Gene
+-,I-Gene
+coenzyme,I-Gene
+A,I-Gene
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+novel,O
+68,O
+-,O
+bp,O
+deletion,O
+involving,O
+3,O
+',O
+splice,O
+site,O
+of,O
+intron,O
+7,O
+,,O
+causing,O
+exon,O
+8,O
+skipping,O
+in,O
+a,O
+Caucasian,O
+patient,O
+with,O
+beta,O
+-,O
+ketothiolase,O
+deficiency,O
+.,O
+ , 
+#1301924
+Myotonic,O
+dystrophy,O
+:,O
+another,O
+case,O
+of,O
+too,O
+many,O
+repeats,O
+?,O
+ , 
+Myotonic,O
+dystrophy,O
+(,O
+DM,O
+),O
+is,O
+an,O
+adult,O
+form,O
+of,O
+muscular,O
+dystrophy,O
+affecting,O
+about,O
+1,O
+in,O
+8,000,O
+individuals,O
+in,O
+most,O
+populations,O
+.,O
+ , 
+Although,O
+common,O
+symptoms,O
+include,O
+progressive,O
+muscle,O
+weakness,O
+and,O
+stiffness,O
+,,O
+it,O
+is,O
+characterised,O
+by,O
+a,O
+heterogeneous,O
+clinical,O
+picture,O
+.,O
+ , 
+Despite,O
+this,O
+variation,O
+in,O
+both,O
+the,O
+nature,O
+and,O
+severity,O
+of,O
+the,O
+symptoms,O
+seen,O
+in,O
+affected,O
+individuals,O
+,,O
+DM,O
+is,O
+genetically,O
+homogeneous,O
+,,O
+segregating,O
+as,O
+a,O
+single,O
+locus,O
+on,O
+the,O
+proximal,O
+long,O
+arm,O
+of,O
+human,O
+chromosome,O
+19,O
+.,O
+ , 
+As,O
+the,O
+biochemical,O
+abnormality,O
+underlying,O
+the,O
+disease,O
+was,O
+unknown,O
+,,O
+a,O
+reverse,O
+genetics,O
+(,O
+or,O
+positional,O
+cloning,O
+),O
+strategy,O
+for,O
+identifying,O
+the,O
+gene,O
+responsible,O
+was,O
+adopted,O
+.,O
+ , 
+The,O
+resulting,O
+collaborative,O
+effort,O
+culminated,O
+in,O
+the,O
+detection,O
+of,O
+the,O
+molecular,O
+mutation,O
+event,O
+and,O
+the,O
+gene,O
+within,O
+which,O
+it,O
+lies,O
+:,O
+the,O
+expansion,O
+of,O
+a,O
+trinucleotide,O
+repeat,O
+(,O
+CTG,O
+),O
+at,O
+the,O
+3,O
+',O
+end,O
+of,O
+a,O
+gene,O
+encoding,O
+a,O
+member,O
+of,O
+the,O
+cyclic,O
+AMP,O
+-,O
+dependent,O
+protein,O
+kinase,O
+family,O
+.,O
+ , 
+This,O
+has,O
+diagnostic,O
+implications,O
+since,O
+an,O
+easy,O
+,,O
+reliable,O
+and,O
+predictive,O
+test,O
+can,O
+now,O
+be,O
+offered,O
+to,O
+individuals,O
+with,O
+a,O
+family,O
+history,O
+of,O
+DM,O
+.,O
+ , 
+These,O
+findings,O
+are,O
+also,O
+a,O
+prerequisite,O
+for,O
+further,O
+studies,O
+concerning,O
+the,O
+biochemical,O
+and,O
+physiological,O
+aetiology,O
+of,O
+DM,O
+and,O
+possible,O
+therapeutic,O
+strategies,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+the,O
+striking,O
+similarity,O
+between,O
+findings,O
+at,O
+the,O
+DNA,O
+level,O
+in,O
+DM,O
+and,O
+those,O
+in,O
+fragile,O
+X,O
+syndrome,O
+and,O
+spinal,O
+and,O
+bulbar,O
+muscular,O
+atrophy,O
+suggests,O
+that,O
+the,O
+mechanism,O
+leading,O
+to,O
+the,O
+increase,O
+in,O
+copy,O
+number,O
+of,O
+trinucleotide,O
+repeats,O
+at,O
+particular,O
+loci,O
+may,O
+be,O
+responsible,O
+for,O
+a,O
+number,O
+of,O
+other,O
+genetic,O
+diseases,O
+.,O
+ , 
+#22434506
+Large,O
+-,O
+scale,O
+objective,O
+phenotyping,O
+of,O
+3D,O
+facial,O
+morphology,O
+.,O
+ , 
+Abnormal,O
+phenotypes,O
+have,O
+played,O
+significant,O
+roles,O
+in,O
+the,O
+discovery,O
+of,O
+gene,O
+function,O
+,,O
+but,O
+organized,O
+collection,O
+of,O
+phenotype,O
+data,O
+has,O
+been,O
+overshadowed,O
+by,O
+developments,O
+in,O
+sequencing,O
+technology,O
+.,O
+ , 
+In,O
+order,O
+to,O
+study,O
+phenotypes,O
+systematically,O
+,,O
+large,O
+-,O
+scale,O
+projects,O
+with,O
+standardized,O
+objective,O
+assessment,O
+across,O
+populations,O
+are,O
+considered,O
+necessary,O
+.,O
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+The,O
+report,O
+of,O
+the,O
+2006,O
+Human,O
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+Project,O
+meeting,O
+(,O
+Cotton,O
+et,O
+al,O
+,,O
+2007,O
+),O
+recommended,O
+documentation,O
+of,O
+phenotypes,O
+through,O
+electronic,O
+means,O
+by,O
+collaborative,O
+groups,O
+of,O
+computational,O
+scientists,O
+and,O
+clinicians,O
+using,O
+standard,O
+,,O
+structured,O
+descriptions,O
+of,O
+disease,O
+-,O
+specific,O
+phenotypes,O
+.,O
+ , 
+In,O
+this,O
+report,O
+,,O
+we,O
+describe,O
+progress,O
+over,O
+the,O
+past,O
+decade,O
+in,O
+three,O
+-,O
+dimensional,O
+(,O
+3D,O
+),O
+digital,O
+imaging,O
+and,O
+shape,O
+analysis,O
+of,O
+the,O
+face,O
+,,O
+and,O
+future,O
+prospects,O
+for,O
+large,O
+-,O
+scale,O
+facial,O
+phenotyping,O
+.,O
+ , 
+Illustrative,O
+examples,O
+are,O
+given,O
+throughout,O
+using,O
+a,O
+collection,O
+of,O
+1,107,O
+3D,O
+face,O
+images,O
+of,O
+healthy,O
+controls,O
+and,O
+individuals,O
+with,O
+a,O
+range,O
+of,O
+genetic,O
+conditions,O
+involving,O
+facial,O
+dysmorphism,O
+.,O
+ , 
+#19058223
+Mutational,O
+profiling,O
+of,O
+cancer,O
+candidate,O
+genes,O
+in,O
+glioblastoma,O
+,,O
+melanoma,O
+and,O
+pancreatic,O
+carcinoma,O
+reveals,O
+a,O
+snapshot,O
+of,O
+their,O
+genomic,O
+landscapes,O
+.,O
+ , 
+A,O
+recent,O
+systematic,O
+analysis,O
+of,O
+18.191,O
+well,O
+annotated,O
+coding,O
+sequences,O
+(,O
+RefSeq,O
+),O
+in,O
+breast,O
+and,O
+colorectal,O
+cancers,O
+has,O
+led,O
+to,O
+the,O
+identification,O
+of,O
+somatic,O
+mutations,O
+in,O
+1.718,O
+genes,O
+(,O
+Wood,O
+et,O
+al,O
+.,O
+,,O
+2007,O
+),O
+.,O
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+Based,O
+on,O
+statistical,O
+parameters,O
+280,O
+of,O
+these,O
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+been,O
+denominated,O
+candidate,O
+cancer,O
+(,O
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+),O
+genes,O
+.,O
+ , 
+This,O
+analysis,O
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+provided,O
+an,O
+interesting,O
+snapshot,O
+of,O
+the,O
+landscape,O
+of,O
+tumor,O
+genomes,O
+by,O
+showing,O
+that,O
+they,O
+contain,O
+a,O
+few,O
+frequently,O
+mutated,O
+genes,O
+(,O
+denominated,O
+',O
+mountains,O
+',O
+),O
+.,O
+ , 
+On,O
+the,O
+contrary,O
+,,O
+the,O
+large,O
+majority,O
+of,O
+CAN,B-Gene
+genes,O
+are,O
+altered,O
+at,O
+low,O
+frequency,O
+(,O
+designated,O
+',O
+hills,O
+',O
+),O
+.,O
+ , 
+Whether,O
+',O
+hill,O
+',O
+type,O
+CAN,B-Gene
+genes,O
+are,O
+tumor,O
+specific,O
+is,O
+largely,O
+unknown,O
+.,O
+ , 
+To,O
+address,O
+this,O
+question,O
+we,O
+evaluated,O
+the,O
+mutational,O
+profiles,O
+of,O
+27,O
+',O
+hill,O
+',O
+CAN,B-Gene
+genes,O
+in,O
+glioblastoma,O
+,,O
+melanoma,O
+and,O
+pancreatic,O
+carcinoma,O
+by,O
+sequencing,O
+the,O
+exons,O
+previously,O
+found,O
+mutated,O
+by,O
+Wood,O
+and,O
+colleagues,O
+.,O
+ , 
+Only,O
+4,O
+of,O
+the,O
+breast,O
+/,O
+colorectal,O
+',O
+hill,O
+',O
+type,O
+CAN,B-Gene
+genes,O
+(,B-Gene
+SMAD4,I-Gene
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+,,I-Gene
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+MMP2,B-Gene
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+mutated,O
+in,O
+melanoma,O
+and,O
+pancreatic,O
+carcinoma,O
+,,O
+while,O
+none,O
+was,O
+altered,O
+in,O
+glioblastoma,O
+.,O
+ , 
+These,O
+results,O
+suggest,O
+that,O
+',O
+hill,O
+',O
+type,O
+CAN,B-Gene
+genes,O
+are,O
+not,O
+frequently,O
+shared,O
+by,O
+different,O
+tumor,O
+types,O
+and,O
+that,O
+their,O
+mutation,O
+patterns,O
+are,O
+tissue,O
+specific,O
+.,O
+ , 
+Tumor,O
+-,O
+specific,O
+genome,O
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+profiling,O
+will,O
+be,O
+required,O
+to,O
+identify,O
+',O
+hill,O
+',O
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+CAN,B-Gene
+genes,O
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+the,O
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+each,O
+cancer,O
+lineage,O
+.,O
+ , 
+#19559399
+Loss,O
+-,O
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+in,O
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+dioxygenase,O
+-,O
+encoding,O
+FTO,B-Gene
+gene,O
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+severe,O
+growth,O
+retardation,O
+and,O
+multiple,O
+malformations,O
+.,O
+ , 
+FTO,B-Gene
+is,O
+a,O
+nuclear,O
+protein,O
+belonging,O
+to,O
+the,O
+AlkB,O
+-,O
+related,O
+non,O
+-,O
+haem,O
+iron-,O
+and,O
+2,O
+-,O
+oxoglutarate,O
+-,O
+dependent,O
+dioxygenase,O
+family,O
+.,O
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+Although,O
+polymorphisms,O
+within,O
+the,O
+first,O
+intron,O
+of,O
+the,O
+FTO,B-Gene
+gene,O
+have,O
+been,O
+associated,O
+with,O
+obesity,O
+,,O
+the,O
+physiological,O
+role,O
+of,O
+FTO,B-Gene
+remains,O
+unknown,O
+.,O
+ , 
+Here,O
+we,O
+show,O
+that,O
+a,O
+R316Q,B-SNP
+mutation,O
+,,O
+inactivating,O
+FTO,B-Gene
+enzymatic,O
+activity,O
+,,O
+is,O
+responsible,O
+for,O
+an,O
+autosomal,O
+-,O
+recessive,O
+lethal,O
+syndrome,O
+.,O
+ , 
+Cultured,O
+skin,O
+fibroblasts,O
+from,O
+affected,O
+subjects,O
+showed,O
+impaired,O
+proliferation,O
+and,O
+accelerated,O
+senescence,O
+.,O
+ , 
+These,O
+findings,O
+indicate,O
+that,O
+FTO,B-Gene
+is,O
+essential,O
+for,O
+normal,O
+development,O
+of,O
+the,O
+central,O
+nervous,O
+and,O
+cardiovascular,O
+systems,O
+in,O
+human,O
+and,O
+establish,O
+that,O
+a,O
+mutation,O
+in,O
+a,O
+human,O
+member,O
+of,O
+the,O
+AlkB,O
+-,O
+related,O
+dioxygenase,O
+family,O
+results,O
+in,O
+a,O
+severe,O
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+syndrome,O
+.,O
+ , 
+#8079996
+Design,O
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+sample,O
+-,O
+size,O
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+detection,O
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+a,O
+disease,O
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+The,O
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+linkage,O
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+linked,O
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+aid,O
+in,O
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+fine,O
+mapping,O
+of,O
+disease,O
+loci,O
+.,O
+ , 
+We,O
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+the,O
+power,O
+of,O
+several,O
+designs,O
+for,O
+sampling,O
+individuals,O
+with,O
+different,O
+disease,O
+genotypes,O
+.,O
+ , 
+As,O
+expected,O
+,,O
+haplotype,O
+data,O
+provide,O
+the,O
+greatest,O
+power,O
+for,O
+detecting,O
+disequilibrium,O
+,,O
+but,O
+,,O
+in,O
+the,O
+absence,O
+of,O
+parental,O
+information,O
+to,O
+resolve,O
+the,O
+phase,O
+of,O
+double,O
+heterozygotes,O
+,,O
+the,O
+most,O
+powerful,O
+design,O
+samples,O
+only,O
+individuals,O
+homozygous,O
+at,O
+the,O
+trait,O
+locus,O
+.,O
+ , 
+For,O
+rare,O
+diseases,O
+,,O
+such,O
+a,O
+scheme,O
+is,O
+generally,O
+not,O
+feasible,O
+,,O
+and,O
+we,O
+also,O
+provide,O
+power,O
+and,O
+sample,O
+-,O
+size,O
+calculations,O
+for,O
+designs,O
+that,O
+sample,O
+heterozygotes,O
+.,O
+ , 
+The,O
+results,O
+provide,O
+information,O
+useful,O
+in,O
+planning,O
+disequilibrium,O
+studies,O
+.,O
+ , 
+#1463020
+Importance,O
+sampling,O
+.,O
+ , 
+I.,O
+Computing,O
+multimodel,O
+p,O
+values,O
+in,O
+linkage,O
+analysis,O
+.,O
+ , 
+In,O
+linkage,O
+analysis,O
+,,O
+when,O
+the,O
+lod,O
+score,O
+is,O
+maximized,O
+over,O
+multiple,O
+genetic,O
+models,O
+,,O
+standard,O
+asymptotic,O
+approximation,O
+of,O
+the,O
+significance,O
+level,O
+does,O
+not,O
+apply,O
+.,O
+ , 
+Monte,O
+Carlo,O
+methods,O
+can,O
+be,O
+used,O
+to,O
+estimate,O
+the,O
+p,O
+value,O
+,,O
+but,O
+procedures,O
+currently,O
+used,O
+are,O
+extremely,O
+inefficient,O
+.,O
+ , 
+We,O
+propose,O
+a,O
+Monte,O
+Carlo,O
+procedure,O
+based,O
+on,O
+the,O
+concept,O
+of,O
+importance,O
+sampling,O
+,,O
+which,O
+can,O
+be,O
+thousands,O
+of,O
+times,O
+more,O
+efficient,O
+than,O
+current,O
+procedures,O
+.,O
+ , 
+With,O
+a,O
+reasonable,O
+amount,O
+of,O
+computing,O
+time,O
+,,O
+extremely,O
+accurate,O
+estimates,O
+of,O
+the,O
+p,O
+values,O
+can,O
+be,O
+obtained,O
+.,O
+ , 
+Both,O
+theoretical,O
+results,O
+and,O
+an,O
+example,O
+of,O
+maturity,O
+-,O
+onset,O
+diabetes,O
+of,O
+the,O
+young,O
+(,O
+MODY,O
+),O
+are,O
+presented,O
+to,O
+illustrate,O
+the,O
+efficiency,O
+performance,O
+of,O
+our,O
+method,O
+.,O
+ , 
+Relations,O
+between,O
+single,O
+-,O
+model,O
+and,O
+multimodel,O
+p,O
+values,O
+are,O
+explored,O
+.,O
+ , 
+The,O
+new,O
+procedure,O
+is,O
+also,O
+used,O
+to,O
+investigate,O
+the,O
+performance,O
+of,O
+asymptotic,O
+approximations,O
+in,O
+a,O
+single,O
+model,O
+situation,O
+.,O
+ , 
+#1415228
+The,O
+tyrosinase,O
+-,O
+positive,O
+oculocutaneous,O
+albinism,O
+locus,O
+maps,O
+to,O
+chromosome,O
+15q11.2,O
+-,O
+q12,O
+.,O
+ , 
+Tyrosinase,O
+-,O
+positive,O
+oculocutaneous,O
+albinism,O
+(,O
+ty,O
+-,O
+pos,O
+OCA,O
+),O
+,,O
+an,O
+autosomal,O
+recessive,O
+disorder,O
+of,O
+the,O
+melanin,O
+biosynthetic,O
+pathway,O
+,,O
+is,O
+the,O
+most,O
+common,O
+type,O
+of,O
+albinism,O
+occurring,O
+worldwide,O
+.,O
+ , 
+In,O
+southern,O
+African,O
+Bantu,O
+-,O
+speaking,O
+negroids,O
+it,O
+has,O
+an,O
+overall,O
+prevalence,O
+of,O
+about,O
+1/3,900,O
+.,O
+ , 
+Since,O
+the,O
+basic,O
+biochemical,O
+defect,O
+is,O
+unknown,O
+,,O
+a,O
+linkage,O
+study,O
+with,O
+candidate,O
+loci,O
+,,O
+candidate,O
+chromosomal,O
+regions,O
+,,O
+and,O
+random,O
+loci,O
+was,O
+undertaken,O
+.,O
+ , 
+The,O
+ty,O
+-,O
+pos,O
+OCA,O
+locus,O
+was,O
+found,O
+to,O
+be,O
+linked,O
+to,O
+two,O
+arbitrary,O
+loci,O
+,,O
+D15S10,O
+and,O
+D15S13,O
+,,O
+in,O
+the,O
+Prader,O
+-,O
+Willi,O
+/,O
+Angelman,O
+chromosomal,O
+region,O
+on,O
+chromosome,O
+15q11.2,O
+-,O
+q12,O
+.,O
+ , 
+The,O
+pink,O
+-,O
+eyed,O
+dilute,O
+locus,O
+,,O
+p,O
+,,O
+on,O
+mouse,O
+chromosome,O
+7,O
+,,O
+maps,O
+close,O
+to,O
+a,O
+region,O
+of,O
+homology,O
+on,O
+human,O
+chromosome,O
+15q,O
+,,O
+and,O
+we,O
+postulate,O
+that,O
+the,O
+ty,O
+-,O
+pos,O
+OCA,O
+and,O
+p,O
+loci,O
+are,O
+homologous,O
+.,O
+ , 
+#1329505
+SSCP,O
+and,O
+segregation,O
+analysis,O
+of,O
+the,O
+human,B-Gene
+type,I-Gene
+X,I-Gene
+collagen,I-Gene
+gene,O
+(,B-Gene
+COL10A1,I-Gene
+),I-Gene
+in,O
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+forms,O
+of,O
+chondrodysplasia,O
+.,O
+ , 
+Type,O
+X,O
+collagen,O
+is,O
+a,O
+homotrimeric,O
+,,O
+short,O
+chain,O
+,,O
+nonfibrillar,O
+collagen,O
+that,O
+is,O
+expressed,O
+exclusively,O
+by,O
+hypertrophic,O
+chondrocytes,O
+at,O
+the,O
+sites,O
+of,O
+endochondral,O
+ossification,O
+.,O
+ , 
+The,O
+distribution,O
+and,O
+pattern,O
+of,O
+expression,O
+of,O
+the,O
+type,B-Gene
+X,I-Gene
+collagen,I-Gene
+gene,O
+(,B-Gene
+COL10A1,I-Gene
+),I-Gene
+suggests,O
+that,O
+mutations,O
+altering,O
+the,O
+structure,O
+and,O
+synthesis,O
+of,O
+the,O
+protein,O
+may,O
+be,O
+responsible,O
+for,O
+causing,O
+heritable,O
+forms,O
+of,O
+chondrodysplasia,O
+.,O
+ , 
+We,O
+investigated,O
+whether,O
+mutations,O
+within,O
+the,O
+human,O
+COL10A1,B-Gene
+gene,O
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+responsible,O
+for,O
+causing,O
+the,O
+disorders,O
+achondroplasia,O
+,,O
+hypochondroplasia,O
+,,O
+pseudoachondroplasia,O
+,,O
+and,O
+thanatophoric,O
+dysplasia,O
+,,O
+by,O
+analyzing,O
+the,O
+coding,O
+regions,O
+of,O
+the,O
+gene,O
+by,O
+using,O
+PCR,O
+and,O
+the,O
+single,O
+-,O
+stranded,O
+conformational,O
+polymorphism,O
+technique,O
+.,O
+ , 
+By,O
+this,O
+approach,O
+,,O
+seven,O
+sequence,O
+changes,O
+were,O
+identified,O
+within,O
+and,O
+flanking,O
+the,O
+coding,O
+regions,O
+of,O
+the,O
+gene,O
+of,O
+the,O
+affected,O
+persons,O
+.,O
+ , 
+We,O
+demonstrated,O
+that,O
+six,O
+of,O
+these,O
+sequence,O
+changes,O
+were,O
+not,O
+responsible,O
+for,O
+causing,O
+these,O
+forms,O
+of,O
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+polymorphic,O
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+nature,O
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+The,O
+sequence,O
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+demonstrate,O
+discordant,O
+segregation,O
+between,O
+the,O
+COL10A1,B-Gene
+locus,O
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+achondroplasia,O
+and,O
+pseudoachondroplasia,O
+,,O
+in,O
+nuclear,O
+families,O
+.,O
+ , 
+This,O
+lack,O
+of,O
+segregation,O
+suggests,O
+that,O
+mutations,O
+within,O
+or,O
+near,O
+the,O
+COL10A1,B-Gene
+locus,O
+are,O
+not,O
+responsible,O
+for,O
+these,O
+disorders,O
+.,O
+ , 
+The,O
+seventh,O
+sequence,O
+change,O
+resulted,O
+in,O
+a,O
+valine,O
+-,O
+to,O
+-,O
+methionine,O
+substitution,O
+in,O
+the,O
+carboxyl,O
+-,O
+terminal,O
+domain,O
+of,O
+the,O
+molecule,O
+and,O
+was,O
+identified,O
+in,O
+only,O
+two,O
+hypochondroplasic,O
+individuals,O
+from,O
+a,O
+single,O
+family,O
+.,O
+ , 
+Segregation,O
+analysis,O
+in,O
+this,O
+family,O
+was,O
+inconclusive,O
+,,O
+and,O
+the,O
+significance,O
+of,O
+this,O
+substitution,O
+remains,O
+uncertain,O
+.,O
+ , 
+#9382097
+Neonatal,O
+,,O
+lethal,O
+noncompaction,O
+of,O
+the,O
+left,O
+ventricular,O
+myocardium,O
+is,O
+allelic,O
+with,O
+Barth,O
+syndrome,O
+.,O
+ , 
+Loss,O
+-,O
+of,O
+-,O
+function,O
+mutations,O
+in,O
+the,O
+G4.5,O
+gene,O
+have,O
+been,O
+shown,O
+to,O
+cause,O
+Barth,O
+syndrome,O
+(,O
+BTHS,O
+),O
+,,O
+an,O
+X,O
+-,O
+linked,O
+disorder,O
+characterized,O
+by,O
+cardiac,O
+and,O
+skeletal,O
+myopathy,O
+,,O
+short,O
+stature,O
+,,O
+and,O
+neutropenia,O
+.,O
+ , 
+We,O
+recently,O
+reported,O
+a,O
+family,O
+with,O
+a,O
+severe,O
+X,O
+-,O
+linked,O
+cardiomyopathy,O
+described,O
+as,O
+isolated,O
+noncompaction,O
+of,O
+the,O
+left,O
+ventricular,O
+myocardium,O
+(,O
+INVM,O
+),O
+.,O
+ , 
+Other,O
+findings,O
+associated,O
+with,O
+BTHS,O
+(,O
+skeletal,O
+myopathy,O
+,,O
+neutropenia,O
+,,O
+growth,O
+retardation,O
+,,O
+elevated,O
+urinary,O
+organic,O
+acids,O
+,,O
+and,O
+mitochondrial,O
+abnormalities,O
+),O
+were,O
+either,O
+absent,O
+or,O
+inconsistent,O
+.,O
+ , 
+A,O
+linkage,O
+study,O
+of,O
+the,O
+X,O
+chromosome,O
+localized,O
+INVM,O
+to,O
+the,O
+Xq28,O
+region,O
+near,O
+the,O
+BTHS,O
+locus,O
+,,O
+suggesting,O
+that,O
+these,O
+disorders,O
+are,O
+allelic,O
+.,O
+ , 
+We,O
+screened,O
+the,O
+G4.5,B-Gene
+gene,O
+for,O
+mutations,O
+in,O
+this,O
+family,O
+with,O
+SSCP,O
+and,O
+direct,O
+sequencing,O
+and,O
+found,O
+a,O
+novel,O
+glycine,B-SNP
+-,I-SNP
+to,I-SNP
+-,I-SNP
+arginine,I-SNP
+substitution,I-SNP
+at,I-SNP
+position,I-SNP
+197,I-SNP
+.,I-SNP
+ , 
+This,O
+position,O
+is,O
+conserved,O
+in,O
+a,O
+homologous,O
+Caenorhabditis,O
+elegans,O
+protein,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+INVM,O
+is,O
+a,O
+severe,O
+allelic,O
+variant,O
+of,O
+BTHS,O
+with,O
+a,O
+specific,O
+effect,O
+on,O
+the,O
+heart,O
+.,O
+ , 
+This,O
+finding,O
+provides,O
+further,O
+structure,O
+-,O
+function,O
+information,O
+about,O
+the,O
+G4.5,B-Gene
+gene,O
+product,O
+and,O
+has,O
+implications,O
+for,O
+unexplained,O
+cases,O
+of,O
+severe,O
+infantile,O
+hypertrophic,O
+cardiomyopathy,O
+in,O
+males,O
+.,O
+ , 
+#9401007
+Charcot,O
+-,O
+Marie,O
+-,O
+Tooth,O
+disease,O
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+intermediate,O
+motor,O
+nerve,O
+conduction,O
+velocities,O
+:,O
+characterization,O
+of,O
+14,O
+Cx32,B-Gene
+mutations,O
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+35,O
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+.,O
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+Charcot,O
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+Tooth,O
+disease,O
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+autosomal,O
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+recessively,O
+or,O
+linked,O
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+X,O
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+X,O
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+Charcot,O
+-,O
+Marie,O
+-,O
+Tooth,O
+disease,O
+(,O
+CMTX,O
+),O
+is,O
+a,O
+sensorimotor,O
+peripheral,O
+neuropathy,O
+in,O
+which,O
+males,O
+have,O
+usually,O
+more,O
+severe,O
+clinical,O
+symptoms,O
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+decreased,O
+nerve,O
+conduction,O
+velocities,O
+than,O
+do,O
+females,O
+.,O
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+CMTX,O
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+associated,O
+with,O
+mutations,O
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+connexin,B-Gene
+32,I-Gene
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+Cx32,I-Gene
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+DNA,O
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+35,O
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+,,O
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+the,O
+17p11.2,O
+duplication,O
+,,O
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+with,O
+median,O
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+conduction,O
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+30,O
+and,O
+40,O
+m,O
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+of,O
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+mutations,O
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+ , 
+The,O
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+gene,O
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+detect,O
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+Thirteen,O
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+characterized,O
+by,O
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+.,O
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+In,O
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+entire,O
+Cx32,B-Gene
+coding,O
+region,O
+in,O
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+remaining,O
+index,O
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+that,O
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+A,O
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+(,O
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+in,O
+the,O
+coding,O
+region,O
+of,O
+the,O
+Cx32,B-Gene
+gene,O
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+CMT,O
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+intermediate,O
+MNCV,O
+,,O
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+duplications,O
+.,O
+ , 
+Most,O
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+these,O
+mutations,O
+(,O
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+by,O
+SSCP,O
+.,O
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+#12687502
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+microdeletions,O
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+by,O
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+chromosome,O
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+chromatid,O
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+in,O
+Sotos,O
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+Sotos,O
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+(,O
+SoS,O
+),O
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+and,O
+postnatal,O
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+with,O
+advanced,O
+bone,O
+age,O
+;,O
+a,O
+dysmorphic,O
+face,O
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+macrocephaly,O
+and,O
+pointed,O
+chin,O
+;,O
+large,O
+hands,O
+and,O
+feet,O
+;,O
+mental,O
+retardation,O
+;,O
+and,O
+possible,O
+susceptibility,O
+to,O
+tumors,O
+.,O
+ , 
+It,O
+has,O
+been,O
+shown,O
+that,O
+the,O
+major,O
+cause,O
+of,O
+SoS,O
+is,O
+haploinsufficiency,O
+of,O
+the,O
+NSD1,B-Gene
+gene,O
+at,O
+5q35,O
+,,O
+because,O
+the,O
+majority,O
+of,O
+patients,O
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+either,O
+a,O
+common,O
+microdeletion,O
+including,O
+NSD1,B-Gene
+or,O
+a,O
+truncated,O
+type,O
+of,O
+point,O
+mutation,O
+in,O
+NSD1,B-Gene
+.,I-Gene
+ , 
+In,O
+the,O
+present,O
+study,O
+,,O
+we,O
+traced,O
+the,O
+parental,O
+origin,O
+of,O
+the,O
+microdeletions,O
+in,O
+26,O
+patients,O
+with,O
+SoS,O
+by,O
+the,O
+use,O
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+16,O
+microsatellite,O
+markers,O
+at,O
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+flanking,O
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+deleted,O
+region,O
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+Deletions,O
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+18,O
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+20,O
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+cases,O
+occurred,O
+in,O
+the,O
+paternally,O
+derived,O
+chromosome,O
+5,O
+,,O
+whereas,O
+those,O
+in,O
+the,O
+maternally,O
+derived,O
+chromosome,O
+were,O
+found,O
+in,O
+only,O
+two,O
+cases,O
+.,O
+ , 
+Haplotyping,O
+analysis,O
+of,O
+the,O
+marker,O
+loci,O
+revealed,O
+that,O
+the,O
+paternal,O
+deletion,O
+in,O
+five,O
+of,O
+seven,O
+informative,O
+cases,O
+and,O
+the,O
+maternal,O
+deletion,O
+in,O
+one,O
+case,O
+arose,O
+through,O
+an,O
+intrachromosomal,O
+rearrangement,O
+,,O
+and,O
+two,O
+other,O
+cases,O
+of,O
+the,O
+paternal,O
+deletion,O
+involved,O
+an,O
+interchromosomal,O
+event,O
+,,O
+suggesting,O
+that,O
+the,O
+common,O
+microdeletion,O
+observed,O
+in,O
+SoS,O
+did,O
+not,O
+occur,O
+through,O
+a,O
+uniform,O
+mechanism,O
+but,O
+preferentially,O
+arose,O
+prezygotically,O
+.,O
+ , 
+#7726181
+MtDNA,O
+haplogroups,O
+in,O
+Native,O
+Americans,O
+.,O
+ , 
+#16909383
+A,O
+new,O
+autosomal,O
+recessive,O
+form,O
+of,O
+Stickler,O
+syndrome,O
+is,O
+caused,O
+by,O
+a,O
+mutation,O
+in,O
+the,O
+COL9A1,B-Gene
+gene,O
+.,O
+ , 
+Stickler,O
+syndrome,O
+is,O
+characterized,O
+by,O
+ophthalmic,O
+,,O
+articular,O
+,,O
+orofacial,O
+,,O
+and,O
+auditory,O
+manifestations,O
+.,O
+ , 
+It,O
+has,O
+an,O
+autosomal,O
+dominant,O
+inheritance,O
+pattern,O
+and,O
+is,O
+caused,O
+by,O
+mutations,O
+in,O
+COL2A1,B-Gene
+,,I-Gene
+COL11A1,B-Gene
+,,I-Gene
+and,O
+COL11A2,B-Gene
+.,I-Gene
+ , 
+We,O
+describe,O
+a,O
+family,O
+of,O
+Moroccan,O
+origin,O
+that,O
+consists,O
+of,O
+four,O
+children,O
+with,O
+Stickler,O
+syndrome,O
+,,O
+six,O
+unaffected,O
+children,O
+,,O
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+two,O
+unaffected,O
+parents,O
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+are,O
+distant,O
+relatives,O
+(,O
+fifth,O
+degree,O
+),O
+.,O
+ , 
+All,O
+family,O
+members,O
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+clinically,O
+investigated,O
+for,O
+ear,O
+,,O
+nose,O
+,,O
+and,O
+throat,O
+;,O
+ophthalmologic,O
+;,O
+and,O
+radiological,O
+abnormalities,O
+.,O
+ , 
+Four,O
+children,O
+showed,O
+symptoms,O
+characteristic,O
+of,O
+Stickler,O
+syndrome,O
+,,O
+including,O
+moderate,O
+-,O
+to,O
+-,O
+severe,O
+sensorineural,O
+hearing,O
+loss,O
+,,O
+moderate,O
+-,O
+to,O
+-,O
+high,O
+myopia,O
+with,O
+vitreoretinopathy,O
+,,O
+and,O
+epiphyseal,O
+dysplasia,O
+.,O
+ , 
+We,O
+considered,O
+the,O
+COL9A1,B-Gene
+gene,O
+,,O
+located,O
+on,O
+chromosome,O
+6q13,O
+,,O
+to,O
+be,O
+a,O
+candidate,O
+gene,O
+on,O
+the,O
+basis,O
+of,O
+the,O
+structural,O
+association,O
+with,O
+collagen,O
+types,O
+II,O
+and,O
+XI,O
+and,O
+because,O
+of,O
+the,O
+high,O
+expression,O
+in,O
+the,O
+human,O
+inner,O
+ear,O
+indicated,O
+by,O
+cDNA,O
+microarray,O
+.,O
+ , 
+Mutation,O
+analysis,O
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+the,O
+coding,O
+region,O
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+the,O
+COL9A1,B-Gene
+gene,O
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+a,O
+homozygous,O
+R295X,B-SNP
+mutation,O
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+the,O
+four,O
+affected,O
+children,O
+.,O
+ , 
+The,O
+parents,O
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+of,O
+the,O
+R295X,B-SNP
+mutation,O
+.,O
+ , 
+Two,O
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+children,O
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+the,O
+wild,O
+-,O
+type,O
+allele,O
+.,O
+ , 
+None,O
+of,O
+the,O
+family,O
+members,O
+except,O
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+homozygous,O
+R295X,B-SNP
+carriers,O
+had,O
+any,O
+signs,O
+of,O
+Stickler,O
+syndrome,O
+.,O
+ , 
+Therefore,O
+,,O
+COL9A1,B-Gene
+is,O
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+fourth,O
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+gene,O
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+can,O
+cause,O
+Stickler,O
+syndrome,O
+.,O
+ , 
+In,O
+contrast,O
+to,O
+the,O
+three,O
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+Stickler,O
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+genes,O
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+a,O
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+an,O
+autosomal,O
+recessive,O
+inheritance,O
+pattern,O
+.,O
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+This,O
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+a,O
+major,O
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+the,O
+genetic,O
+counseling,O
+of,O
+patients,O
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+Stickler,O
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+on,O
+the,O
+understanding,O
+of,O
+the,O
+pathophysiology,O
+of,O
+collagens,O
+.,O
+ , 
+Mutation,O
+analysis,O
+of,O
+this,O
+gene,O
+is,O
+recommended,O
+in,O
+patients,O
+with,O
+Stickler,O
+syndrome,O
+with,O
+possible,O
+autosomal,O
+recessive,O
+inheritance,O
+.,O
+ , 
+#18460397
+Differential,O
+expression,O
+of,O
+PTEN,O
+-,O
+targeting,O
+microRNAs,O
+miR-19a,O
+and,O
+miR-21,O
+in,O
+Cowden,O
+syndrome,O
+.,O
+ , 
+Germline,O
+mutations,O
+in,O
+the,O
+gene,O
+encoding,O
+phosphatase,O
+and,O
+tensin,O
+homolog,O
+deleted,O
+on,O
+chromosome,O
+ten,O
+(,B-Gene
+PTEN,I-Gene
+[,O
+MIM,O
+601728,O
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+are,O
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+a,O
+number,O
+of,O
+clinically,O
+distinct,O
+heritable,O
+cancer,O
+syndromes,O
+,,O
+including,O
+both,O
+Cowden,O
+syndrome,O
+(,O
+CS,O
+),O
+and,O
+Bannayan,O
+-,O
+Riley,O
+-,O
+Ruvalcaba,O
+syndrome,O
+(,O
+BRRS,O
+),O
+.,O
+ , 
+Seemingly,O
+identical,O
+pathogenic,O
+PTEN,B-Gene
+mutations,O
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+been,O
+observed,O
+in,O
+patients,O
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+CS,O
+and,O
+BRRS,O
+,,O
+as,O
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+as,O
+in,O
+patients,O
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+incomplete,O
+features,O
+of,O
+CS,O
+,,O
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+to,O
+as,O
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+-,O
+like,O
+(,O
+CSL,O
+),O
+patients,O
+.,O
+ , 
+These,O
+observations,O
+indicate,O
+that,O
+additional,O
+,,O
+unidentified,O
+,,O
+genetic,O
+and,O
+epigenetic,O
+factors,O
+act,O
+as,O
+phenotypic,O
+modifiers,O
+in,O
+these,O
+disorders,O
+.,O
+ , 
+These,O
+genetic,O
+factors,O
+could,O
+also,O
+contribute,O
+to,O
+disease,O
+in,O
+patients,O
+with,O
+CS,O
+,,O
+CSL,O
+,,O
+or,O
+BRRS,O
+without,O
+identifiable,O
+PTEN,B-Gene
+mutations,O
+.,O
+ , 
+Two,O
+potential,O
+modifiers,O
+are,O
+miR-19a,O
+and,O
+miR-21,O
+,,O
+which,O
+are,O
+previously,O
+identified,O
+PTEN,O
+-,O
+targeting,O
+miRNAs,O
+.,O
+ , 
+We,O
+investigated,O
+the,O
+role,O
+of,O
+these,O
+miRNAs,O
+by,O
+characterizing,O
+their,O
+relative,O
+expression,O
+levels,O
+in,O
+PTEN,O
+-,O
+mutation,O
+-,O
+positive,O
+and,O
+PTEN,O
+-,O
+mutation,O
+-,O
+negative,O
+patients,O
+with,O
+CS,O
+,,O
+CSL,O
+,,O
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+BRRS,O
+.,O
+ , 
+Interestingly,O
+,,O
+we,O
+observed,O
+differential,O
+expression,O
+of,O
+miR-19a,O
+and,O
+miR-21,O
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+our,O
+PTEN,O
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+positive,O
+patients,O
+.,O
+ , 
+Both,O
+were,O
+found,O
+to,O
+be,O
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+overexpressed,O
+within,O
+this,O
+group,O
+(,O
+p,O
+<,O
+0.01,O
+),O
+and,O
+were,O
+inversely,O
+correlated,O
+with,O
+germline,O
+PTEN,B-Gene
+protein,O
+levels,O
+.,O
+ , 
+Similarly,O
+,,O
+the,O
+relative,O
+expression,O
+of,O
+miR-19a,O
+and,O
+miR-21,O
+was,O
+differentially,O
+expressed,O
+in,O
+a,O
+series,O
+of,O
+PTEN,O
+-,O
+mutation,O
+-,O
+negative,O
+patients,O
+with,O
+CS,O
+or,O
+CSL,O
+with,O
+variable,O
+clinical,O
+phenotypes,O
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+length,O
+PTEN,B-Gene
+protein,O
+expression,O
+.,O
+ , 
+Among,O
+PTEN,O
+-,O
+mutation,O
+-,O
+positive,O
+patients,O
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+CS,O
+,,O
+both,O
+miRNAs,O
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+significantly,O
+overexpressed,O
+(,O
+p,O
+=,O
+0.006,O
+-,O
+0.013,O
+),O
+.,O
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+Taken,O
+together,O
+,,O
+our,O
+study,O
+results,O
+suggest,O
+that,O
+differential,O
+expression,O
+of,O
+PTEN,O
+-,O
+targeting,O
+miR-19a,O
+and,O
+miR-21,O
+modulates,O
+the,O
+PTEN,B-Gene
+protein,O
+levels,O
+and,O
+the,O
+CS,O
+and,O
+CSL,O
+phenotypes,O
+,,O
+irrespective,O
+of,O
+the,O
+patient,O
+'s,O
+mutation,O
+status,O
+,,O
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+support,O
+their,O
+roles,O
+as,O
+genetic,O
+modifiers,O
+in,O
+CS,O
+and,O
+CSL,O
+.,O
+ , 
+#12552556
+Clinical,O
+and,O
+molecular,O
+study,O
+in,O
+congenital,O
+muscular,O
+dystrophy,O
+with,O
+partial,B-Gene
+laminin,I-Gene
+alpha,I-Gene
+2,I-Gene
+(,B-Gene
+LAMA2,I-Gene
+),I-Gene
+deficiency,O
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+Complete,O
+laminin,B-Gene
+alpha2,I-Gene
+(,B-Gene
+LAMA2,I-Gene
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+causes,O
+approximately,O
+half,O
+of,O
+congenital,O
+muscular,O
+dystrophy,O
+(,O
+CMD,O
+),O
+cases,O
+.,O
+ , 
+Many,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mutations,O
+have,O
+been,O
+reported,O
+in,O
+these,O
+severe,O
+,,O
+neonatal,O
+-,O
+onset,O
+patients,O
+,,O
+but,O
+only,O
+single,O
+missense,O
+mutations,O
+have,O
+been,O
+found,O
+in,O
+milder,O
+CMD,O
+with,O
+partial,O
+laminin,B-Gene
+alpha2,I-Gene
+deficiency,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+studied,O
+nine,O
+patients,O
+diagnosed,O
+with,O
+CMD,O
+who,O
+showed,O
+abnormal,O
+white,O
+-,O
+matter,O
+signal,O
+at,O
+brain,O
+MRI,O
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+partial,O
+deficiency,O
+of,O
+laminin,O
+alpha2,O
+on,O
+immunofluorescence,O
+of,O
+muscle,O
+biopsy,O
+.,O
+ , 
+We,O
+screened,O
+the,O
+entire,O
+9.5,O
+kb,O
+laminin,O
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+mRNA,O
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+patient,O
+muscle,O
+biopsy,O
+by,O
+direct,O
+capillary,O
+automated,O
+sequencing,O
+,,O
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+strand,O
+conformational,O
+polymorphism,O
+(,O
+SSCP,O
+),O
+,,O
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+denaturing,O
+high,O
+performance,O
+liquid,O
+chromatography,O
+(,O
+DHPLC,O
+),O
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+RT,O
+-,O
+PCR,O
+products,O
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+direct,O
+sequencing,O
+of,O
+heteroduplexes,O
+.,O
+ , 
+We,O
+identified,O
+laminin,O
+alpha2,B-Gene
+sequence,O
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+six,O
+of,O
+nine,O
+CMD,O
+patients,O
+.,O
+ , 
+Each,O
+of,O
+the,O
+gene,O
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+,,O
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+one,O
+,,O
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+novel,O
+,,O
+including,O
+three,O
+missense,O
+changes,O
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+two,O
+splice,O
+-,O
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+.,O
+ , 
+The,O
+finding,O
+of,O
+partial,O
+laminin,O
+alpha2,B-Gene
+deficiency,O
+by,O
+immunostaining,O
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+not,O
+specific,O
+for,O
+laminin,O
+alpha2,B-Gene
+gene,O
+mutation,O
+carriers,O
+,,O
+with,O
+only,O
+two,O
+patients,O
+(,O
+22,O
+%,O
+),O
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+clear,O
+causative,O
+mutations,O
+,,O
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+an,O
+additional,O
+three,O
+patients,O
+(,O
+33,O
+%,O
+),O
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+possible,O
+mutations,O
+.,O
+ , 
+The,O
+clinical,O
+presentation,O
+and,O
+disease,O
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+in,O
+the,O
+laminin,O
+alpha2,B-Gene
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+negative,O
+CMD,O
+patients,O
+.,O
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+#7550232
+Four,O
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+mutations,O
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+intermediate,O
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+L,O
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+iduronidase,O
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+(,O
+MPS,O
+IS,O
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+MPS,O
+IH,O
+/,O
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+),O
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+The,O
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+diseases,O
+(,O
+Mucopolysaccharidosis,O
+I,O
+),O
+cover,O
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+spectrum,O
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+clinical,O
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+ranging,O
+from,O
+the,O
+very,O
+severe,O
+(,O
+Hurler,O
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+,,O
+MPS,O
+IH,O
+),O
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+an,O
+intermediate,O
+(,O
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+/,O
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+syndrome,O
+,,O
+MPS,O
+IH,O
+/,O
+S,O
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+a,O
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+mild,O
+form,O
+(,O
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+,,O
+MPS,O
+IS,O
+),O
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+Numerous,O
+mutations,O
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+gene,O
+encoding,O
+alpha,O
+-,O
+L,O
+-,O
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+IDUA,O
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+Hurler,O
+syndrome,O
+,,O
+but,O
+only,O
+three,O
+in,O
+the,O
+other,O
+disorders,O
+.,O
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+We,O
+report,O
+on,O
+novel,O
+mutations,O
+of,O
+the,O
+IDUA,O
+gene,O
+in,O
+one,O
+patient,O
+with,O
+the,O
+Scheie,O
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+and,O
+in,O
+three,O
+patients,O
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+the,O
+Hurler,O
+/,O
+Scheie,O
+syndrome,O
+.,O
+ , 
+The,O
+novel,O
+mutations,O
+,,O
+all,O
+single,O
+base,O
+changes,O
+,,O
+encoded,O
+the,O
+substitutions,O
+R492P,B-SNP
+(,O
+Scheie,O
+),O
+,,O
+and,O
+X654,B-SNP
+G,I-SNP
+,,I-SNP
+P496L,B-SNP
+,,I-SNP
+and,O
+L490P,B-SNP
+(,O
+Hurler,O
+/,O
+Scheie,O
+),O
+.,O
+ , 
+The,O
+L490P,B-SNP
+mutation,O
+was,O
+apparently,O
+homozygous,O
+,,O
+whereas,O
+each,O
+of,O
+the,O
+others,O
+was,O
+found,O
+in,O
+compound,O
+heterozygosity,O
+with,O
+a,O
+Hurler,O
+mutation,O
+.,O
+ , 
+The,O
+deleterious,O
+nature,O
+of,O
+the,O
+mutations,O
+was,O
+confirmed,O
+by,O
+absence,O
+of,O
+enzyme,O
+activity,O
+upon,O
+transfection,O
+of,O
+the,O
+corresponding,O
+mutagenized,O
+cDNAs,O
+into,O
+Cos-1,O
+cells,O
+.,O
+ , 
+These,O
+results,O
+provide,O
+additional,O
+information,O
+for,O
+genotype,O
+-,O
+phenotype,O
+correlations,O
+.,O
+ , 
+#21353196
+Exome,O
+sequencing,O
+identifies,O
+truncating,O
+mutations,O
+in,O
+human,O
+SERPINF1,B-Gene
+in,O
+autosomal,O
+-,O
+recessive,O
+osteogenesis,O
+imperfecta,O
+.,O
+ , 
+Osteogenesis,O
+imperfecta,O
+(,O
+OI,O
+),O
+is,O
+a,O
+heterogeneous,O
+genetic,O
+disorder,O
+characterized,O
+by,O
+bone,O
+fragility,O
+and,O
+susceptibility,O
+to,O
+fractures,O
+after,O
+minimal,O
+trauma,O
+.,O
+ , 
+After,O
+mutations,O
+in,O
+all,O
+known,O
+OI,O
+genes,O
+had,O
+been,O
+excluded,O
+by,O
+Sanger,O
+sequencing,O
+,,O
+we,O
+applied,O
+next,O
+-,O
+generation,O
+sequencing,O
+to,O
+analyze,O
+the,O
+exome,O
+of,O
+a,O
+single,O
+individual,O
+who,O
+has,O
+a,O
+severe,O
+form,O
+of,O
+the,O
+disease,O
+and,O
+whose,O
+parents,O
+are,O
+second,O
+cousins,O
+.,O
+ , 
+A,O
+total,O
+of,O
+26,922,O
+variations,O
+from,O
+the,O
+human,O
+reference,O
+genome,O
+sequence,O
+were,O
+subjected,O
+to,O
+several,O
+filtering,O
+steps,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+we,O
+extracted,O
+the,O
+genotypes,O
+of,O
+all,O
+dbSNP130,O
+-,O
+annotated,O
+SNPs,O
+from,O
+the,O
+exome,O
+sequencing,O
+data,O
+and,O
+used,O
+these,O
+299,494,O
+genotypes,O
+as,O
+markers,O
+for,O
+the,O
+genome,O
+-,O
+wide,O
+identification,O
+of,O
+homozygous,O
+regions,O
+.,O
+ , 
+A,O
+single,O
+homozygous,O
+truncating,O
+mutation,O
+,,O
+affecting,O
+SERPINF1,B-Gene
+on,O
+chromosome,O
+17p13.3,O
+,,O
+that,O
+was,O
+embedded,O
+into,O
+a,O
+homozygous,O
+stretch,O
+of,O
+2.99,O
+Mb,O
+remained,O
+.,O
+ , 
+The,O
+mutation,O
+was,O
+also,O
+homozygous,O
+in,O
+the,O
+affected,O
+brother,O
+of,O
+the,O
+index,O
+patient,O
+.,O
+ , 
+Subsequently,O
+,,O
+we,O
+identified,O
+homozygosity,O
+for,O
+two,O
+different,O
+truncating,O
+SERPINF1,B-Gene
+mutations,O
+in,O
+two,O
+unrelated,O
+patients,O
+with,O
+OI,O
+and,O
+parental,O
+consanguinity,O
+.,O
+ , 
+All,O
+four,O
+individuals,O
+with,O
+SERPINF1,B-Gene
+mutations,O
+have,O
+severe,O
+OI,O
+.,O
+ , 
+Fractures,O
+of,O
+long,O
+bones,O
+and,O
+severe,O
+vertebral,O
+compression,O
+fractures,O
+with,O
+resulting,O
+deformities,O
+were,O
+observed,O
+as,O
+early,O
+as,O
+the,O
+first,O
+year,O
+of,O
+life,O
+in,O
+these,O
+individuals,O
+.,O
+ , 
+Collagen,O
+analyses,O
+with,O
+cultured,O
+dermal,O
+fibroblasts,O
+displayed,O
+no,O
+evidence,O
+for,O
+impaired,O
+collagen,O
+folding,O
+,,O
+posttranslational,O
+modification,O
+,,O
+or,O
+secretion,O
+.,O
+ , 
+SERPINF1,B-Gene
+encodes,O
+pigment,O
+epithelium,O
+-,O
+derived,O
+factor,O
+(,B-Gene
+PEDF,I-Gene
+),I-Gene
+,,O
+a,O
+secreted,O
+glycoprotein,O
+of,O
+the,O
+serpin,O
+superfamily,O
+.,O
+ , 
+PEDF,B-Gene
+is,O
+a,O
+multifunctional,O
+protein,O
+and,O
+one,O
+of,O
+the,O
+strongest,O
+inhibitors,O
+of,O
+angiogenesis,O
+currently,O
+known,O
+in,O
+humans,O
+.,O
+ , 
+Our,O
+data,O
+provide,O
+genetic,O
+evidence,O
+for,O
+PEDF,B-Gene
+involvement,O
+in,O
+human,O
+bone,O
+homeostasis,O
+.,O
+ , 
+#1598907
+A,O
+missense,O
+mutation,O
+(,B-SNP
+Trp86,I-SNP
+-,I-SNP
+---Arg,I-SNP
+),I-SNP
+in,O
+exon,O
+3,O
+of,O
+the,O
+lipoprotein,B-Gene
+lipase,I-Gene
+gene,O
+:,O
+a,O
+cause,O
+of,O
+familial,O
+chylomicronemia,O
+.,O
+ , 
+We,O
+have,O
+investigated,O
+a,O
+patient,O
+of,O
+English,O
+ancestry,O
+with,O
+familial,O
+chylomicronemia,O
+caused,O
+by,O
+lipoprotein,B-Gene
+lipase,I-Gene
+(,B-Gene
+LPL,I-Gene
+),I-Gene
+deficiency,O
+.,O
+ , 
+DNA,O
+sequence,O
+analysis,O
+of,O
+all,O
+exons,O
+and,O
+intron,O
+-,O
+exon,O
+boundaries,O
+of,O
+the,O
+LPL,B-Gene
+gene,O
+identified,O
+two,O
+single,O
+-,O
+base,O
+mutations,O
+,,O
+a,O
+T----C,B-SNP
+transition,I-SNP
+for,I-SNP
+codon,I-SNP
+86,I-SNP
+(,I-SNP
+TGG,I-SNP
+),I-SNP
+at,I-SNP
+nucleotide,I-SNP
+511,I-SNP
+,,I-SNP
+resulting,O
+in,O
+a,O
+Trp86,B-SNP
+-,I-SNP
+---Arg,I-SNP
+substitution,O
+,,O
+and,O
+a,O
+C----T,B-SNP
+transition,I-SNP
+at,I-SNP
+nucleotide,I-SNP
+571,I-SNP
+,,I-SNP
+involving,O
+the,O
+codon,O
+CAG,O
+encoding,O
+Gln106,O
+and,O
+producing,O
+Gln106,B-SNP
+-,I-SNP
+---Stop,I-SNP
+,,I-SNP
+a,O
+mutation,O
+described,O
+by,O
+Emi,O
+et,O
+al,O
+.,O
+ , 
+The,O
+functional,O
+significance,O
+of,O
+the,O
+two,O
+mutations,O
+was,O
+confirmed,O
+by,O
+in,O
+vitro,O
+expression,O
+and,O
+enzyme,O
+activity,O
+assays,O
+of,O
+the,O
+mutant,O
+LPL,B-Gene
+.,I-Gene
+ , 
+Linkage,O
+analysis,O
+established,O
+that,O
+the,O
+patient,O
+is,O
+a,O
+compound,O
+heterozygote,O
+for,O
+the,O
+two,O
+mutations,O
+.,O
+ , 
+The,O
+Trp86,B-SNP
+-,I-SNP
+---Arg,I-SNP
+mutation,O
+in,O
+exon,O
+3,O
+is,O
+the,O
+first,O
+natural,O
+mutation,O
+identified,O
+outside,O
+exons,O
+4,O
+-,O
+6,O
+,,O
+which,O
+encompass,O
+the,O
+catalytic,O
+triad,O
+residues,O
+.,O
+ , 
+#19026398
+Mutations,O
+in,O
+contactin-1,B-Gene
+,,I-Gene
+a,O
+neural,O
+adhesion,O
+and,O
+neuromuscular,O
+junction,O
+protein,O
+,,O
+cause,O
+a,O
+familial,O
+form,O
+of,O
+lethal,O
+congenital,O
+myopathy,O
+.,O
+ , 
+We,O
+have,O
+previously,O
+reported,O
+a,O
+group,O
+of,O
+patients,O
+with,O
+congenital,O
+onset,O
+weakness,O
+associated,O
+with,O
+a,O
+deficiency,O
+of,O
+members,O
+of,O
+the,O
+syntrophin,O
+-,O
+alpha,O
+-,O
+dystrobrevin,O
+subcomplex,O
+and,O
+have,O
+demonstrated,O
+that,O
+loss,O
+of,O
+syntrophin,O
+and,O
+dystrobrevin,O
+from,O
+the,O
+sarcolemma,O
+of,O
+skeletal,O
+muscle,O
+can,O
+also,O
+be,O
+associated,O
+with,O
+denervation,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+have,O
+further,O
+studied,O
+four,O
+individuals,O
+from,O
+a,O
+consanguineous,O
+Egyptian,O
+family,O
+with,O
+a,O
+lethal,O
+congenital,O
+myopathy,O
+inherited,O
+in,O
+an,O
+autosomal,O
+-,O
+recessive,O
+fashion,O
+and,O
+characterized,O
+by,O
+a,O
+secondary,O
+loss,O
+of,O
+beta2,O
+-,O
+syntrophin,O
+and,O
+alpha,O
+-,O
+dystrobrevin,O
+from,O
+the,O
+muscle,O
+sarcolemma,O
+,,O
+central,O
+nervous,O
+system,O
+involvement,O
+,,O
+and,O
+fetal,O
+akinesia,O
+.,O
+ , 
+We,O
+performed,O
+homozygosity,O
+mapping,O
+and,O
+candidate,O
+gene,O
+analysis,O
+and,O
+identified,O
+a,O
+mutation,O
+that,O
+segregates,O
+with,O
+disease,O
+within,O
+CNTN1,B-Gene
+,,I-Gene
+the,O
+gene,O
+encoding,O
+for,O
+the,O
+neural,O
+immunoglobulin,O
+family,O
+adhesion,O
+molecule,O
+,,O
+contactin-1,B-Gene
+.,I-Gene
+ , 
+Contactin-1,B-Gene
+transcripts,O
+were,O
+markedly,O
+decreased,O
+on,O
+gene,O
+-,O
+expression,O
+arrays,O
+of,O
+muscle,O
+from,O
+affected,O
+family,O
+members,O
+compared,O
+to,O
+controls,O
+.,O
+ , 
+We,O
+demonstrate,O
+that,O
+contactin-1,B-Gene
+is,O
+expressed,O
+at,O
+the,O
+neuromuscular,O
+junction,O
+(,O
+NMJ,O
+),O
+in,O
+mice,O
+and,O
+man,O
+in,O
+addition,O
+to,O
+the,O
+previously,O
+documented,O
+expression,O
+in,O
+the,O
+central,O
+and,O
+peripheral,O
+nervous,O
+system,O
+.,O
+ , 
+In,O
+patients,O
+with,O
+secondary,O
+dystroglycanopathies,O
+,,O
+we,O
+show,O
+that,O
+contactin-1,B-Gene
+is,O
+abnormally,O
+localized,O
+to,O
+the,O
+sarcolemma,O
+instead,O
+of,O
+exclusively,O
+at,O
+the,O
+NMJ,O
+.,O
+ , 
+The,O
+cntn1,O
+null,O
+mouse,O
+presents,O
+with,O
+ataxia,O
+,,O
+progressive,O
+muscle,O
+weakness,O
+,,O
+and,O
+postnatal,O
+lethality,O
+,,O
+similar,O
+to,O
+the,O
+affected,O
+members,O
+in,O
+this,O
+family,O
+.,O
+ , 
+We,O
+propose,O
+that,O
+loss,O
+of,O
+contactin-1,B-Gene
+from,O
+the,O
+NMJ,O
+impairs,O
+communication,O
+or,O
+adhesion,O
+between,O
+nerve,O
+and,O
+muscle,O
+resulting,O
+in,O
+the,O
+severe,O
+myopathic,O
+phenotype,O
+.,O
+ , 
+This,O
+disorder,O
+is,O
+part,O
+of,O
+the,O
+continuum,O
+in,O
+the,O
+clinical,O
+spectrum,O
+of,O
+congenital,O
+myopathies,O
+and,O
+congenital,O
+myasthenic,O
+syndromes,O
+.,O
+ , 
+#20506298
+Dissecting,O
+the,O
+pathogenic,O
+mechanisms,O
+of,O
+mutations,O
+in,O
+the,O
+pore,O
+region,O
+of,O
+the,O
+human,O
+cone,O
+photoreceptor,O
+cyclic,O
+nucleotide,O
+-,O
+gated,O
+channel,O
+.,O
+ , 
+The,O
+CNGA3,B-Gene
+gene,O
+encodes,O
+the,O
+A3,O
+subunit,O
+of,O
+the,O
+cone,O
+photoreceptor,O
+cyclic,O
+nucleotide,O
+-,O
+gated,O
+(,O
+CNG,O
+),O
+channel,O
+,,O
+an,O
+essential,O
+component,O
+of,O
+the,O
+phototransduction,O
+cascade,O
+.,O
+ , 
+Certain,O
+mutations,O
+in,O
+CNGA3,O
+cause,O
+autosomal,O
+recessive,O
+achromatopsia,O
+,,O
+a,O
+retinal,O
+disorder,O
+characterized,O
+by,O
+severely,O
+reduced,O
+visual,O
+acuity,O
+,,O
+lack,O
+of,O
+color,O
+discrimination,O
+,,O
+photophobia,O
+,,O
+and,O
+nystagmus,O
+.,O
+ , 
+We,O
+identified,O
+three,O
+novel,O
+mutations,O
+in,O
+the,O
+pore,O
+-,O
+forming,O
+region,O
+of,O
+CNGA3,B-Gene
+(,B-SNP
+L363P,I-SNP
+,,I-SNP
+G367V,B-SNP
+,,I-SNP
+and,O
+E376,B-SNP
+K,I-SNP
+),I-SNP
+in,O
+patients,O
+diagnosed,O
+with,O
+achromatopsia,O
+.,O
+ , 
+We,O
+assessed,O
+the,O
+expression,O
+and,O
+function,O
+of,O
+channels,O
+with,O
+these,O
+three,O
+new,O
+and,O
+two,O
+previously,O
+described,O
+mutations,O
+(,B-SNP
+S341P,I-SNP
+and,O
+P372S,B-SNP
+),I-SNP
+in,O
+a,O
+heterologous,O
+HEK293,O
+cell,O
+expression,O
+system,O
+using,O
+Western,O
+blot,O
+,,O
+subcellular,O
+localization,O
+on,O
+the,O
+basis,O
+of,O
+immunocytochemistry,O
+,,O
+calcium,O
+imaging,O
+,,O
+and,O
+patch,O
+clamp,O
+recordings,O
+.,O
+ , 
+In,O
+this,O
+first,O
+comparative,O
+functional,O
+analysis,O
+of,O
+disease,O
+-,O
+associated,O
+mutations,O
+in,O
+the,O
+pore,O
+of,O
+a,O
+CNG,O
+channel,O
+,,O
+we,O
+found,O
+impaired,O
+surface,O
+expression,O
+of,O
+S341P,B-SNP
+,,I-SNP
+L363P,B-SNP
+,,I-SNP
+and,O
+P372S,B-SNP
+mutants,O
+and,O
+reduced,O
+macroscopic,O
+currents,O
+for,O
+channels,O
+with,O
+the,O
+mutations,O
+S341P,B-SNP
+,,I-SNP
+G367V,B-SNP
+,,I-SNP
+and,O
+E376K.,B-SNP
+Calcium,O
+imaging,O
+and,O
+patch,O
+clamp,O
+experiments,O
+after,O
+incubation,O
+at,O
+37,O
+degrees,O
+C,O
+revealed,O
+nonfunctional,O
+homo-,O
+and,O
+heteromeric,O
+channels,O
+in,O
+all,O
+five,O
+mutants,O
+,,O
+but,O
+incubation,O
+at,O
+27,O
+degrees,O
+C,O
+combined,O
+with,O
+coexpression,O
+of,O
+the,O
+B3,O
+subunit,O
+restored,O
+residual,O
+function,O
+of,O
+channels,O
+with,O
+the,O
+mutations,O
+S341P,B-SNP
+,,I-SNP
+G367V,B-SNP
+,,I-SNP
+and,O
+E376K.,B-SNP
+ , 
+#9382104
+A,O
+novel,O
+locus,O
+for,O
+autosomal,O
+dominant,O
+nonsyndromic,O
+hearing,O
+loss,O
+,,O
+DFNA13,B-Gene
+,,I-Gene
+maps,O
+to,O
+chromosome,O
+6p,O
+.,O
+ , 
+Nonsyndromic,O
+hearing,O
+loss,O
+(,O
+NSHL,O
+),O
+is,O
+the,O
+most,O
+common,O
+type,O
+of,O
+hearing,O
+impairment,O
+in,O
+the,O
+elderly,O
+.,O
+ , 
+Environmental,O
+and,O
+hereditary,O
+factors,O
+play,O
+an,O
+etiologic,O
+role,O
+,,O
+although,O
+the,O
+relative,O
+contribution,O
+of,O
+each,O
+is,O
+unknown,O
+.,O
+ , 
+To,O
+date,O
+,,O
+39,O
+NSHL,O
+genes,O
+have,O
+been,O
+localized,O
+.,O
+ , 
+Twelve,O
+produce,O
+autosomal,O
+dominant,O
+hearing,O
+loss,O
+,,O
+most,O
+frequently,O
+postlingual,O
+in,O
+onset,O
+and,O
+progressive,O
+in,O
+nature,O
+.,O
+ , 
+We,O
+have,O
+ascertained,O
+a,O
+large,O
+,,O
+multigenerational,O
+family,O
+in,O
+which,O
+a,O
+gene,O
+for,O
+autosomal,O
+dominant,O
+NSHL,O
+is,O
+segregating,O
+.,O
+ , 
+Affected,O
+individuals,O
+experience,O
+progressive,O
+hearing,O
+loss,O
+beginning,O
+in,O
+the,O
+2d-4th,O
+decades,O
+,,O
+eventually,O
+making,O
+the,O
+use,O
+of,O
+amplification,O
+mandatory,O
+.,O
+ , 
+A,O
+novel,O
+locus,O
+,,O
+DFNA13,B-Gene
+,,I-Gene
+was,O
+identified,O
+on,O
+chromosome,O
+6p,O
+;,O
+the,O
+disease,O
+gene,O
+maps,O
+to,O
+a,O
+4,O
+-,O
+cM,O
+interval,O
+flanked,O
+by,O
+D6S1663,O
+and,O
+D6S1691,O
+,,O
+with,O
+a,O
+maximum,O
+two,O
+-,O
+point,O
+LOD,O
+score,O
+of,O
+6.409,O
+at,O
+D6S299,O
+.,O
+ , 
+#20652909
+A,O
+custom,O
+148,O
+gene,O
+-,O
+based,O
+resequencing,O
+chip,O
+and,O
+the,O
+SNP,O
+explorer,O
+software,O
+:,O
+new,O
+tools,O
+to,O
+study,O
+antibody,O
+deficiency,O
+.,O
+ , 
+Hyper,O
+-,O
+IgM,O
+syndrome,O
+and,O
+Common,O
+Variable,O
+Immunodeficiency,O
+are,O
+heterogeneous,O
+disorders,O
+characterized,O
+by,O
+a,O
+predisposition,O
+to,O
+serious,O
+infection,O
+and,O
+impaired,O
+or,O
+absent,O
+neutralizing,O
+antibody,O
+responses,O
+.,O
+ , 
+Although,O
+a,O
+number,O
+of,O
+single,O
+gene,O
+defects,O
+have,O
+been,O
+associated,O
+with,O
+these,O
+immune,O
+deficiency,O
+disorders,O
+,,O
+the,O
+genetic,O
+basis,O
+of,O
+many,O
+cases,O
+is,O
+not,O
+known,O
+.,O
+ , 
+To,O
+facilitate,O
+mutation,O
+screening,O
+in,O
+patients,O
+with,O
+these,O
+syndromes,O
+,,O
+we,O
+have,O
+developed,O
+a,O
+custom,O
+300,O
+-,O
+kb,O
+resequencing,O
+array,O
+,,O
+the,O
+Hyper,O
+-,O
+IgM,O
+/,O
+CVID,O
+chip,O
+,,O
+which,O
+interrogates,O
+1,576,O
+coding,O
+exons,O
+and,O
+intron,O
+-,O
+exon,O
+junction,O
+regions,O
+from,O
+148,O
+genes,O
+implicated,O
+in,O
+B,O
+-,O
+cell,O
+development,O
+and,O
+immunoglobulin,O
+isotype,O
+switching,O
+.,O
+ , 
+Genomic,O
+DNAs,O
+extracted,O
+from,O
+patients,O
+were,O
+hybridized,O
+to,O
+the,O
+array,O
+using,O
+a,O
+high,O
+-,O
+throughput,O
+protocol,O
+for,O
+target,O
+sequence,O
+amplification,O
+,,O
+pooling,O
+,,O
+and,O
+hybridization,O
+.,O
+ , 
+A,O
+Web,O
+-,O
+based,O
+application,O
+,,O
+SNP,O
+Explorer,O
+,,O
+was,O
+developed,O
+to,O
+directly,O
+analyze,O
+and,O
+visualize,O
+the,O
+single,O
+nucleotide,O
+polymorphism,O
+(,O
+SNP,O
+),O
+annotation,O
+and,O
+for,O
+quality,O
+filtering,O
+.,O
+ , 
+Several,O
+mutations,O
+in,O
+known,O
+disease,O
+-,O
+susceptibility,O
+genes,O
+such,O
+as,O
+CD40LG,B-Gene
+,,I-Gene
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+TRAF3IP2,B-Gene
+,,I-Gene
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+patient,O
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+direct,O
+sequencing,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+the,O
+Hyper,O
+-,O
+IgM,O
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+SNP,O
+Explorer,O
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+a,O
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+-,O
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+#11295840
+Identification,O
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+#11156534
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+After,O
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+On,O
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+In,O
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+glycine,O
+-,O
+cleavage,O
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+-,O
+chain,O
+alpha,O
+-,O
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+In,O
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+,,O
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+pyruvate,O
+carboxylase,O
+,,O
+mitochondrial,O
+aconitase,O
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+Immunoblot,O
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+levels,O
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+,,O
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+assembly,O
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+.,O
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+To,O
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+molecular,O
+defect,O
+,,O
+analysis,O
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+-,O
+fusion,O
+was,O
+performed,O
+between,O
+the,O
+present,O
+study,O
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+fibroblasts,O
+(,O
+recipients,O
+),O
+and,O
+a,O
+panel,O
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+A9,O
+mouse,O
+:,O
+human,O
+hybrids,O
+(,O
+donors,O
+),O
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+Cuthbert,O
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+.,O
+(,O
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+),O
+.,O
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+Complementation,O
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+cells,O
+from,O
+both,O
+families,O
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+the,O
+mouse,O
+:,O
+human,O
+hybrid,O
+clone,O
+carrying,O
+human,O
+chromosome,O
+2,O
+.,O
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+These,O
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+indicate,O
+that,O
+the,O
+underlying,O
+defect,O
+in,O
+our,O
+patients,O
+is,O
+under,O
+the,O
+control,O
+of,O
+a,O
+nuclear,O
+gene,O
+,,O
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+locus,O
+of,O
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+is,O
+on,O
+chromosome,O
+2,O
+.,O
+ , 
+A,O
+5,O
+-,O
+cM,O
+interval,O
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+been,O
+identified,O
+as,O
+potentially,O
+containing,O
+the,O
+critical,O
+region,O
+for,O
+the,O
+unknown,O
+gene,O
+.,O
+ , 
+This,O
+interval,O
+maps,O
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+region,O
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+#8956047
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+(,B-Gene
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+Wolman,O
+disease,O
+.,O
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+#17594715
+Spectrum,O
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+ALMS1,B-Gene
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+in,O
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+.,O
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+Alström,O
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+is,O
+a,O
+monogenic,O
+recessive,O
+disorder,O
+featuring,O
+an,O
+array,O
+of,O
+clinical,O
+manifestations,O
+,,O
+with,O
+systemic,O
+fibrosis,O
+and,O
+multiple,O
+organ,O
+involvement,O
+,,O
+including,O
+retinal,O
+degeneration,O
+,,O
+hearing,O
+loss,O
+,,O
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+,,O
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+mellitus,O
+,,O
+dilated,O
+cardiomyopathy,O
+(,O
+DCM,O
+),O
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+urological,O
+dysfunction,O
+,,O
+and,O
+pulmonary,O
+,,O
+hepatic,O
+,,O
+and,O
+renal,O
+failure,O
+.,O
+ , 
+We,O
+evaluated,O
+a,O
+large,O
+cohort,O
+of,O
+patients,O
+with,O
+Alström,O
+syndrome,O
+for,O
+mutations,O
+in,O
+the,O
+ALMS1,B-Gene
+gene,O
+.,O
+ , 
+In,O
+total,O
+,,O
+79,O
+disease,O
+-,O
+causing,O
+variants,O
+were,O
+identified,O
+,,O
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+which,O
+55,O
+are,O
+novel,O
+mutations,O
+.,O
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+The,O
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+primarily,O
+clustered,O
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+exons,O
+8,O
+,,O
+10,O
+,,O
+and,O
+16,O
+,,O
+although,O
+we,O
+also,O
+identified,O
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+mutations,O
+in,O
+exons,O
+12,O
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+18,O
+.,O
+ , 
+Most,O
+alleles,O
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+only,O
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+45/79,O
+),O
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+several,O
+were,O
+found,O
+recurrently,O
+.,O
+ , 
+Founder,O
+effects,O
+are,O
+likely,O
+in,O
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+of,O
+English,O
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+Turkish,O
+descent,O
+.,O
+ , 
+We,O
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+identified,O
+66,O
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+functional,O
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+identity,O
+of,O
+the,O
+protein,O
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+of,O
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+amino,O
+acid,O
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+.,O
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+A,O
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+association,O
+study,O
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+18,O
+phenotypic,O
+parameters,O
+in,O
+a,O
+subset,O
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+58,O
+patients,O
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+suggestive,O
+associations,O
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+16,O
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+onset,O
+of,O
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+(,O
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+0.02,O
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+(,O
+P,O
+=,O
+0.02,O
+),O
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+(,O
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+0.03,O
+),O
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+A,O
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+association,O
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+between,O
+alterations,O
+in,O
+exon,O
+8,O
+and,O
+absent,O
+,,O
+mild,O
+,,O
+or,O
+delayed,O
+renal,O
+disease,O
+(,O
+P,O
+=,O
+0.0007,O
+),O
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+This,O
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+implications,O
+for,O
+the,O
+understanding,O
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+the,O
+molecular,O
+mechanisms,O
+of,O
+ALMS1,O
+and,O
+provides,O
+the,O
+basis,O
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+further,O
+investigation,O
+of,O
+how,O
+alternative,O
+splicing,O
+of,O
+ALMS1,B-Gene
+contributes,O
+to,O
+the,O
+severity,O
+of,O
+the,O
+disease,O
+.,O
+ , 
+#21394830
+A,O
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+type,O
+1,O
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+NF1,B-Gene
+-,I-Gene
+splice,O
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+of,O
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+complex,O
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+.,O
+ , 
+Here,O
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+in,O
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+NF1,O
+patient,O
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+ , 
+Quantification,O
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+cells,O
+carrying,O
+the,O
+NF1,B-Gene
+mutation,O
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+samples,O
+derived,O
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+(,B-SNP
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+.,O
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+Hence,O
+,,O
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+concluded,O
+that,O
+the,O
+mild,O
+phenotype,O
+observed,O
+in,O
+this,O
+patient,O
+is,O
+the,O
+result,O
+of,O
+the,O
+presence,O
+of,O
+mosaicism,O
+together,O
+with,O
+the,O
+benign,O
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+splice,O
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+.,O
+ , 
+Finally,O
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+aim,O
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+therapeutic,O
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+this,O
+patient,O
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+antisense,O
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+Our,O
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+better,O
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+#15386213
+Statistical,O
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+Admixture,O
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+a,O
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+genes,O
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+to,O
+complex,O
+traits,O
+.,O
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+This,O
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+samples,O
+from,O
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+detect,O
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+loci,O
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+risk,O
+alleles,O
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+Although,O
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+a,O
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+genomic,O
+tools,O
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+make,O
+this,O
+a,O
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+and,O
+attractive,O
+option,O
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+complex,O
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+mapping,O
+.,O
+ , 
+In,O
+this,O
+article,O
+,,O
+we,O
+describe,O
+new,O
+statistical,O
+methods,O
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+analyzing,O
+multipoint,O
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+-,O
+mapping,O
+studies,O
+to,O
+detect,O
+",O
+ancestry,O
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+.,O
+",O
+ , 
+The,O
+new,O
+test,O
+statistics,O
+do,O
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+assume,O
+a,O
+particular,O
+disease,O
+model,O
+;,O
+instead,O
+,,O
+they,O
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+simply,O
+on,O
+the,O
+extent,O
+to,O
+which,O
+the,O
+sample,O
+'s,O
+ancestry,O
+proportions,O
+at,O
+a,O
+locus,O
+deviate,O
+from,O
+the,O
+genome,O
+average,O
+.,O
+ , 
+Our,O
+power,O
+calculations,O
+show,O
+that,O
+,,O
+for,O
+loci,O
+at,O
+which,O
+the,O
+underlying,O
+risk,O
+-,O
+allele,O
+frequencies,O
+are,O
+substantially,O
+different,O
+in,O
+the,O
+ancestral,O
+populations,O
+,,O
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+power,O
+of,O
+admixture,O
+mapping,O
+can,O
+be,O
+comparable,O
+to,O
+that,O
+of,O
+association,O
+mapping,O
+but,O
+with,O
+a,O
+far,O
+smaller,O
+number,O
+of,O
+markers,O
+.,O
+ , 
+We,O
+also,O
+show,O
+that,O
+,,O
+although,O
+",O
+ancestry,O
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+markers,O
+",O
+(,O
+AIMs,O
+),O
+are,O
+superior,O
+to,O
+random,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+(,O
+SNPs,O
+),O
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+SNPs,O
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+AIMs,O
+are,O
+not,O
+available,O
+.,O
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+Hence,O
+,,O
+researchers,O
+who,O
+study,O
+admixed,O
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+in,O
+which,O
+AIMs,O
+are,O
+not,O
+available,O
+can,O
+perform,O
+admixture,O
+mapping,O
+with,O
+the,O
+use,O
+of,O
+modestly,O
+higher,O
+densities,O
+of,O
+random,O
+markers,O
+.,O
+ , 
+Software,O
+to,O
+perform,O
+the,O
+gene,O
+-,O
+mapping,O
+calculations,O
+,,O
+",O
+MALDsoft,O
+,,O
+",O
+is,O
+freely,O
+available,O
+on,O
+the,O
+Pritchard,O
+Lab,O
+Web,O
+site,O
+.,O
+ , 
+#16909394
+Mutations,O
+in,O
+the,O
+CEP290,B-Gene
+(,B-Gene
+NPHP6,I-Gene
+),I-Gene
+gene,O
+are,O
+a,O
+frequent,O
+cause,O
+of,O
+Leber,O
+congenital,O
+amaurosis,O
+.,O
+ , 
+Leber,O
+congenital,O
+amaurosis,O
+(,O
+LCA,O
+),O
+is,O
+one,O
+of,O
+the,O
+main,O
+causes,O
+of,O
+childhood,O
+blindness,O
+.,O
+ , 
+To,O
+date,O
+,,O
+mutations,O
+in,O
+eight,O
+genes,O
+have,O
+been,O
+described,O
+,,O
+which,O
+together,O
+account,O
+for,O
+approximately,O
+45,O
+%,O
+of,O
+LCA,O
+cases,O
+.,O
+ , 
+We,O
+localized,O
+the,O
+genetic,O
+defect,O
+in,O
+a,O
+consanguineous,O
+LCA,O
+-,O
+affected,O
+family,O
+from,O
+Quebec,O
+and,O
+identified,O
+a,O
+splice,O
+defect,O
+in,O
+a,O
+gene,O
+encoding,O
+a,O
+centrosomal,O
+protein,O
+(,B-Gene
+CEP290,I-Gene
+),I-Gene
+.,O
+ , 
+The,O
+defect,O
+is,O
+caused,O
+by,O
+an,O
+intronic,O
+mutation,O
+(,B-SNP
+c.2991,I-SNP
++,I-SNP
+1655A-->G,I-SNP
+),I-SNP
+that,O
+creates,O
+a,O
+strong,O
+splice,O
+-,O
+donor,O
+site,O
+and,O
+inserts,O
+a,O
+cryptic,O
+exon,O
+in,O
+the,O
+CEP290,B-Gene
+messenger,O
+RNA,O
+.,O
+ , 
+This,O
+mutation,O
+was,O
+detected,O
+in,O
+16,O
+(,O
+21,O
+%,O
+),O
+of,O
+76,O
+unrelated,O
+patients,O
+with,O
+LCA,O
+,,O
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+homozygously,O
+or,O
+in,O
+combination,O
+with,O
+a,O
+second,O
+deleterious,O
+mutation,O
+on,O
+the,O
+other,O
+allele,O
+.,O
+ , 
+CEP290,B-Gene
+mutations,O
+therefore,O
+represent,O
+one,O
+of,O
+the,O
+most,O
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+causes,O
+of,O
+LCA,O
+identified,O
+so,O
+far,O
+.,O
+ , 
+#15154117
+A,O
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+haplotype,O
+of,O
+the,O
+nicotine,B-Gene
+acetylcholine,I-Gene
+receptor,I-Gene
+alpha,I-Gene
+4,I-Gene
+subunit,I-Gene
+gene,O
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+with,O
+vulnerability,O
+to,O
+nicotine,O
+addiction,O
+in,O
+men,O
+.,O
+ , 
+Nicotine,O
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+major,O
+addictive,O
+substance,O
+in,O
+cigarettes,O
+,,O
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+genes,O
+involved,O
+in,O
+sensing,O
+nicotine,O
+are,O
+logical,O
+candidates,O
+for,O
+vulnerability,O
+to,O
+nicotine,O
+addiction,O
+.,O
+ , 
+We,O
+studied,O
+six,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+(,O
+SNPs,O
+),O
+in,O
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+CHRNA4,B-Gene
+gene,O
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+four,O
+SNPs,O
+in,O
+the,O
+CHRNB2,B-Gene
+gene,O
+with,O
+respect,O
+to,O
+nicotine,O
+dependence,O
+in,O
+a,O
+collection,O
+of,O
+901,O
+subjects,O
+(,O
+815,O
+siblings,O
+and,O
+86,O
+parents,O
+),O
+from,O
+222,O
+nuclear,O
+families,O
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+multiple,O
+nicotine,O
+-,O
+addicted,O
+siblings,O
+.,O
+ , 
+The,O
+subjects,O
+were,O
+assessed,O
+for,O
+addiction,O
+by,O
+both,O
+the,O
+Fagerstrom,O
+Test,O
+for,O
+Nicotine,O
+Dependence,O
+(,O
+FTND,O
+),O
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+Revised,O
+Tolerance,O
+Questionnaire,O
+(,O
+RTQ,O
+),O
+.,O
+ , 
+Because,O
+only,O
+5.8,O
+%,O
+of,O
+female,O
+offspring,O
+were,O
+smokers,O
+,,O
+only,O
+male,O
+subjects,O
+were,O
+included,O
+in,O
+the,O
+final,O
+analyses,O
+(,O
+621,O
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+from,O
+206,O
+families,O
+),O
+.,O
+ , 
+Univariate,O
+(,O
+single,O
+-,O
+marker,O
+),O
+family,O
+-,O
+based,O
+association,O
+tests,O
+(,O
+FBATs,O
+),O
+demonstrated,O
+that,O
+variant,O
+alleles,O
+at,O
+two,O
+SNPs,O
+,,O
+rs1044396,O
+and,O
+rs1044397,O
+,,O
+in,O
+exon,O
+5,O
+of,O
+the,O
+CHRNA4,B-Gene
+gene,O
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+significantly,O
+associated,O
+with,O
+a,O
+protective,O
+effect,O
+against,O
+nicotine,O
+addiction,O
+as,O
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+a,O
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+a,O
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+(,O
+i.e.,O
+,,O
+age,O
+-,O
+adjusted,O
+FTND,O
+and,O
+RTQ,O
+scores,O
+),O
+,,O
+which,O
+was,O
+consistent,O
+with,O
+the,O
+results,O
+of,O
+the,O
+global,O
+haplotype,O
+FBAT,O
+.,O
+ , 
+Furthermore,O
+,,O
+the,O
+haplotype,O
+-,O
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+FBAT,O
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+a,O
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+(,O
+22.5,O
+%,O
+),O
+CHRNA4,B-Gene
+haplotype,O
+,,O
+GCTATA,O
+,,O
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+was,O
+significantly,O
+associated,O
+with,O
+both,O
+a,O
+protective,O
+effect,O
+against,O
+nicotine,O
+addiction,O
+as,O
+a,O
+dichotomized,O
+trait,O
+(,O
+Z=-3.04,O
+,,O
+P<.005,O
+),O
+and,O
+significant,O
+decreases,O
+of,O
+age,O
+-,O
+adjusted,O
+FTND,O
+(,O
+Z=-3.31,O
+,,O
+P<.005,O
+),O
+or,O
+RTQ,O
+scores,O
+(,O
+Z=-2.73,O
+,,O
+P=.006,O
+),O
+.,O
+ , 
+Our,O
+findings,O
+provide,O
+strong,O
+evidence,O
+suggesting,O
+a,O
+common,O
+CHRNA4,B-Gene
+haplotype,O
+might,O
+be,O
+protective,O
+against,O
+vulnerability,O
+to,O
+nicotine,O
+addiction,O
+in,O
+men,O
+.,O
+ , 
+#9915955
+Localization,O
+of,O
+a,O
+gene,O
+for,O
+familial,O
+hemophagocytic,O
+lymphohistiocytosis,O
+at,O
+chromosome,O
+9q21.3,O
+-,O
+22,O
+by,O
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+mapping,O
+.,O
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+Familial,O
+hemophagocytic,O
+lymphohistiocytosis,O
+(,O
+FHL,O
+),O
+,,O
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+known,O
+as,O
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+erythrophagocytic,O
+lymphohistiocytosis,O
+and,O
+familial,O
+histiocytic,O
+reticulosis,O
+,,O
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+a,O
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+recessive,O
+disorder,O
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+early,O
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+by,O
+excessive,O
+immune,O
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+.,O
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+Linkage,O
+of,O
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+disease,O
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+approximately,O
+7.8,O
+-,O
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+region,O
+between,O
+markers,O
+D9S1867,O
+and,O
+D9S1790,O
+at,O
+9q21.3,O
+-,O
+22,O
+was,O
+identified,O
+by,O
+homozygosity,O
+mapping,O
+in,O
+four,O
+inbred,O
+FHL,O
+families,O
+of,O
+Pakistani,O
+descent,O
+with,O
+a,O
+combined,O
+maximum,O
+multipoint,O
+LOD,O
+score,O
+of,O
+6.05,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+genetic,O
+locus,O
+to,O
+be,O
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+in,O
+FHL,O
+.,O
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+However,O
+,,O
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+descent,O
+across,O
+this,O
+interval,O
+could,O
+not,O
+be,O
+demonstrated,O
+in,O
+an,O
+additional,O
+affected,O
+kindred,O
+of,O
+Arab,O
+origin,O
+,,O
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+LOD,O
+score,O
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+-0.12,O
+.,O
+ , 
+The,O
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+significant,O
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+linkage,O
+to,O
+9q,O
+markers,O
+(,O
+LOD,O
+score,O
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+heterogeneity,O
+,,O
+5.00,O
+),O
+.,O
+ , 
+Identification,O
+of,O
+the,O
+gene(s,O
+),O
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+in,O
+the,O
+pathogenesis,O
+of,O
+FHL,O
+will,O
+contribute,O
+to,O
+an,O
+understanding,O
+of,O
+the,O
+control,O
+of,O
+T,O
+-,O
+lymphocyte,O
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+macrophage,O
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+,,O
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+is,O
+central,O
+to,O
+homeostasis,O
+in,O
+the,O
+immune,O
+system,O
+.,O
+ , 
+#8430703
+The,O
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+X,O
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+Xq27,O
+is,O
+most,O
+reasonably,O
+explained,O
+by,O
+ascertainment,O
+bias,O
+:,O
+heterozygous,O
+expression,O
+of,O
+recessive,O
+mutations,O
+is,O
+a,O
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+means,O
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+detecting,O
+unbalanced,O
+X,O
+inactivation,O
+.,O
+ , 
+#8723680
+Characterization,O
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+arylsulfatase,B-Gene
+A,I-Gene
+missense,O
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+D335V,B-SNP
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+T274,B-SNP
+M,I-SNP
+causing,O
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+.,O
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+Metachromatic,O
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+deficiency,O
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+arylsulfatase,B-Gene
+A.,I-Gene
+We,O
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+a,O
+novel,O
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+6,O
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+substitution,O
+of,O
+Asp335,B-SNP
+by,I-SNP
+Val,I-SNP
+.,I-SNP
+ , 
+In,O
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+transfections,O
+no,O
+enzyme,O
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+this,O
+mutation,O
+.,O
+ , 
+Examination,O
+of,O
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+effects,O
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+mutant,O
+enzyme,O
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+,,O
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+mutant,O
+enzyme,O
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+inactive,O
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+degraded,O
+in,O
+an,O
+early,O
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+compartment,O
+.,O
+ , 
+We,O
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+M,I-SNP
+),I-SNP
+.,O
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+The,O
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+Met274,B-SNP
+substituted,I-SNP
+arylsulfatase,I-SNP
+is,O
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+35,O
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+Most,O
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+.,O
+ , 
+#12474144
+Support,O
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+,,I-Gene
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+-,O
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+Genetic,O
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+(,O
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+.,O
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+There,O
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+significance,O
+of,O
+this,O
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+.,O
+ , 
+Since,O
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+gene,O
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+located,O
+in,O
+the,O
+center,O
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+the,O
+linkage,O
+peak,O
+on,O
+chromosome,O
+6p,O
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+we,O
+reported,O
+earlier,O
+,,O
+we,O
+decided,O
+to,O
+test,O
+six,O
+of,O
+the,O
+most,O
+positive,O
+DNA,O
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+in,O
+a,O
+sib,O
+-,O
+pair,O
+sample,O
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+in,O
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+independently,O
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+triads,O
+comprising,O
+203,O
+families,O
+,,O
+including,O
+the,O
+families,O
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+which,O
+we,O
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+on,O
+chromosome,O
+6p,O
+.,O
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+Evidence,O
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+in,O
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+sample,O
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+P=.00068,O
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+SNP,O
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+),O
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+Multilocus,O
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+significance,O
+further,O
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+.00002,O
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+a,O
+two,O
+-,O
+locus,O
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+.00001,O
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+a,O
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+-,O
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+Estimation,O
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+for,O
+six,O
+-,O
+locus,O
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+haplotype,O
+with,O
+a,O
+frequency,O
+of,O
+73.4,O
+%,O
+in,O
+transmitted,O
+,,O
+and,O
+only,O
+57.6,O
+%,O
+in,O
+nontransmitted,O
+,,O
+parental,O
+haplotypes,O
+.,O
+ , 
+All,O
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+six,O
+-,O
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+at,O
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+>,O
+1,O
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+less,O
+often,O
+transmitted,O
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+nontransmitted,O
+.,O
+ , 
+Our,O
+results,O
+represent,O
+a,O
+first,O
+successful,O
+replication,O
+of,O
+linkage,O
+disequilibrium,O
+in,O
+psychiatric,O
+genetics,O
+detected,O
+in,O
+a,O
+region,O
+with,O
+previous,O
+evidence,O
+of,O
+linkage,O
+and,O
+will,O
+encourage,O
+the,O
+search,O
+for,O
+causes,O
+of,O
+schizophrenia,O
+by,O
+the,O
+genetic,O
+approach,O
+.,O
+ , 
+#22503632
+SHANK1,B-Gene
+Deletions,O
+in,O
+Males,O
+with,O
+Autism,O
+Spectrum,O
+Disorder,O
+.,O
+ , 
+Recent,O
+studies,O
+have,O
+highlighted,O
+the,O
+involvement,O
+of,O
+rare,O
+(,O
+<,O
+1,O
+%,O
+frequency,O
+),O
+copy,O
+-,O
+number,O
+variations,O
+and,O
+point,O
+mutations,O
+in,O
+the,O
+genetic,O
+etiology,O
+of,O
+autism,O
+spectrum,O
+disorder,O
+(,O
+ASD,O
+),O
+;,O
+these,O
+variants,O
+particularly,O
+affect,O
+genes,O
+involved,O
+in,O
+the,O
+neuronal,O
+synaptic,O
+complex,O
+.,O
+ , 
+The,O
+SHANK,O
+gene,O
+family,O
+consists,O
+of,O
+three,O
+members,O
+(,B-Gene
+SHANK1,I-Gene
+,,I-Gene
+SHANK2,B-Gene
+,,I-Gene
+and,O
+SHANK3,B-Gene
+),I-Gene
+,,O
+which,O
+encode,O
+scaffolding,O
+proteins,O
+required,O
+for,O
+the,O
+proper,O
+formation,O
+and,O
+function,O
+of,O
+neuronal,O
+synapses,O
+.,O
+ , 
+Although,O
+SHANK2,B-Gene
+and,O
+SHANK3,B-Gene
+mutations,O
+have,O
+been,O
+implicated,O
+in,O
+ASD,O
+and,O
+intellectual,O
+disability,O
+,,O
+the,O
+involvement,O
+of,O
+SHANK1,B-Gene
+is,O
+unknown,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+assess,O
+microarray,O
+data,O
+from,O
+1,158,O
+Canadian,O
+and,O
+456,O
+European,O
+individuals,O
+with,O
+ASD,O
+to,O
+discover,O
+microdeletions,O
+at,O
+the,O
+SHANK1,B-Gene
+locus,O
+on,O
+chromosome,O
+19,O
+.,O
+ , 
+We,O
+identify,O
+a,O
+hemizygous,O
+SHANK1,B-Gene
+deletion,O
+that,O
+segregates,O
+in,O
+a,O
+four,O
+-,O
+generation,O
+family,O
+in,O
+which,O
+male,O
+carriers,O
+--,O
+but,O
+not,O
+female,O
+carriers,O
+--,O
+have,O
+ASD,O
+with,O
+higher,O
+functioning,O
+.,O
+ , 
+A,O
+de,O
+novo,O
+SHANK1,B-Gene
+deletion,O
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+also,O
+detected,O
+in,O
+an,O
+unrelated,O
+male,O
+individual,O
+with,O
+ASD,O
+with,O
+higher,O
+functioning,O
+,,O
+and,O
+no,O
+equivalent,O
+SHANK1,B-Gene
+mutations,O
+were,O
+found,O
+in,O
+>,O
+15,000,O
+controls,O
+(,O
+p,O
+=,O
+0.009,O
+),O
+.,O
+ , 
+The,O
+discovery,O
+of,O
+apparent,O
+reduced,O
+penetrance,O
+of,O
+ASD,O
+in,O
+females,O
+bearing,O
+inherited,O
+autosomal,O
+SHANK1,B-Gene
+deletions,O
+provides,O
+a,O
+possible,O
+contributory,O
+model,O
+for,O
+the,O
+male,O
+gender,O
+bias,O
+in,O
+autism,O
+.,O
+ , 
+The,O
+data,O
+are,O
+also,O
+informative,O
+for,O
+clinical,O
+-,O
+genetics,O
+interpretations,O
+of,O
+both,O
+inherited,O
+and,O
+sporadic,O
+forms,O
+of,O
+ASD,O
+involving,O
+SHANK1,B-Gene
+.,I-Gene
+ , 
+#15611928
+Fine,O
+mapping,O
+and,O
+positional,O
+candidate,O
+studies,O
+identify,O
+HLA,B-Gene
+-,I-Gene
+G,I-Gene
+as,O
+an,O
+asthma,O
+susceptibility,O
+gene,O
+on,O
+chromosome,O
+6p21,O
+.,O
+ , 
+Asthma,O
+affects,O
+nearly,O
+14,O
+million,O
+people,O
+worldwide,O
+and,O
+has,O
+been,O
+steadily,O
+increasing,O
+in,O
+frequency,O
+for,O
+the,O
+past,O
+50,O
+years,O
+.,O
+ , 
+Although,O
+environmental,O
+factors,O
+clearly,O
+influence,O
+the,O
+onset,O
+,,O
+progression,O
+,,O
+and,O
+severity,O
+of,O
+this,O
+disease,O
+,,O
+family,O
+and,O
+twin,O
+studies,O
+indicate,O
+that,O
+genetic,O
+variation,O
+also,O
+influences,O
+susceptibility,O
+.,O
+ , 
+Linkage,O
+of,O
+asthma,O
+and,O
+related,O
+phenotypes,O
+to,O
+chromosome,O
+6p21,O
+has,O
+been,O
+reported,O
+in,O
+seven,O
+genome,O
+screens,O
+,,O
+making,O
+it,O
+the,O
+most,O
+replicated,O
+region,O
+of,O
+the,O
+genome,O
+.,O
+ , 
+However,O
+,,O
+because,O
+many,O
+genes,O
+with,O
+individually,O
+small,O
+effects,O
+are,O
+likely,O
+to,O
+contribute,O
+to,O
+risk,O
+,,O
+identification,O
+of,O
+asthma,O
+susceptibility,O
+loci,O
+has,O
+been,O
+challenging,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+present,O
+evidence,O
+from,O
+four,O
+independent,O
+samples,O
+in,O
+support,O
+of,O
+HLA,B-Gene
+-,I-Gene
+G,I-Gene
+as,O
+a,O
+novel,O
+asthma,O
+and,O
+bronchial,O
+hyperresponsiveness,O
+susceptibility,O
+gene,O
+in,O
+the,O
+human,O
+leukocyte,O
+antigen,O
+region,O
+on,O
+chromosome,O
+6p21,O
+,,O
+and,O
+we,O
+speculate,O
+that,O
+this,O
+gene,O
+might,O
+contribute,O
+to,O
+risk,O
+for,O
+other,O
+inflammatory,O
+diseases,O
+that,O
+show,O
+linkage,O
+to,O
+this,O
+region,O
+.,O
+ , 
+#16917930
+Structural,O
+assessment,O
+of,O
+single,O
+amino,O
+acid,O
+mutations,O
+:,O
+application,O
+to,O
+TP53,B-Gene
+function,O
+.,O
+ , 
+Single,O
+amino,O
+acid,O
+substitution,O
+is,O
+the,O
+type,O
+of,O
+protein,O
+alteration,O
+most,O
+related,O
+to,O
+human,O
+diseases,O
+.,O
+ , 
+Current,O
+studies,O
+seek,O
+primarily,O
+to,O
+distinguish,O
+neutral,O
+mutations,O
+from,O
+harmful,O
+ones,O
+.,O
+ , 
+Very,O
+few,O
+methods,O
+offer,O
+an,O
+explanation,O
+of,O
+the,O
+final,O
+prediction,O
+result,O
+in,O
+terms,O
+of,O
+the,O
+probable,O
+structural,O
+or,O
+functional,O
+effect,O
+on,O
+the,O
+protein,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+describe,O
+the,O
+use,O
+of,O
+three,O
+novel,O
+parameters,O
+to,O
+identify,O
+experimentally,O
+-,O
+verified,O
+critical,O
+residues,O
+of,O
+the,O
+TP53,B-Gene
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+(,B-Gene
+p53,I-Gene
+),I-Gene
+.,O
+ , 
+The,O
+first,O
+two,O
+parameters,O
+make,O
+use,O
+of,O
+a,O
+surface,O
+clustering,O
+method,O
+to,O
+calculate,O
+the,O
+protein,O
+surface,O
+area,O
+of,O
+highly,O
+conserved,O
+regions,O
+or,O
+regions,O
+with,O
+high,O
+nonlocal,O
+atomic,O
+interaction,O
+energy,O
+(,O
+ANOLEA,O
+),O
+score,O
+.,O
+ , 
+These,O
+parameters,O
+help,O
+identify,O
+important,O
+functional,O
+regions,O
+on,O
+the,O
+surface,O
+of,O
+a,O
+protein,O
+.,O
+ , 
+The,O
+last,O
+parameter,O
+involves,O
+the,O
+use,O
+of,O
+a,O
+new,O
+method,O
+for,O
+pseudobinding,O
+free,O
+-,O
+energy,O
+estimation,O
+to,O
+specifically,O
+probe,O
+the,O
+importance,O
+of,O
+residue,O
+side,O
+-,O
+chains,O
+to,O
+the,O
+stability,O
+of,O
+protein,O
+fold,O
+.,O
+ , 
+A,O
+decision,O
+tree,O
+was,O
+designed,O
+to,O
+optimally,O
+combine,O
+these,O
+three,O
+parameters,O
+.,O
+ , 
+The,O
+result,O
+was,O
+compared,O
+to,O
+the,O
+functional,O
+data,O
+stored,O
+in,O
+the,O
+International,O
+Agency,O
+for,O
+Research,O
+on,O
+Cancer,O
+(,O
+IARC,O
+),O
+ , 
+TP53,B-Gene
+mutation,O
+database,O
+.,O
+ , 
+The,O
+final,O
+prediction,O
+achieved,O
+a,O
+prediction,O
+accuracy,O
+of,O
+70,O
+%,O
+and,O
+a,O
+Matthews,O
+correlation,O
+coefficient,O
+of,O
+0.45,O
+.,O
+ , 
+It,O
+also,O
+showed,O
+a,O
+high,O
+specificity,O
+of,O
+91.8,O
+%,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+85,O
+correctly,O
+identified,O
+important,O
+residues,O
+represented,O
+81.7,O
+%,O
+of,O
+the,O
+total,O
+mutations,O
+recorded,O
+in,O
+the,O
+database,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+the,O
+method,O
+was,O
+able,O
+to,O
+correctly,O
+assign,O
+a,O
+probable,O
+functional,O
+or,O
+structural,O
+role,O
+to,O
+the,O
+residues,O
+.,O
+ , 
+Such,O
+information,O
+could,O
+be,O
+critical,O
+for,O
+the,O
+interpretation,O
+and,O
+prediction,O
+of,O
+the,O
+effect,O
+of,O
+missense,O
+mutations,O
+,,O
+as,O
+it,O
+not,O
+only,O
+provided,O
+the,O
+fundamental,O
+explanation,O
+of,O
+the,O
+observed,O
+effect,O
+,,O
+but,O
+also,O
+helped,O
+design,O
+the,O
+most,O
+appropriate,O
+laboratory,O
+experiment,O
+to,O
+verify,O
+the,O
+prediction,O
+results,O
+.,O
+ , 
+#20579627
+X,O
+-,O
+linked,O
+cone,O
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+caused,O
+by,O
+mutation,O
+of,O
+the,O
+red,O
+and,O
+green,O
+cone,O
+opsins,O
+.,O
+ , 
+X,O
+-,O
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+cone,O
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+cone,O
+-,O
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+dystrophies,O
+(,O
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+XLCORD,O
+),O
+are,O
+a,O
+heterogeneous,O
+group,O
+of,O
+progressive,O
+disorders,O
+that,O
+solely,O
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+primarily,O
+affect,O
+cone,O
+photoreceptors,O
+.,O
+ , 
+Mutations,O
+in,O
+exon,O
+ORF15,O
+of,O
+the,O
+RPGR,B-Gene
+gene,O
+are,O
+the,O
+most,O
+common,O
+underlying,O
+cause,O
+.,O
+ , 
+In,O
+a,O
+previous,O
+study,O
+,,O
+we,O
+excluded,O
+RPGR,B-Gene
+exon,O
+ORF15,O
+in,O
+some,O
+families,O
+with,O
+XLCOD,O
+.,O
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+Here,O
+,,O
+we,O
+report,O
+genetic,O
+mapping,O
+of,O
+XLCOD,O
+to,O
+Xq26.1,O
+-,O
+qter,O
+.,O
+ , 
+A,O
+significant,O
+LOD,O
+score,O
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+detected,O
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+marker,O
+DXS8045,O
+(,O
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+=,O
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+[,O
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+ , 
+The,O
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+locus,O
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+the,O
+cone,O
+opsin,O
+gene,O
+array,O
+on,O
+Xq28,O
+.,O
+ , 
+Analysis,O
+of,O
+the,O
+array,O
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+a,O
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+(,B-SNP
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+529T,I-SNP
+>,I-SNP
+C,I-SNP
+ , 
+[,B-SNP
+p.,I-SNP
+W177R,I-SNP
+],I-SNP
+),O
+in,O
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+3,O
+of,O
+both,O
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+long,O
+-,O
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+(,B-SNP
+LW,I-SNP
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+),O
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+medium,O
+-,O
+wavelength,O
+-,O
+sensitive,O
+(,O
+MW,O
+,,O
+green,O
+),O
+cone,O
+opsin,O
+genes,O
+that,O
+segregated,O
+with,O
+disease,O
+.,O
+ , 
+Both,O
+exon,O
+3,O
+sequences,O
+were,O
+identical,O
+and,O
+were,O
+derived,O
+from,O
+the,O
+MW,O
+gene,O
+as,O
+a,O
+result,O
+of,O
+gene,O
+conversion,O
+.,O
+ , 
+The,O
+amino,O
+acid,O
+W177,O
+is,O
+highly,O
+conserved,O
+in,O
+visual,O
+and,O
+nonvisual,O
+opsins,O
+across,O
+species,O
+.,O
+ , 
+We,O
+show,O
+that,O
+W177R,B-SNP
+in,O
+MW,O
+opsin,O
+and,O
+the,O
+equivalent,O
+W161R,B-SNP
+mutation,O
+in,O
+rod,O
+opsin,O
+result,O
+in,O
+protein,O
+misfolding,O
+and,O
+retention,O
+in,O
+the,O
+endoplasmic,O
+reticulum,O
+.,O
+ , 
+We,O
+also,O
+demonstrate,O
+that,O
+W177R,B-SNP
+misfolding,O
+,,O
+unlike,O
+the,O
+P23H,B-SNP
+mutation,O
+in,O
+rod,O
+opsin,O
+that,O
+causes,O
+retinitis,O
+pigmentosa,O
+,,O
+is,O
+not,O
+rescued,O
+by,O
+treatment,O
+with,O
+the,O
+pharmacological,O
+chaperone,O
+9,O
+-,O
+cis,O
+-,O
+retinal,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+LW,O
+/,O
+MW,O
+cone,O
+opsin,O
+gene,O
+array,O
+can,O
+,,O
+therefore,O
+,,O
+lead,O
+to,O
+a,O
+spectrum,O
+of,O
+disease,O
+,,O
+ranging,O
+from,O
+color,O
+blindness,O
+to,O
+progressive,O
+cone,O
+dystrophy,O
+(,O
+XLCOD5,O
+),O
+.,O
+ , 
+#15800845
+Quantitative,O
+founder,O
+-,O
+effect,O
+analysis,O
+of,O
+French,O
+Canadian,O
+families,O
+identifies,O
+specific,O
+loci,O
+contributing,O
+to,O
+metabolic,O
+phenotypes,O
+of,O
+hypertension,O
+.,O
+ , 
+The,O
+Saguenay,O
+-,O
+Lac,O
+St,O
+-,O
+Jean,O
+population,O
+of,O
+Quebec,O
+is,O
+relatively,O
+isolated,O
+and,O
+has,O
+genealogical,O
+records,O
+dating,O
+to,O
+the,O
+17th,O
+-,O
+century,O
+French,O
+founders,O
+.,O
+ , 
+In,O
+120,O
+extended,O
+families,O
+with,O
+at,O
+least,O
+one,O
+sib,O
+pair,O
+affected,O
+with,O
+early,O
+-,O
+onset,O
+hypertension,O
+and/or,O
+dyslipidemia,O
+,,O
+we,O
+analyzed,O
+the,O
+genetic,O
+determinants,O
+of,O
+hypertension,O
+and,O
+related,O
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+metabolic,O
+conditions,O
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+Variance,O
+-,O
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+46,O
+loci,O
+after,O
+100,000,O
+permutations,O
+.,O
+ , 
+The,O
+most,O
+prominent,O
+clusters,O
+of,O
+overlapping,O
+quantitative,O
+-,O
+trait,O
+loci,O
+were,O
+on,O
+chromosomes,O
+1,O
+and,O
+3,O
+,,O
+a,O
+finding,O
+supported,O
+by,O
+principal,O
+-,O
+components,O
+and,O
+bivariate,O
+analyses,O
+.,O
+ , 
+These,O
+genetic,O
+determinants,O
+were,O
+further,O
+tested,O
+by,O
+classifying,O
+families,O
+by,O
+use,O
+of,O
+LOD,O
+score,O
+density,O
+analysis,O
+for,O
+each,O
+measured,O
+phenotype,O
+at,O
+every,O
+5,O
+cM.,O
+Our,O
+study,O
+showed,O
+the,O
+founder,O
+effect,O
+over,O
+several,O
+generations,O
+and,O
+classes,O
+of,O
+living,O
+individuals,O
+.,O
+ , 
+This,O
+quantitative,O
+genealogical,O
+approach,O
+supports,O
+the,O
+notion,O
+of,O
+the,O
+ancestral,O
+causality,O
+of,O
+traits,O
+uniquely,O
+present,O
+and,O
+inherited,O
+in,O
+distinct,O
+family,O
+classes,O
+.,O
+ , 
+With,O
+the,O
+founder,O
+effect,O
+,,O
+traits,O
+determined,O
+within,O
+population,O
+subsets,O
+are,O
+measurably,O
+and,O
+quantitatively,O
+transmitted,O
+through,O
+generational,O
+lineage,O
+,,O
+with,O
+a,O
+precise,O
+component,O
+contributing,O
+to,O
+phenotypic,O
+variance,O
+.,O
+ , 
+These,O
+methods,O
+should,O
+accelerate,O
+the,O
+uncovering,O
+of,O
+causal,O
+haplotypes,O
+in,O
+complex,O
+diseases,O
+such,O
+as,O
+hypertension,O
+and,O
+metabolic,O
+syndrome,O
+.,O
+ , 
+#10205286
+Genomewide,O
+Transmission,O
+/,O
+Disequilibrium,O
+testing,O
+:,O
+a,O
+correction,O
+.,O
+ , 
+#14695528
+Subtelomeric,O
+deletions,O
+detected,O
+in,O
+patients,O
+with,O
+idiopathic,O
+mental,O
+retardation,O
+using,O
+multiplex,O
+ligation,O
+-,O
+dependent,O
+probe,O
+amplification,O
+(,O
+MLPA,O
+),O
+.,O
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+Subtelomeric,O
+rearrangements,O
+are,O
+responsible,O
+for,O
+5,O
+%,O
+to,O
+10,O
+%,O
+of,O
+cases,O
+of,O
+unexplained,O
+mental,O
+retardation,O
+.,O
+ , 
+Despite,O
+their,O
+clinical,O
+relevance,O
+,,O
+methods,O
+to,O
+screen,O
+for,O
+these,O
+cytogenetically,O
+invisible,O
+abnormalities,O
+on,O
+a,O
+routine,O
+base,O
+are,O
+scarce,O
+.,O
+ , 
+We,O
+screened,O
+patients,O
+with,O
+idiopathic,O
+mental,O
+retardation,O
+for,O
+subtelomeric,O
+aberrations,O
+using,O
+multiplex,O
+ligation,O
+-,O
+dependent,O
+probe,O
+amplification,O
+(,O
+MLPA,O
+),O
+.,O
+ , 
+This,O
+recently,O
+developed,O
+technique,O
+is,O
+based,O
+on,O
+PCR,O
+amplification,O
+of,O
+ligated,O
+probes,O
+hybridized,O
+to,O
+chromosome,O
+ends,O
+.,O
+ , 
+Currently,O
+,,O
+41,O
+telomeres,O
+can,O
+be,O
+screened,O
+in,O
+just,O
+two,O
+multiplex,O
+reactions,O
+.,O
+ , 
+Four,O
+subtelomeric,O
+rearrangements,O
+(,O
+5.3,O
+%,O
+),O
+were,O
+detected,O
+in,O
+a,O
+group,O
+of,O
+75,O
+patients,O
+with,O
+mild,O
+to,O
+severe,O
+mental,O
+retardation,O
+in,O
+combination,O
+with,O
+dysmorphic,O
+features,O
+and/or,O
+a,O
+familial,O
+history,O
+of,O
+mental,O
+retardation,O
+:,O
+two,O
+terminal,O
+1p,O
+deletions,O
+,,O
+a,O
+terminal,O
+1q,O
+deletion,O
+,,O
+and,O
+a,O
+terminal,O
+3p,O
+deletion,O
+.,O
+ , 
+Deletions,O
+could,O
+be,O
+verified,O
+by,O
+FISH,O
+and,O
+marker,O
+analysis,O
+.,O
+ , 
+In,O
+one,O
+case,O
+the,O
+MLPA,O
+indicated,O
+a,O
+terminal,O
+21q,O
+deletion,O
+due,O
+to,O
+a,O
+3,O
+-,O
+bp,O
+deletion,O
+at,O
+the,O
+site,O
+of,O
+the,O
+probe,O
+,,O
+giving,O
+a,O
+false,O
+-,O
+positive,O
+rate,O
+of,O
+1.3,O
+%,O
+.,O
+ , 
+This,O
+study,O
+demonstrates,O
+that,O
+MLPA,O
+is,O
+a,O
+fast,O
+and,O
+reliable,O
+screening,O
+method,O
+,,O
+potentially,O
+suitable,O
+for,O
+use,O
+in,O
+routine,O
+diagnostics,O
+.,O
+ , 
+#10677322
+Estimation,O
+of,O
+variance,O
+components,O
+of,O
+quantitative,O
+traits,O
+in,O
+inbred,O
+populations,O
+.,O
+ , 
+Use,O
+of,O
+variance,O
+-,O
+component,O
+estimation,O
+for,O
+mapping,O
+of,O
+quantitative,O
+-,O
+trait,O
+loci,O
+in,O
+humans,O
+is,O
+a,O
+subject,O
+of,O
+great,O
+current,O
+interest,O
+.,O
+ , 
+When,O
+only,O
+trait,O
+values,O
+,,O
+not,O
+genotypic,O
+information,O
+,,O
+are,O
+considered,O
+,,O
+variance,O
+-,O
+component,O
+estimation,O
+can,O
+also,O
+be,O
+used,O
+to,O
+estimate,O
+heritability,O
+of,O
+a,O
+quantitative,O
+trait,O
+.,O
+ , 
+Inbred,O
+pedigrees,O
+present,O
+special,O
+challenges,O
+for,O
+variance,O
+-,O
+component,O
+estimation,O
+.,O
+ , 
+First,O
+,,O
+there,O
+are,O
+more,O
+variance,O
+components,O
+to,O
+be,O
+estimated,O
+in,O
+the,O
+inbred,O
+case,O
+,,O
+even,O
+for,O
+a,O
+relatively,O
+simple,O
+model,O
+including,O
+additive,O
+,,O
+dominance,O
+,,O
+and,O
+environmental,O
+effects,O
+.,O
+ , 
+Second,O
+,,O
+more,O
+identity,O
+coefficients,O
+need,O
+to,O
+be,O
+calculated,O
+from,O
+an,O
+inbred,O
+pedigree,O
+in,O
+order,O
+to,O
+perform,O
+the,O
+estimation,O
+,,O
+and,O
+these,O
+are,O
+computationally,O
+more,O
+difficult,O
+to,O
+obtain,O
+in,O
+the,O
+inbred,O
+than,O
+in,O
+the,O
+outbred,O
+case,O
+.,O
+ , 
+As,O
+a,O
+result,O
+,,O
+inbreeding,O
+effects,O
+have,O
+generally,O
+been,O
+ignored,O
+in,O
+practice,O
+.,O
+ , 
+We,O
+describe,O
+here,O
+the,O
+calculation,O
+of,O
+identity,O
+coefficients,O
+and,O
+estimation,O
+of,O
+variance,O
+components,O
+of,O
+quantitative,O
+traits,O
+in,O
+large,O
+inbred,O
+pedigrees,O
+,,O
+using,O
+the,O
+example,O
+of,O
+HDL,B-Gene
+in,O
+the,O
+Hutterites,O
+.,O
+ , 
+We,O
+use,O
+a,O
+multivariate,O
+normal,O
+model,O
+for,O
+the,O
+genetic,O
+effects,O
+,,O
+extending,O
+the,O
+central,O
+-,O
+limit,O
+theorem,O
+of,O
+Lange,O
+to,O
+allow,O
+for,O
+both,O
+inbreeding,O
+and,O
+dominance,O
+under,O
+the,O
+assumptions,O
+of,O
+our,O
+variance,O
+-,O
+component,O
+model,O
+.,O
+ , 
+We,O
+use,O
+simulated,O
+examples,O
+to,O
+give,O
+an,O
+indication,O
+of,O
+under,O
+what,O
+conditions,O
+one,O
+has,O
+the,O
+power,O
+to,O
+detect,O
+the,O
+additional,O
+variance,O
+components,O
+and,O
+to,O
+examine,O
+their,O
+impact,O
+on,O
+variance,O
+-,O
+component,O
+estimation,O
+.,O
+ , 
+We,O
+discuss,O
+the,O
+implications,O
+for,O
+mapping,O
+and,O
+heritability,O
+estimation,O
+by,O
+use,O
+of,O
+variance,O
+components,O
+in,O
+inbred,O
+populations,O
+.,O
+ , 
+#8940265
+Mucopolysaccharidosis,O
+type,O
+II,O
+(,O
+Hunter,O
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+):,O
+mutation,O
+",O
+hot,O
+spots,O
+",O
+in,O
+the,O
+iduronate-2,B-Gene
+-,I-Gene
+sulfatase,I-Gene
+gene,O
+.,O
+ , 
+Mucopolysaccharidosis,O
+type,O
+II,O
+(,O
+MPS,O
+II,O
+,,O
+Hunter,O
+syndrome,O
+),O
+is,O
+an,O
+X,O
+-,O
+chromosomal,O
+storage,O
+disorder,O
+due,O
+to,O
+deficiency,O
+of,O
+the,O
+lysosomal,O
+enzyme,O
+iduronate-2,B-Gene
+-,I-Gene
+sulfatase,I-Gene
+(,B-Gene
+IDS,I-Gene
+),I-Gene
+.,O
+ , 
+We,O
+have,O
+identified,O
+IDS,B-Gene
+mutations,O
+in,O
+a,O
+total,O
+of,O
+31,O
+families,O
+/,O
+patients,O
+with,O
+MPS,O
+II,O
+,,O
+of,O
+which,O
+20,O
+are,O
+novel,O
+and,O
+unique,O
+and,O
+a,O
+further,O
+1,O
+is,O
+novel,O
+but,O
+has,O
+been,O
+found,O
+in,O
+3,O
+unrelated,O
+patients,O
+.,O
+ , 
+One,O
+of,O
+the,O
+mutations,O
+detected,O
+is,O
+of,O
+special,O
+interest,O
+as,O
+an,O
+AG-->G,O
+substitution,O
+in,O
+an,O
+intron,O
+,,O
+far,O
+apart,O
+from,O
+the,O
+coding,O
+region,O
+,,O
+is,O
+deleterious,O
+by,O
+creating,O
+a,O
+new,O
+5'-splice,O
+-,O
+donor,O
+site,O
+that,O
+results,O
+in,O
+the,O
+inclusion,O
+of,O
+a,O
+78,O
+-,O
+bp,O
+intronic,O
+sequence,O
+.,O
+ , 
+While,O
+the,O
+distribution,O
+of,O
+gene,O
+rearrangements,O
+(,O
+deletions,O
+,,O
+insertions,O
+,,O
+and,O
+duplications,O
+),O
+of,O
+<,O
+20,O
+bp,O
+seems,O
+to,O
+be,O
+random,O
+over,O
+the,O
+IDS,B-Gene
+gene,O
+,,O
+the,O
+analysis,O
+of,O
+a,O
+total,O
+of,O
+101,O
+point,O
+mutations,O
+lying,O
+within,O
+the,O
+coding,O
+region,O
+shows,O
+that,O
+they,O
+tend,O
+to,O
+be,O
+more,O
+frequent,O
+in,O
+exons,O
+III,O
+,,O
+VIII,O
+,,O
+and,O
+IX,O
+.,O
+ , 
+Forty,O
+-,O
+seven,O
+percent,O
+of,O
+the,O
+point,O
+mutations,O
+are,O
+at,O
+CpG,O
+dinucleotides,O
+,,O
+of,O
+which,O
+G,O
+:,O
+C,O
+-,O
+to,O
+-,O
+A,O
+:,O
+T,O
+transitions,O
+constitute,O
+nearly,O
+80,O
+%,O
+.,O
+ , 
+Almost,O
+all,O
+recurrent,O
+point,O
+mutations,O
+involve,O
+CpG,O
+sites,O
+.,O
+ , 
+Analysis,O
+of,O
+a,O
+collective,O
+of,O
+50,O
+families,O
+studied,O
+in,O
+our,O
+laboratory,O
+,,O
+to,O
+date,O
+,,O
+revealed,O
+that,O
+mutations,O
+occur,O
+more,O
+frequently,O
+in,O
+male,O
+meioses,O
+(,O
+estimated,O
+male,O
+-,O
+to,O
+-,O
+female,O
+ratio,O
+between,O
+3.76,O
+and,O
+6.3,O
+),O
+.,O
+ , 
+#8723688
+Two,O
+novel,O
+frameshift,O
+mutations,O
+causing,O
+premature,O
+stop,O
+codons,O
+in,O
+a,O
+patient,O
+with,O
+the,O
+severe,O
+form,O
+of,O
+Maroteaux,O
+-,O
+Lamy,O
+syndrome,O
+.,O
+ , 
+#8651286
+Finding,O
+genes,O
+on,O
+the,O
+X,O
+chromosome,O
+by,O
+which,O
+homo,O
+may,O
+have,O
+become,O
+sapiens,O
+.,O
+ , 
+#16380917
+Robust,O
+estimation,O
+of,O
+experimentwise,O
+P,O
+values,O
+applied,O
+to,O
+a,O
+genome,O
+scan,O
+of,O
+multiple,O
+asthma,O
+traits,O
+identifies,O
+a,O
+new,O
+region,O
+of,O
+significant,O
+linkage,O
+on,O
+chromosome,O
+20q13,O
+.,O
+ , 
+Over,O
+30,O
+genomic,O
+regions,O
+show,O
+linkage,O
+to,O
+asthma,O
+traits,O
+.,O
+ , 
+Six,O
+asthma,O
+genes,O
+have,O
+been,O
+cloned,O
+,,O
+but,O
+the,O
+putative,O
+loci,O
+in,O
+many,O
+linked,O
+regions,O
+have,O
+not,O
+been,O
+identified,O
+.,O
+ , 
+To,O
+search,O
+for,O
+asthma,O
+susceptibility,O
+loci,O
+,,O
+we,O
+performed,O
+genomewide,O
+univariate,O
+linkage,O
+analyses,O
+of,O
+seven,O
+asthma,O
+traits,O
+,,O
+using,O
+202,O
+Australian,O
+families,O
+ascertained,O
+through,O
+a,O
+twin,O
+proband,O
+.,O
+ , 
+House,O
+-,O
+dust,O
+mite,O
+sensitivity,O
+(,O
+Dpter,O
+),O
+exceeded,O
+the,O
+empirical,O
+threshold,O
+for,O
+significant,O
+linkage,O
+at,O
+102,O
+cM,O
+on,O
+chromosome,O
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+,,O
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+marker,O
+D20S173,O
+(,O
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+pointwise,O
+P,O
+=,O
+.00001,O
+ , 
+and,O
+genomewide,O
+P,O
+=,O
+.005,O
+,,O
+both,O
+uncorrected,O
+for,O
+multiple,O
+-,O
+trait,O
+testing,O
+),O
+.,O
+ , 
+Atopy,O
+,,O
+bronchial,O
+hyperresponsiveness,O
+(,O
+BHR,O
+),O
+,,O
+and,O
+forced,O
+expiratory,O
+volume,O
+in,O
+1,O
+s,O
+(,O
+FEV1,O
+),O
+were,O
+also,O
+linked,O
+to,O
+this,O
+region,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+16,O
+regions,O
+were,O
+linked,O
+to,O
+at,O
+least,O
+one,O
+trait,O
+at,O
+the,O
+suggestive,O
+level,O
+,,O
+including,O
+12q24,O
+,,O
+which,O
+has,O
+consistently,O
+shown,O
+linkage,O
+to,O
+asthma,O
+traits,O
+in,O
+other,O
+studies,O
+.,O
+ , 
+Some,O
+regions,O
+were,O
+expected,O
+to,O
+be,O
+false,O
+-,O
+positives,O
+arising,O
+from,O
+multiple,O
+-,O
+trait,O
+testing,O
+.,O
+ , 
+To,O
+address,O
+this,O
+,,O
+we,O
+developed,O
+a,O
+new,O
+approach,O
+to,O
+estimate,O
+genomewide,O
+significance,O
+that,O
+accounts,O
+for,O
+multiple,O
+-,O
+trait,O
+testing,O
+and,O
+for,O
+correlation,O
+between,O
+traits,O
+and,O
+that,O
+does,O
+not,O
+require,O
+a,O
+Bonferroni,O
+correction,O
+.,O
+ , 
+With,O
+this,O
+approach,O
+,,O
+Dpter,O
+remained,O
+significantly,O
+linked,O
+to,O
+20q13,O
+(,O
+empirical,O
+genomewide,O
+P,O
+=,O
+.042,O
+),O
+,,O
+and,O
+airway,O
+obstruction,O
+remained,O
+linked,O
+to,O
+12q24,O
+at,O
+the,O
+suggestive,O
+level,O
+.,O
+ , 
+Finally,O
+,,O
+we,O
+extended,O
+this,O
+method,O
+to,O
+show,O
+that,O
+the,O
+linkage,O
+of,O
+Dpter,O
+,,O
+atopy,O
+,,O
+BHR,O
+,,O
+FEV1,O
+,,O
+asthma,O
+,,O
+and,O
+airway,O
+obstruction,O
+to,O
+chromosome,O
+20q13,O
+is,O
+unlikely,O
+to,O
+be,O
+due,O
+to,O
+chance,O
+and,O
+may,O
+result,O
+from,O
+a,O
+quantitative,O
+trait,O
+locus,O
+in,O
+this,O
+region,O
+that,O
+affects,O
+several,O
+of,O
+these,O
+traits,O
+.,O
+ , 
+#21901788
+Estimating,O
+the,O
+degree,O
+of,O
+identity,O
+by,O
+descent,O
+in,O
+consanguineous,O
+couples,O
+.,O
+ , 
+In,O
+some,O
+clinical,O
+and,O
+research,O
+settings,O
+,,O
+it,O
+is,O
+often,O
+necessary,O
+to,O
+identify,O
+the,O
+true,O
+level,O
+of,O
+",O
+identity,O
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+descent,O
+",O
+(,O
+IBD,O
+),O
+between,O
+two,O
+individuals,O
+.,O
+ , 
+However,O
+,,O
+as,O
+the,O
+individuals,O
+become,O
+more,O
+distantly,O
+related,O
+,,O
+it,O
+is,O
+increasingly,O
+difficult,O
+to,O
+accurately,O
+calculate,O
+this,O
+value,O
+.,O
+ , 
+Consequently,O
+,,O
+we,O
+have,O
+developed,O
+a,O
+computer,O
+program,O
+that,O
+uses,O
+genome,O
+-,O
+wide,O
+SNP,O
+genotype,O
+data,O
+from,O
+related,O
+individuals,O
+to,O
+estimate,O
+the,O
+size,O
+and,O
+extent,O
+of,O
+IBD,O
+in,O
+their,O
+genomes,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+the,O
+software,O
+can,O
+compare,O
+a,O
+couple,O
+'s,O
+IBD,O
+regions,O
+with,O
+either,O
+the,O
+autozygous,O
+regions,O
+of,O
+a,O
+relative,O
+affected,O
+by,O
+an,O
+autosomal,O
+recessive,O
+disease,O
+of,O
+unknown,O
+cause,O
+,,O
+or,O
+the,O
+IBD,O
+regions,O
+in,O
+the,O
+parents,O
+of,O
+the,O
+affected,O
+relative,O
+.,O
+ , 
+It,O
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+then,O
+possible,O
+to,O
+calculate,O
+the,O
+probability,O
+of,O
+one,O
+of,O
+the,O
+couple,O
+'s,O
+children,O
+suffering,O
+from,O
+the,O
+same,O
+disease,O
+.,O
+ , 
+The,O
+software,O
+works,O
+by,O
+finding,O
+SNPs,O
+that,O
+exclude,O
+any,O
+possible,O
+IBD,O
+and,O
+then,O
+identifies,O
+regions,O
+that,O
+lack,O
+these,O
+SNPs,O
+,,O
+while,O
+exceeding,O
+a,O
+minimum,O
+size,O
+and,O
+number,O
+of,O
+SNPs,O
+.,O
+ , 
+The,O
+accuracy,O
+of,O
+the,O
+algorithm,O
+was,O
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+by,O
+estimating,O
+the,O
+pairwise,O
+IBD,O
+between,O
+different,O
+members,O
+of,O
+a,O
+large,O
+pedigree,O
+with,O
+varying,O
+known,O
+coefficients,O
+of,O
+genetic,O
+relationship,O
+(,O
+CGR,O
+),O
+.,O
+ , 
+#15714686
+2004,O
+William,O
+Allan,O
+Award,O
+address,O
+.,O
+ , 
+Cloning,O
+of,O
+the,O
+DMD,B-Gene
+gene,O
+.,O
+ , 
+#16826533
+Mutations,O
+in,O
+WNT7A,B-Gene
+cause,O
+a,O
+range,O
+of,O
+limb,O
+malformations,O
+,,O
+including,O
+Fuhrmann,O
+syndrome,O
+and,O
+Al,O
+-,O
+Awadi,O
+/,O
+Raas,O
+-,O
+Rothschild,O
+/,O
+Schinzel,O
+phocomelia,O
+syndrome,O
+.,O
+ , 
+Fuhrmann,O
+syndrome,O
+and,O
+the,O
+Al,O
+-,O
+Awadi,O
+/,O
+Raas,O
+-,O
+Rothschild,O
+/,O
+Schinzel,O
+phocomelia,O
+syndrome,O
+are,O
+considered,O
+to,O
+be,O
+distinct,O
+limb,O
+-,O
+malformation,O
+disorders,O
+characterized,O
+by,O
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+degrees,O
+of,O
+limb,O
+aplasia,O
+/,O
+hypoplasia,O
+and,O
+joint,O
+dysplasia,O
+in,O
+humans,O
+.,O
+ , 
+In,O
+families,O
+with,O
+these,O
+syndromes,O
+,,O
+we,O
+found,O
+homozygous,O
+missense,O
+mutations,O
+in,O
+the,O
+dorsoventral,B-Gene
+-,I-Gene
+patterning,I-Gene
+gene,O
+WNT7A,B-Gene
+and,O
+confirmed,O
+their,O
+functional,O
+significance,O
+in,O
+retroviral,O
+-,O
+mediated,O
+transfection,O
+of,O
+chicken,O
+mesenchyme,O
+cell,O
+cultures,O
+and,O
+developing,O
+limbs,O
+.,O
+ , 
+The,O
+results,O
+suggest,O
+that,O
+a,O
+partial,O
+loss,O
+of,O
+WNT7A,B-Gene
+function,O
+causes,O
+Fuhrmann,O
+syndrome,O
+(,O
+and,O
+a,O
+phenotype,O
+similar,O
+to,O
+mouse,O
+Wnt7a,B-Gene
+knockout,O
+),O
+,,O
+whereas,O
+the,O
+more,O
+-,O
+severe,O
+limb,O
+truncation,O
+phenotypes,O
+observed,O
+in,O
+Al,O
+-,O
+Awadi,O
+/,O
+Raas,O
+-,O
+Rothschild,O
+/,O
+Schinzel,O
+phocomelia,O
+syndrome,O
+result,O
+from,O
+null,O
+mutations,O
+(,O
+and,O
+cause,O
+a,O
+phenotype,O
+similar,O
+to,O
+mouse,O
+Shh,O
+knockout,O
+),O
+.,O
+ , 
+These,O
+findings,O
+illustrate,O
+the,O
+specific,O
+and,O
+conserved,O
+importance,O
+of,O
+WNT7A,B-Gene
+in,O
+multiple,O
+aspects,O
+of,O
+vertebrate,O
+limb,O
+development,O
+.,O
+ , 
+#17579354
+Women,O
+heterozygous,O
+for,O
+NALP7,B-Gene
+/,B-Gene
+NLRP7,I-Gene
+mutations,O
+are,O
+at,O
+risk,O
+for,O
+reproductive,O
+wastage,O
+:,O
+report,O
+of,O
+two,O
+novel,O
+mutations,O
+.,O
+ , 
+Familial,O
+recurrent,O
+hydatidiform,O
+moles,O
+are,O
+a,O
+rare,O
+recessive,O
+condition,O
+in,O
+which,O
+molar,O
+tissues,O
+have,O
+biparental,O
+contribution,O
+to,O
+their,O
+genome,O
+.,O
+ , 
+One,O
+maternal,O
+locus,O
+responsible,O
+for,O
+this,O
+condition,O
+has,O
+been,O
+mapped,O
+to,O
+19q13.4,O
+and,O
+the,O
+causative,O
+gene,O
+,,O
+NALP7,B-Gene
+,,I-Gene
+identified,O
+(,O
+HUGO,O
+-,O
+approved,O
+nomenclature,O
+is,O
+now,O
+NLRP7,B-Gene
+),I-Gene
+.,O
+ , 
+Here,O
+we,O
+report,O
+a,O
+first,O
+stop,O
+codon,O
+,,O
+c.295G,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+Glu99X,I-SNP
+),I-SNP
+and,O
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+missense,O
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+,,O
+c.1970A,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+Asp657Val,I-SNP
+),I-SNP
+in,O
+NLRP7,B-Gene
+in,O
+two,O
+sisters,O
+with,O
+RHMs,O
+.,O
+ , 
+We,O
+found,O
+these,O
+two,O
+mutations,O
+and,O
+a,O
+previously,O
+reported,O
+one,O
+,,O
+c.2078G,B-SNP
+>,I-SNP
+C,I-SNP
+(,B-SNP
+p.,I-SNP
+Arg693Pro,I-SNP
+),I-SNP
+in,O
+a,O
+homozygous,O
+state,O
+,,O
+in,O
+males,O
+with,O
+normal,O
+reproductive,O
+outcomes,O
+.,O
+ , 
+This,O
+suggests,O
+that,O
+NLRP7,B-Gene
+is,O
+not,O
+required,O
+for,O
+normal,O
+spermatogenesis,O
+.,O
+ , 
+The,O
+mother,O
+of,O
+the,O
+patients,O
+is,O
+heterozygous,O
+for,O
+Glu99X,B-SNP
+and,O
+had,O
+one,O
+stillbirth,O
+and,O
+three,O
+normal,O
+pregnancies,O
+.,O
+ , 
+Our,O
+data,O
+on,O
+this,O
+new,O
+family,O
+and,O
+on,O
+heterozygous,O
+women,O
+from,O
+previously,O
+reported,O
+families,O
+indicate,O
+that,O
+women,O
+heterozygous,O
+for,O
+NLRP7,B-Gene
+mutations,O
+are,O
+at,O
+risk,O
+for,O
+reproductive,O
+wastage,O
+without,O
+the,O
+manifestation,O
+of,O
+molar,O
+phenotype,O
+.,O
+ , 
+#15514891
+Polymorphisms,O
+in,O
+the,O
+sclerosteosis,B-Gene
+/,I-Gene
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+Buchem,I-Gene
+disease,I-Gene
+gene,O
+(,B-Gene
+SOST,I-Gene
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+bone,O
+-,O
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+in,O
+elderly,O
+whites,O
+.,O
+ , 
+Osteoporosis,O
+has,O
+a,O
+strong,O
+genetic,O
+component,O
+,,O
+but,O
+the,O
+genes,O
+involved,O
+are,O
+poorly,O
+defined,O
+.,O
+ , 
+We,O
+studied,O
+whether,O
+the,O
+sclerosteosis,B-Gene
+/,I-Gene
+van,I-Gene
+Buchem,I-Gene
+disease,I-Gene
+gene,O
+(,B-Gene
+SOST,I-Gene
+),I-Gene
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+an,O
+osteoporosis,O
+-,O
+risk,O
+gene,O
+by,O
+examining,O
+its,O
+association,O
+with,O
+bone,O
+-,O
+mineral,O
+density,O
+(,O
+BMD,O
+),O
+.,O
+ , 
+Mutations,O
+in,O
+SOST,B-Gene
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+in,O
+sclerosteosis,O
+,,O
+and,O
+alterations,O
+in,O
+the,O
+SOST,B-Gene
+gene,O
+expression,O
+may,O
+be,O
+causal,O
+in,O
+the,O
+closely,O
+related,O
+van,O
+Buchem,O
+disease,O
+.,O
+ , 
+We,O
+used,O
+a,O
+set,O
+of,O
+eight,O
+polymorphisms,O
+from,O
+the,O
+SOST,B-Gene
+gene,O
+region,O
+to,O
+genotype,O
+1,939,O
+elderly,O
+men,O
+and,O
+women,O
+from,O
+a,O
+large,O
+population,O
+-,O
+based,O
+prospective,O
+-,O
+cohort,O
+study,O
+of,O
+Dutch,O
+whites,O
+.,O
+ , 
+A,O
+3,O
+-,O
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+(,O
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+presumed,O
+SOST,B-Gene
+promoter,O
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+(,B-Gene
+SRP3,I-Gene
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+the,O
+femoral,O
+neck,O
+(,O
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+),O
+(,O
+P=.05,O
+),O
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+(,O
+LS,O
+),O
+(,O
+P=.01,O
+),O
+,,O
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+evidence,O
+of,O
+an,O
+allele,O
+-,O
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+in,O
+the,O
+oldest,O
+age,O
+group,O
+(,O
+P=.006,O
+),O
+.,O
+ , 
+Similarly,O
+,,O
+a,O
+G,O
+variant,O
+(,O
+f=0.40,O
+),O
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+the,O
+van,O
+Buchem,O
+deletion,O
+region,O
+(,B-Gene
+SRP9,I-Gene
+),I-Gene
+was,O
+associated,O
+with,O
+increased,O
+BMD,O
+in,O
+men,O
+at,O
+the,O
+FN,O
+(,O
+P=.007,O
+),O
+and,O
+LS,O
+(,O
+P=.02,O
+),O
+.,O
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+In,O
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+cases,O
+,,O
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+between,O
+extreme,O
+genotypes,O
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+0.2,O
+SD,O
+.,O
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+We,O
+observed,O
+no,O
+genotype,O
+effects,O
+on,O
+fracture,O
+risk,O
+,,O
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+the,O
+234,O
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+fractures,O
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+8.2,O
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+-,O
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+and,O
+for,O
+the,O
+146,O
+vertebral,O
+prevalent,O
+fractures,O
+analyzed,O
+.,O
+ , 
+We,O
+did,O
+not,O
+find,O
+association,O
+between,O
+any,O
+of,O
+several,O
+frequent,O
+haplotypes,O
+across,O
+the,O
+SOST,B-Gene
+gene,O
+region,O
+and,O
+BMD,O
+.,O
+ , 
+We,O
+did,O
+find,O
+evidence,O
+of,O
+additive,O
+effects,O
+of,O
+SRP3,B-Gene
+with,O
+the,O
+COLIA1,B-Gene
+Sp1,O
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+not,O
+with,O
+haplotypes,O
+of,O
+3,O
+',O
+polymorphisms,O
+in,O
+the,O
+vitamin,O
+-,O
+D,O
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+The,O
+SOST,B-Gene
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+age,O
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+0.5,O
+SD,O
+difference,O
+in,O
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+at,O
+LS,O
+in,O
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+oldest,O
+age,O
+group,O
+(,O
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+The,O
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+these,O
+moderate,O
+SOST,B-Gene
+genotype,O
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+mediated,O
+remains,O
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+be,O
+elucidated,O
+,,O
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+it,O
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+#7977360
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+Unbalanced,O
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+fetal,O
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+ , 
+The,O
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+.,O
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+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+four,O
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+of,O
+de,O
+novo,O
+secondary,O
+trisomy,O
+13,O
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+presented,O
+.,O
+ , 
+FISH,O
+using,O
+alpha,O
+-,O
+satellite,O
+sequences,O
+,,O
+rDNA,O
+,,O
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+a,O
+pTRI-6,O
+satellite,O
+I,O
+sequence,O
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+to,O
+the,O
+short,O
+arm,O
+of,O
+chromosome,O
+13,O
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+ribosomal,O
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+Three,O
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+this,O
+sequence,O
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+the,O
+rearrangement,O
+,,O
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+both,O
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+strong,O
+positive,O
+hybridization,O
+signals,O
+.,O
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+Eleven,O
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+used,O
+to,O
+characterize,O
+the,O
+rearrangements,O
+.,O
+ , 
+Of,O
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+four,O
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+,,O
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+translocation,O
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+.,O
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+A,O
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+derived,O
+rob(13q13q,O
+),O
+.,O
+ , 
+No,O
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+in,O
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+isochromosome,O
+.,O
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+The,O
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+molecular,O
+chromosomal,O
+structure,O
+of,O
+these,O
+cases,O
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+previous,O
+studies,O
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+de,O
+novo,O
+acrocentric,O
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+ , 
+#10712212
+The,O
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+human,O
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+:,O
+a,O
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+mitochondrial,O
+,,O
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+,,O
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+Y,O
+-,O
+chromosome,O
+data,O
+.,O
+ , 
+We,O
+report,O
+a,O
+comparison,O
+of,O
+worldwide,O
+genetic,O
+variation,O
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+255,O
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+autosomal,O
+,,O
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+,,O
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+Y,O
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+Variation,O
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+use,O
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+30,O
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+(,O
+RSPs,O
+),O
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+60,O
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+-,O
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+-,O
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+(,O
+STRPs,O
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+LINE-1,O
+element,O
+,,O
+611,O
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+-,O
+region,O
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+10,O
+Y,O
+-,O
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+.,O
+ , 
+Analysis,O
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+these,O
+data,O
+reveals,O
+substantial,O
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+among,O
+this,O
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+array,O
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+genetic,O
+systems,O
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+With,O
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+Europeans,O
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+Africans,O
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+largest,O
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+unique,O
+alleles,O
+,,O
+for,O
+most,O
+systems,O
+.,O
+ , 
+GST,O
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+11%-18,O
+%,O
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+the,O
+autosomal,O
+systems,O
+and,O
+are,O
+two,O
+to,O
+three,O
+times,O
+higher,O
+for,O
+the,O
+mtDNA,O
+sequence,O
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+Y,O
+-,O
+chromosome,O
+RSPs,O
+.,O
+ , 
+This,O
+difference,O
+is,O
+expected,O
+because,O
+of,O
+the,O
+lower,O
+effective,O
+population,O
+size,O
+of,O
+mtDNA,O
+and,O
+Y,O
+chromosomes,O
+.,O
+ , 
+A,O
+lower,O
+value,O
+is,O
+seen,O
+for,O
+Y,O
+-,O
+chromosome,O
+STRs,O
+,,O
+reflecting,O
+a,O
+relative,O
+lack,O
+of,O
+continental,O
+population,O
+structure,O
+,,O
+as,O
+a,O
+result,O
+of,O
+rapid,O
+mutation,O
+and,O
+genetic,O
+drift,O
+.,O
+ , 
+Africa,O
+has,O
+higher,O
+GST,O
+values,O
+than,O
+does,O
+either,O
+Europe,O
+or,O
+Asia,O
+for,O
+all,O
+systems,O
+except,O
+the,O
+Y,O
+-,O
+chromosome,O
+STRs,O
+and,O
+Alus,O
+.,O
+ , 
+All,O
+systems,O
+except,O
+the,O
+Y,O
+-,O
+chromosome,O
+STRs,O
+show,O
+less,O
+variation,O
+between,O
+populations,O
+within,O
+continents,O
+than,O
+between,O
+continents,O
+.,O
+ , 
+These,O
+results,O
+are,O
+reassuring,O
+in,O
+their,O
+consistency,O
+and,O
+offer,O
+broad,O
+support,O
+for,O
+an,O
+African,O
+origin,O
+of,O
+modern,O
+human,O
+populations,O
+.,O
+ , 
+#12474146
+A,O
+susceptibility,O
+gene,O
+for,O
+psoriatic,O
+arthritis,O
+maps,O
+to,O
+chromosome,O
+16q,O
+:,O
+evidence,O
+for,O
+imprinting,O
+.,O
+ , 
+Several,O
+genetic,O
+loci,O
+have,O
+been,O
+reported,O
+for,O
+psoriasis,O
+,,O
+but,O
+none,O
+has,O
+been,O
+specifically,O
+linked,O
+to,O
+psoriatic,O
+arthritis,O
+(,O
+PsA,O
+),O
+,,O
+a,O
+condition,O
+that,O
+affects,O
+>,O
+10,O
+%,O
+of,O
+patients,O
+with,O
+psoriasis,O
+.,O
+ , 
+A,O
+genetic,O
+component,O
+for,O
+PsA,O
+is,O
+suggested,O
+by,O
+segregation,O
+within,O
+families,O
+and,O
+high,O
+concordance,O
+among,O
+identical,O
+twins,O
+.,O
+ , 
+We,O
+performed,O
+a,O
+linkage,O
+scan,O
+to,O
+map,O
+genes,O
+contributing,O
+to,O
+PsA.,O
+ , 
+We,O
+identified,O
+178,O
+patients,O
+with,O
+PsA,O
+out,O
+of,O
+906,O
+patients,O
+who,O
+were,O
+included,O
+in,O
+our,O
+genetic,O
+study,O
+of,O
+psoriasis,O
+.,O
+ , 
+Using,O
+a,O
+comprehensive,O
+genealogy,O
+database,O
+,,O
+we,O
+were,O
+able,O
+to,O
+connect,O
+100,O
+of,O
+these,O
+into,O
+39,O
+families,O
+.,O
+ , 
+We,O
+genotyped,O
+the,O
+patients,O
+using,O
+a,O
+framework,O
+marker,O
+set,O
+of,O
+1,000,O
+microsatellite,O
+markers,O
+,,O
+with,O
+an,O
+average,O
+density,O
+of,O
+3,O
+cM,O
+,,O
+and,O
+performed,O
+multipoint,O
+,,O
+affected,O
+-,O
+only,O
+,,O
+allele,O
+-,O
+sharing,O
+linkage,O
+analysis,O
+using,O
+the,O
+Allegro,O
+program,O
+.,O
+ , 
+On,O
+the,O
+basis,O
+of,O
+the,O
+initial,O
+results,O
+,,O
+we,O
+genotyped,O
+more,O
+markers,O
+for,O
+the,O
+most,O
+prominent,O
+loci,O
+.,O
+ , 
+A,O
+linkage,O
+with,O
+a,O
+LOD,O
+score,O
+of,O
+2.17,O
+was,O
+observed,O
+on,O
+chromosome,O
+16q,O
+.,O
+ , 
+The,O
+linkage,O
+analysis,O
+,,O
+conditioned,O
+on,O
+paternal,O
+transmission,O
+to,O
+affected,O
+individuals,O
+,,O
+gave,O
+a,O
+LOD,O
+score,O
+of,O
+4.19,O
+,,O
+whereas,O
+a,O
+LOD,O
+score,O
+of,O
+only,O
+1.03,O
+was,O
+observed,O
+when,O
+conditioned,O
+for,O
+maternal,O
+transmission,O
+.,O
+ , 
+A,O
+suggestive,O
+locus,O
+on,O
+chromosome,O
+16q,O
+has,O
+previously,O
+been,O
+implicated,O
+in,O
+psoriasis,O
+.,O
+ , 
+Our,O
+data,O
+indicate,O
+that,O
+a,O
+gene,O
+at,O
+this,O
+locus,O
+may,O
+be,O
+involved,O
+in,O
+paternal,O
+transmission,O
+of,O
+PsA.,O
+ , 
+#8651318
+Detection,O
+of,O
+linkage,O
+to,O
+affective,O
+disorders,O
+in,O
+the,O
+catalogued,O
+Amish,O
+pedigrees,O
+:,O
+a,O
+reply,O
+to,O
+Pauls,O
+et,O
+al,O
+.,O
+ , 
+#9545410
+A,O
+gene,O
+for,O
+familial,O
+juvenile,O
+polyposis,O
+maps,O
+to,O
+chromosome,O
+18q21.1,O
+.,O
+ , 
+Familial,O
+juvenile,O
+polyposis,O
+(,O
+FJP,O
+),O
+is,O
+a,O
+hamartomatouspolyposis,O
+syndrome,O
+in,O
+which,O
+affected,O
+family,O
+members,O
+develop,O
+upper,O
+and,O
+lower,O
+gastrointestinal,O
+juvenile,O
+polyps,O
+and,O
+are,O
+at,O
+increased,O
+risk,O
+for,O
+gastrointestinal,O
+cancer,O
+.,O
+ , 
+A,O
+genetic,O
+locus,O
+for,O
+FJP,O
+has,O
+not,O
+yet,O
+been,O
+identified,O
+by,O
+linkage,O
+;,O
+therefore,O
+,,O
+the,O
+objective,O
+of,O
+this,O
+study,O
+was,O
+to,O
+perform,O
+a,O
+focused,O
+genome,O
+screen,O
+in,O
+a,O
+large,O
+family,O
+segregating,O
+FJP,O
+.,O
+ , 
+No,O
+evidence,O
+for,O
+linkage,O
+was,O
+found,O
+with,O
+markers,O
+near,O
+MSH2,B-Gene
+,,I-Gene
+MLH1,B-Gene
+,,I-Gene
+MCC,B-Gene
+,,I-Gene
+APC,B-Gene
+,,I-Gene
+HMPS,B-Gene
+,,I-Gene
+CDKN2A,B-Gene
+,,I-Gene
+JP1,B-Gene
+,,I-Gene
+PTEN,B-Gene
+,,I-Gene
+KRAS2,B-Gene
+,,I-Gene
+TP53,B-Gene
+,,I-Gene
+or,O
+LKB1,B-Gene
+.,I-Gene
+ , 
+Linkage,O
+to,O
+FJP,O
+was,O
+established,O
+with,O
+several,O
+markers,O
+from,O
+chromosome,O
+18q21.1,O
+.,O
+ , 
+The,O
+maximum,O
+LOD,O
+score,O
+was,O
+5.00,O
+,,O
+with,O
+marker,O
+D18S1099,O
+(,O
+recombination,O
+fraction,O
+of,O
+.001,O
+),O
+.,O
+ , 
+Analysis,O
+of,O
+critical,O
+recombinants,O
+places,O
+the,O
+FJP,O
+gene,O
+in,O
+an,O
+11.9,O
+-,O
+cM,O
+interval,O
+bounded,O
+by,O
+D18S1118,O
+and,O
+D18S487,O
+,,O
+a,O
+region,O
+that,O
+also,O
+contains,O
+the,O
+tumor,O
+-,O
+suppressor,O
+genes,O
+DCC,B-Gene
+and,O
+DPC4,B-Gene
+.,I-Gene
+ , 
+These,O
+data,O
+demonstrate,O
+localization,O
+of,O
+a,O
+gene,O
+for,O
+FJP,O
+to,O
+chromosome,O
+18q21.1,O
+by,O
+linkage,O
+,,O
+and,O
+they,O
+raise,O
+the,O
+possibility,O
+that,O
+either,O
+DCC,B-Gene
+or,O
+DPC4,B-Gene
+could,O
+be,O
+responsible,O
+for,O
+FJP,O
+.,O
+ , 
+#7537150
+Identification,O
+of,O
+six,O
+mutations,O
+(,B-SNP
+R31L,I-SNP
+,,I-SNP
+441delA,B-SNP
+,,I-SNP
+681delC,B-SNP
+,,I-SNP
+1461ins4,B-SNP
+,,I-SNP
+W1089R,B-SNP
+,,I-SNP
+E1104X,B-SNP
+),I-SNP
+in,O
+the,O
+cystic,B-Gene
+fibrosis,I-Gene
+transmembrane,I-Gene
+conductance,I-Gene
+regulator,I-Gene
+(,B-Gene
+CFTR,I-Gene
+),I-Gene
+gene,O
+.,O
+ , 
+Six,O
+new,O
+mutations,O
+have,O
+been,O
+identified,O
+in,O
+the,O
+CFTR,O
+gene,O
+.,O
+ , 
+These,O
+mutations,O
+,,O
+representing,O
+three,O
+different,O
+categories,O
+--,O
+missense,O
+(,B-SNP
+R31L,I-SNP
+,,I-SNP
+W1098R,B-SNP
+),I-SNP
+,,O
+nonsense,O
+(,B-SNP
+E1104X,I-SNP
+),I-SNP
+,,O
+and,O
+frameshift,O
+(,B-SNP
+441delA,I-SNP
+,,I-SNP
+681delC,B-SNP
+,,I-SNP
+1461ins4)--are,B-SNP
+located,O
+in,O
+exons,O
+2,O
+,,O
+4,O
+,,O
+5,O
+,,O
+9,O
+,,O
+and,O
+17b,O
+of,O
+the,O
+gene,O
+and,O
+presumed,O
+to,O
+cause,O
+cystic,O
+fibrosis,O
+(,O
+CF,O
+),O
+in,O
+patients,O
+.,O
+ , 
+All,O
+these,O
+mutations,O
+are,O
+probably,O
+rare,O
+in,O
+the,O
+population,O
+,,O
+as,O
+no,O
+additional,O
+examples,O
+were,O
+found,O
+for,O
+any,O
+of,O
+them,O
+in,O
+a,O
+cohort,O
+of,O
+545,O
+CF,O
+patients,O
+.,O
+ , 
+Our,O
+study,O
+also,O
+revealed,O
+a,O
+benign,O
+sequence,O
+variation,O
+(,B-SNP
+3499,I-SNP
++,I-SNP
+45T-->C,I-SNP
+),I-SNP
+in,O
+intron,O
+17b,O
+.,O
+ , 
+#7611281
+Tyrosinase,O
+inhibition,O
+due,O
+to,O
+interaction,O
+of,O
+homocyst(e)ine,O
+with,O
+copper,O
+:,O
+the,O
+mechanism,O
+for,O
+reversible,O
+hypopigmentation,O
+in,O
+homocystinuria,O
+due,O
+to,O
+cystathionine,O
+beta,O
+-,O
+synthase,O
+deficiency,O
+.,O
+ , 
+Deficiency,O
+of,O
+cystathionine,O
+beta,O
+-,O
+synthase,O
+(,O
+CBS,O
+),O
+is,O
+a,O
+genetic,O
+disorder,O
+of,O
+transsulfuration,O
+resulting,O
+in,O
+elevated,O
+plasma,O
+homocyst(e)ine,O
+and,O
+methionine,O
+and,O
+decreased,O
+cysteine,O
+.,O
+ , 
+Affected,O
+patients,O
+have,O
+multisystem,O
+involvement,O
+,,O
+which,O
+may,O
+include,O
+light,O
+skin,O
+and,O
+hair,O
+.,O
+ , 
+Reversible,O
+hypopigmentation,O
+in,O
+treated,O
+homocystinuric,O
+patients,O
+has,O
+been,O
+infrequently,O
+reported,O
+,,O
+and,O
+the,O
+mechanism,O
+is,O
+undefined,O
+.,O
+ , 
+Two,O
+CBS,O
+-,O
+deficient,O
+homocystinuric,O
+patients,O
+manifested,O
+darkening,O
+of,O
+their,O
+hypopigmented,O
+hair,O
+following,O
+treatment,O
+that,O
+decreased,O
+plasma,O
+homocyst(e)ine,O
+.,O
+ , 
+We,O
+hypothesized,O
+that,O
+homocyst(e)ine,O
+inhibits,O
+tyrosinase,O
+,,O
+the,O
+major,O
+pigment,O
+enzyme,O
+.,O
+ , 
+The,O
+activity,O
+of,O
+tyrosinase,O
+extracted,O
+from,O
+pigmented,O
+human,O
+melanoma,O
+cells,O
+(,O
+MNT-1,O
+),O
+that,O
+were,O
+grown,O
+in,O
+the,O
+presence,O
+of,O
+homocysteine,O
+was,O
+reduced,O
+in,O
+comparison,O
+to,O
+that,O
+extracted,O
+from,O
+cells,O
+grown,O
+without,O
+homocysteine,O
+.,O
+ , 
+Copper,O
+sulfate,O
+restored,O
+homocyst(e)ine,O
+-,O
+inhibited,O
+tyrosinase,O
+activity,O
+when,O
+added,O
+to,O
+the,O
+culture,O
+cell,O
+media,O
+at,O
+a,O
+proportion,O
+of,O
+1.25,O
+mol,O
+of,O
+copper,O
+sulfate,O
+per,O
+1,O
+mol,O
+of,O
+DL,O
+-,O
+homocysteine,O
+.,O
+ , 
+Holo,O
+-,O
+tyrosinase,O
+activity,O
+was,O
+inhibited,O
+by,O
+adding,O
+DL,O
+-,O
+homocysteine,O
+to,O
+the,O
+assay,O
+reaction,O
+mixture,O
+,,O
+and,O
+the,O
+addition,O
+of,O
+copper,O
+sulfate,O
+to,O
+the,O
+reaction,O
+mixture,O
+prevented,O
+this,O
+inhibition,O
+.,O
+ , 
+Other,O
+tested,O
+compounds,O
+,,O
+L,O
+-,O
+cystine,O
+and,O
+betaine,O
+did,O
+not,O
+affect,O
+tyrosinase,O
+activity,O
+.,O
+ , 
+Our,O
+data,O
+suggest,O
+that,O
+reversible,O
+hypopigmentation,O
+in,O
+homocystinuria,O
+is,O
+the,O
+result,O
+of,O
+tyrosinase,O
+inhibition,O
+by,O
+homocyst(e)ine,O
+and,O
+that,O
+the,O
+probable,O
+mechanism,O
+of,O
+this,O
+inhibition,O
+is,O
+the,O
+interaction,O
+of,O
+homocyst(e)ine,O
+with,O
+copper,O
+at,O
+the,O
+active,O
+site,O
+of,O
+tyrosinase,O
+.,O
+ , 
+#9143927
+Deletions,O
+spanning,O
+the,O
+neurofibromatosis,B-Gene
+type,I-Gene
+1,I-Gene
+gene,O
+:,O
+implications,O
+for,O
+genotype,O
+-,O
+phenotype,O
+correlations,O
+in,O
+neurofibromatosis,O
+type,O
+1,O
+?,O
+ , 
+Neurofibromatosis,O
+type,O
+1,O
+(,O
+NF1,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+disorder,O
+characterized,O
+by,O
+abnormalities,O
+of,O
+tissues,O
+predominantly,O
+derived,O
+from,O
+the,O
+neural,O
+crest,O
+.,O
+ , 
+Symptoms,O
+are,O
+highly,O
+variable,O
+and,O
+severity,O
+can,O
+not,O
+be,O
+predicted,O
+,,O
+even,O
+within,O
+families,O
+.,O
+ , 
+DNA,O
+of,O
+84,O
+unrelated,O
+patients,O
+with,O
+NF1,O
+,,O
+unselected,O
+for,O
+clinical,O
+features,O
+or,O
+severity,O
+,,O
+were,O
+screened,O
+with,O
+intragenic,O
+polymorphic,O
+repeat,O
+markers,O
+and,O
+by,O
+Southern,O
+analysis,O
+with,O
+cDNA,O
+probes,O
+.,O
+ , 
+Deletions,O
+of,O
+the,O
+entire,O
+gene,O
+were,O
+detected,O
+in,O
+five,O
+patients,O
+from,O
+four,O
+unrelated,O
+families,O
+.,O
+ , 
+Their,O
+phenotype,O
+resembled,O
+that,O
+of,O
+five,O
+previously,O
+reported,O
+patients,O
+with,O
+deletions,O
+,,O
+including,O
+intellectual,O
+impairment,O
+and,O
+dysmorphic,O
+features,O
+,,O
+but,O
+without,O
+an,O
+excessive,O
+number,O
+of,O
+dermal,O
+neurofibromas,O
+.,O
+ , 
+This,O
+report,O
+supports,O
+the,O
+hypothesis,O
+that,O
+large,O
+deletions,O
+spanning,O
+the,O
+entire,O
+NF1,B-Gene
+gene,O
+may,O
+lead,O
+to,O
+a,O
+specific,O
+phenotype,O
+.,O
+ , 
+#12145747
+Tibial,O
+muscular,O
+dystrophy,O
+is,O
+a,O
+titinopathy,O
+caused,O
+by,O
+mutations,O
+in,O
+TTN,B-Gene
+,,I-Gene
+the,O
+gene,O
+encoding,O
+the,O
+giant,O
+skeletal,O
+-,O
+muscle,O
+protein,O
+titin,O
+.,O
+ , 
+Tibial,O
+muscular,O
+dystrophy,O
+(,O
+TMD,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+late,O
+-,O
+onset,O
+distal,O
+myopathy,O
+linked,O
+to,O
+chromosome,O
+2q31,O
+.,O
+ , 
+The,O
+linked,O
+region,O
+includes,O
+the,O
+giant,O
+TTN,B-Gene
+gene,O
+,,O
+which,O
+encodes,O
+the,O
+central,O
+sarcomeric,O
+protein,O
+,,O
+titin,O
+.,O
+ , 
+We,O
+have,O
+previously,O
+shown,O
+a,O
+secondary,O
+calpain-3,O
+defect,O
+to,O
+be,O
+associated,O
+with,O
+TMD,O
+,,O
+which,O
+further,O
+underscored,O
+that,O
+titin,O
+is,O
+the,O
+candidate,O
+.,O
+ , 
+We,O
+now,O
+report,O
+the,O
+first,O
+mutations,O
+in,O
+TTN,B-Gene
+to,O
+cause,O
+a,O
+human,O
+skeletal,O
+-,O
+muscle,O
+disease,O
+,,O
+TMD,O
+.,O
+ , 
+In,O
+Mex6,O
+,,O
+the,O
+last,O
+exon,O
+of,O
+TTN,B-Gene
+,,I-Gene
+a,O
+unique,O
+11,O
+-,O
+bp,O
+deletion,O
+/,O
+insertion,O
+mutation,O
+,,O
+changing,O
+four,O
+amino,O
+acid,O
+residues,O
+,,O
+completely,O
+cosegregated,O
+with,O
+all,O
+tested,O
+81,O
+Finnish,O
+patients,O
+with,O
+TMD,O
+in,O
+12,O
+unrelated,O
+families,O
+.,O
+ , 
+The,O
+mutation,O
+was,O
+not,O
+found,O
+in,O
+216,O
+Finnish,O
+control,O
+samples,O
+.,O
+ , 
+In,O
+a,O
+French,O
+family,O
+with,O
+TMD,O
+,,O
+a,O
+Leu-->Pro,B-SNP
+mutation,I-SNP
+at,I-SNP
+position,I-SNP
+293,357,I-SNP
+in,O
+Mex6,B-Gene
+was,O
+discovered,O
+.,O
+ , 
+Mex6,B-Gene
+is,O
+adjacent,O
+to,O
+the,O
+known,O
+calpain-3,O
+binding,O
+site,O
+Mex5,B-Gene
+of,O
+M,O
+-,O
+line,O
+titin,O
+.,O
+ , 
+Immunohistochemical,O
+analysis,O
+using,O
+two,O
+exon,O
+-,O
+specific,O
+antibodies,O
+directed,O
+to,O
+the,O
+M,O
+-,O
+line,O
+region,O
+of,O
+titin,O
+demonstrated,O
+the,O
+specific,O
+loss,O
+of,O
+carboxy,O
+-,O
+terminal,O
+titin,O
+epitopes,O
+in,O
+the,O
+TMD,O
+muscle,O
+samples,O
+that,O
+we,O
+studied,O
+,,O
+thus,O
+implicating,O
+a,O
+functional,O
+defect,O
+of,O
+the,O
+M,O
+-,O
+line,O
+titin,O
+in,O
+the,O
+genesis,O
+of,O
+the,O
+TMD,O
+disease,O
+phenotype,O
+.,O
+ , 
+#19230858
+A,O
+genome,O
+-,O
+wide,O
+analysis,O
+identifies,O
+genetic,O
+variants,O
+in,O
+the,O
+RELN,B-Gene
+gene,O
+associated,O
+with,O
+otosclerosis,O
+.,O
+ , 
+Otosclerosis,O
+is,O
+a,O
+common,O
+form,O
+of,O
+progressive,O
+hearing,O
+loss,O
+,,O
+characterized,O
+by,O
+abnormal,O
+bone,O
+remodeling,O
+in,O
+the,O
+otic,O
+capsule,O
+.,O
+ , 
+The,O
+etiology,O
+of,O
+the,O
+disease,O
+is,O
+largely,O
+unknown,O
+,,O
+and,O
+both,O
+environmental,O
+and,O
+genetic,O
+factors,O
+have,O
+been,O
+implicated,O
+.,O
+ , 
+To,O
+identify,O
+genetic,O
+factors,O
+involved,O
+in,O
+otosclerosis,O
+,,O
+we,O
+used,O
+a,O
+case,O
+-,O
+control,O
+discovery,O
+group,O
+to,O
+complete,O
+a,O
+genome,O
+-,O
+wide,O
+association,O
+(,O
+GWA,O
+),O
+study,O
+with,O
+555,000,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+(,O
+SNPs,O
+),O
+,,O
+utilizing,O
+pooled,O
+DNA,O
+samples,O
+.,O
+ , 
+By,O
+individual,O
+genotyping,O
+of,O
+the,O
+top,O
+250,O
+SNPs,O
+in,O
+a,O
+stepwise,O
+strategy,O
+,,O
+we,O
+were,O
+able,O
+to,O
+identify,O
+two,O
+highly,O
+associated,O
+SNPs,O
+that,O
+replicated,O
+in,O
+two,O
+additional,O
+independent,O
+populations,O
+.,O
+ , 
+We,O
+then,O
+genotyped,O
+79,O
+tagSNPs,O
+to,O
+fine,O
+map,O
+the,O
+two,O
+genomic,O
+regions,O
+defined,O
+by,O
+the,O
+associated,O
+SNPs,O
+.,O
+ , 
+The,O
+region,O
+with,O
+the,O
+strongest,O
+association,O
+signal,O
+,,O
+p(combined,O
+),O
+=,O
+ , 
+6.23,O
+x,O
+10(-10,O
+),O
+,,O
+is,O
+on,O
+chromosome,O
+7q22.1,O
+and,O
+spans,O
+intron,O
+1,O
+to,O
+intron,O
+4,O
+of,O
+reelin,B-Gene
+(,B-Gene
+RELN,I-Gene
+),I-Gene
+,,O
+a,O
+gene,O
+known,O
+for,O
+its,O
+role,O
+in,O
+neuronal,O
+migration,O
+.,O
+ , 
+Evidence,O
+for,O
+allelic,O
+heterogeneity,O
+was,O
+found,O
+in,O
+this,O
+region,O
+.,O
+ , 
+Consistent,O
+with,O
+the,O
+GWA,O
+data,O
+,,O
+expression,O
+of,O
+RELN,B-Gene
+was,O
+confirmed,O
+in,O
+the,O
+inner,O
+ear,O
+and,O
+in,O
+stapes,O
+footplate,O
+specimens,O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+we,O
+provide,O
+evidence,O
+that,O
+implicates,O
+RELN,B-Gene
+in,O
+the,O
+pathogenesis,O
+of,O
+otosclerosis,O
+.,O
+ , 
+#22036171
+Mutations,O
+in,O
+POLR3A,B-Gene
+and,O
+POLR3B,B-Gene
+encoding,O
+RNA,O
+Polymerase,O
+III,O
+subunits,O
+cause,O
+an,O
+autosomal,O
+-,O
+recessive,O
+hypomyelinating,O
+leukoencephalopathy,O
+.,O
+ , 
+Congenital,O
+hypomyelinating,O
+disorders,O
+are,O
+a,O
+heterogeneous,O
+group,O
+of,O
+inherited,O
+leukoencephalopathies,O
+characterized,O
+by,O
+abnormal,O
+myelin,O
+formation,O
+.,O
+ , 
+We,O
+have,O
+recently,O
+reported,O
+a,O
+hypomyelinating,O
+syndrome,O
+characterized,O
+by,O
+diffuse,O
+cerebral,O
+hypomyelination,O
+with,O
+cerebellar,O
+atrophy,O
+and,O
+hypoplasia,O
+of,O
+the,O
+corpus,O
+callosum,O
+(,O
+HCAHC,O
+),O
+.,O
+ , 
+We,O
+performed,O
+whole,O
+-,O
+exome,O
+sequencing,O
+of,O
+three,O
+unrelated,O
+individuals,O
+with,O
+HCAHC,O
+and,O
+identified,O
+compound,O
+heterozygous,O
+mutations,O
+in,O
+POLR3B,B-Gene
+in,O
+two,O
+individuals,O
+.,O
+ , 
+The,O
+mutations,O
+include,O
+a,O
+nonsense,O
+mutation,O
+,,O
+a,O
+splice,O
+-,O
+site,O
+mutation,O
+,,O
+and,O
+two,O
+missense,O
+mutations,O
+at,O
+evolutionally,O
+conserved,O
+amino,O
+acids,O
+.,O
+ , 
+Using,O
+reverse,O
+transcription,O
+-,O
+PCR,O
+and,O
+sequencing,O
+,,O
+we,O
+demonstrated,O
+that,O
+the,O
+splice,O
+-,O
+site,O
+mutation,O
+caused,O
+deletion,O
+of,O
+exon,O
+18,O
+from,O
+POLR3B,B-Gene
+mRNA,O
+and,O
+that,O
+the,O
+transcript,O
+harboring,O
+the,O
+nonsense,O
+mutation,O
+underwent,O
+nonsense,O
+-,O
+mediated,O
+mRNA,O
+decay,O
+.,O
+ , 
+We,O
+also,O
+identified,O
+compound,O
+heterozygous,O
+missense,O
+mutations,O
+in,O
+POLR3A,B-Gene
+in,O
+the,O
+remaining,O
+individual,O
+.,O
+ , 
+POLR3A,B-Gene
+ , 
+and,O
+POLR3B,B-Gene
+encode,O
+the,O
+largest,O
+and,O
+second,O
+largest,O
+subunits,O
+of,O
+RNA,O
+Polymerase,O
+III,O
+(,O
+Pol,O
+III,O
+),O
+,,O
+RPC1,B-Gene
+and,O
+RPC2,B-Gene
+,,I-Gene
+respectively,O
+.,O
+ , 
+RPC1,B-Gene
+and,O
+RPC2,B-Gene
+together,O
+form,O
+the,O
+active,O
+center,O
+of,O
+the,O
+polymerase,O
+and,O
+contribute,O
+to,O
+the,O
+catalytic,O
+activity,O
+of,O
+the,O
+polymerase,O
+.,O
+ , 
+Pol,O
+III,O
+is,O
+involved,O
+in,O
+the,O
+transcription,O
+of,O
+small,O
+noncoding,O
+RNAs,O
+,,O
+such,O
+as,O
+5S,O
+ribosomal,O
+RNA,O
+and,O
+all,O
+transfer,O
+RNAs,O
+(,O
+tRNA,O
+),O
+.,O
+ , 
+We,O
+hypothesize,O
+that,O
+perturbation,O
+of,O
+Pol,O
+III,O
+target,O
+transcription,O
+,,O
+especially,O
+of,O
+tRNAs,O
+,,O
+could,O
+be,O
+a,O
+common,O
+pathological,O
+mechanism,O
+underlying,O
+POLR3A,B-Gene
+and,O
+POLR3B,B-Gene
+mutations,O
+.,O
+ , 
+#8829650
+Molecular,O
+basis,O
+of,O
+congenital,O
+erythropoietic,O
+porphyria,O
+:,O
+mutations,O
+in,O
+the,O
+human,O
+uroporphyrinogen,B-Gene
+III,I-Gene
+synthase,I-Gene
+gene,O
+.,O
+ , 
+Congenital,O
+erythropoietic,O
+porphyria,O
+(,O
+CEP,O
+),O
+is,O
+an,O
+autosomal,O
+recessive,O
+inborn,O
+error,O
+of,O
+metabolism,O
+that,O
+results,O
+from,O
+the,O
+markedly,O
+deficient,O
+activity,O
+of,O
+the,O
+fourth,O
+enzyme,O
+in,O
+the,O
+heme,O
+biosynthetic,O
+pathway,O
+,,O
+uroporphyrinogen,O
+III,O
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+(,O
+URO,O
+-,O
+synthase,O
+),O
+.,O
+ , 
+To,O
+date,O
+,,O
+17,O
+mutations,O
+have,O
+been,O
+described,O
+including,O
+11,O
+missense,O
+,,O
+one,O
+nonsense,O
+,,O
+two,O
+mRNA,O
+splicing,O
+defects,O
+,,O
+one,O
+deletion,O
+and,O
+two,O
+coding,O
+region,O
+insertions,O
+.,O
+ , 
+Most,O
+mutations,O
+have,O
+been,O
+identified,O
+in,O
+one,O
+or,O
+a,O
+few,O
+unrelated,O
+families,O
+with,O
+the,O
+exception,O
+of,O
+C73R,B-SNP
+and,O
+L4F,B-SNP
+which,O
+occurred,O
+in,O
+29.6,O
+%,O
+and,O
+9.3,O
+%,O
+of,O
+the,O
+54,O
+mutant,O
+alleles,O
+studied,O
+,,O
+respectively,O
+.,O
+ , 
+Interestingly,O
+,,O
+analysis,O
+of,O
+the,O
+mutant,O
+alleles,O
+identified,O
+only,O
+83,O
+%,O
+of,O
+the,O
+causative,O
+mutations,O
+,,O
+suggesting,O
+that,O
+about,O
+20,O
+%,O
+of,O
+the,O
+mutations,O
+causing,O
+CEP,O
+lie,O
+elsewhere,O
+in,O
+the,O
+gene,O
+.,O
+ , 
+Of,O
+note,O
+,,O
+mutation,O
+V82F,B-SNP
+,,I-SNP
+resulting,O
+from,O
+a,O
+G,B-SNP
+to,I-SNP
+T,I-SNP
+transversion,I-SNP
+of,I-SNP
+the,I-SNP
+last,I-SNP
+nucleotide,I-SNP
+of,I-SNP
+exon,I-SNP
+4,I-SNP
+,,I-SNP
+caused,O
+both,O
+a,O
+missense,O
+mutation,O
+and,O
+an,O
+aberrantly,O
+spliced,O
+RNA,O
+transcript,O
+.,O
+ , 
+Prokaryotic,O
+expression,O
+of,O
+the,O
+mutant,O
+URO,O
+-,O
+synthase,O
+alleles,O
+identified,O
+those,O
+with,O
+significant,O
+residual,O
+activity,O
+,,O
+thereby,O
+permitting,O
+genotype,O
+/,O
+phenotype,O
+predictions,O
+for,O
+this,O
+clinically,O
+heterogeneous,O
+disease,O
+.,O
+ , 
+#20826270
+Protein,B-Gene
+tyrosine,I-Gene
+phosphatase,I-Gene
+PTPN14,B-Gene
+is,O
+a,O
+regulator,O
+of,O
+lymphatic,O
+function,O
+and,O
+choanal,O
+development,O
+in,O
+humans,O
+.,O
+ , 
+The,O
+lymphatic,O
+vasculature,O
+is,O
+essential,O
+for,O
+the,O
+recirculation,O
+of,O
+extracellular,O
+fluid,O
+,,O
+fat,O
+absorption,O
+,,O
+and,O
+immune,O
+function,O
+and,O
+as,O
+a,O
+route,O
+of,O
+tumor,O
+metastasis,O
+.,O
+ , 
+The,O
+dissection,O
+of,O
+molecular,O
+mechanisms,O
+underlying,O
+lymphangiogenesis,O
+has,O
+been,O
+accelerated,O
+by,O
+the,O
+identification,O
+of,O
+tissue,O
+-,O
+specific,O
+lymphatic,O
+endothelial,O
+markers,O
+and,O
+the,O
+study,O
+of,O
+congenital,O
+lymphedema,O
+syndromes,O
+.,O
+ , 
+We,O
+report,O
+the,O
+results,O
+of,O
+genetic,O
+analyses,O
+of,O
+a,O
+kindred,O
+inheriting,O
+a,O
+unique,O
+autosomal,O
+-,O
+recessive,O
+lymphedema,O
+-,O
+choanal,O
+atresia,O
+syndrome,O
+.,O
+ , 
+These,O
+studies,O
+establish,O
+linkage,O
+of,O
+the,O
+trait,O
+to,O
+chromosome,O
+1q32,O
+-,O
+q41,O
+and,O
+identify,O
+a,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mutation,O
+in,O
+PTPN14,B-Gene
+,,I-Gene
+which,O
+encodes,O
+a,O
+nonreceptor,O
+tyrosine,O
+phosphatase,O
+.,O
+ , 
+The,O
+causal,O
+role,O
+of,O
+PTPN14,B-Gene
+deficiency,O
+was,O
+confirmed,O
+by,O
+the,O
+generation,O
+of,O
+a,O
+murine,O
+Ptpn14,B-Gene
+gene,O
+trap,O
+model,O
+that,O
+manifested,O
+lymphatic,O
+hyperplasia,O
+with,O
+lymphedema,O
+.,O
+ , 
+Biochemical,O
+studies,O
+revealed,O
+a,O
+potential,O
+interaction,O
+between,O
+PTPN14,B-Gene
+and,O
+the,O
+vascular,B-Gene
+endothelial,I-Gene
+growth,I-Gene
+factor,I-Gene
+receptor,I-Gene
+3,I-Gene
+(,B-Gene
+VEGFR3,I-Gene
+),I-Gene
+,,O
+a,O
+receptor,O
+tyrosine,O
+kinase,O
+essential,O
+for,O
+lymphangiogenesis,O
+.,O
+ , 
+These,O
+results,O
+suggest,O
+a,O
+unique,O
+and,O
+conserved,O
+role,O
+for,O
+PTPN14,B-Gene
+in,O
+the,O
+regulation,O
+of,O
+lymphatic,O
+development,O
+in,O
+mammals,O
+and,O
+a,O
+nonconserved,O
+role,O
+in,O
+choanal,O
+development,O
+in,O
+humans,O
+.,O
+ , 
+#10577941
+Heterogenous,O
+point,O
+mutations,O
+in,O
+the,O
+mitochondrial,O
+tRNA,O
+Ser(UCN,O
+),O
+precursor,O
+coexisting,O
+with,O
+the,O
+A1555,B-SNP
+G,I-SNP
+mutation,O
+in,O
+deaf,O
+students,O
+from,O
+Mongolia,O
+.,O
+ , 
+#16281286
+Spectrum,O
+of,O
+mutations,O
+in,O
+mut,O
+methylmalonic,O
+acidemia,O
+and,O
+identification,O
+of,O
+a,O
+common,O
+Hispanic,O
+mutation,O
+and,O
+haplotype,O
+.,O
+ , 
+Cobalamin,O
+nonresponsive,O
+methylmalonic,O
+acidemia,O
+(,O
+MMA,O
+,,O
+mut,O
+complementation,O
+class,O
+),O
+results,O
+from,O
+mutations,O
+in,O
+the,O
+nuclear,O
+gene,O
+MUT,B-Gene
+,,I-Gene
+which,O
+codes,O
+for,O
+the,O
+mitochondrial,O
+enzyme,O
+methylmalonyl,O
+CoA,O
+mutase,O
+(,O
+MCM,O
+),O
+.,O
+ , 
+To,O
+better,O
+elucidate,O
+the,O
+spectrum,O
+of,O
+mutations,O
+that,O
+cause,O
+MMA,O
+,,O
+the,O
+MUT,B-Gene
+gene,O
+was,O
+sequenced,O
+in,O
+160,O
+patients,O
+with,O
+mut,O
+MMA,O
+.,O
+ , 
+Sequence,O
+analysis,O
+identified,O
+mutations,O
+in,O
+96,O
+%,O
+of,O
+disease,O
+alleles,O
+.,O
+ , 
+Mutations,O
+were,O
+found,O
+in,O
+all,O
+coding,O
+exons,O
+,,O
+but,O
+predominantly,O
+in,O
+exons,O
+2,O
+,,O
+3,O
+,,O
+6,O
+,,O
+and,O
+11,O
+.,O
+ , 
+A,O
+total,O
+of,O
+116,O
+different,O
+mutations,O
+,,O
+68,O
+of,O
+which,O
+were,O
+novel,O
+,,O
+were,O
+identified,O
+.,O
+ , 
+Of,O
+the,O
+116,O
+different,O
+mutations,O
+,,O
+53,O
+%,O
+were,O
+missense,O
+mutations,O
+,,O
+22,O
+%,O
+were,O
+deletions,O
+,,O
+duplications,O
+or,O
+insertions,O
+,,O
+16,O
+%,O
+were,O
+nonsense,O
+mutations,O
+,,O
+and,O
+9,O
+%,O
+were,O
+splice,O
+-,O
+site,O
+mutations,O
+.,O
+ , 
+Sixty,O
+-,O
+one,O
+of,O
+the,O
+mutations,O
+have,O
+only,O
+been,O
+identified,O
+in,O
+one,O
+family,O
+.,O
+ , 
+A,O
+novel,O
+mutation,O
+in,O
+exon,O
+2,O
+,,O
+c.322C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+R108C,I-SNP
+),I-SNP
+,,O
+was,O
+identified,O
+in,O
+16,O
+of,O
+27,O
+Hispanic,O
+patients,O
+.,O
+ , 
+SNP,O
+genotyping,O
+data,O
+demonstrated,O
+that,O
+Hispanic,O
+patients,O
+with,O
+this,O
+mutation,O
+share,O
+a,O
+common,O
+haplotype,O
+.,O
+ , 
+Three,O
+other,O
+mutations,O
+were,O
+seen,O
+exclusively,O
+in,O
+Hispanic,O
+patients,O
+:,O
+c.280G,B-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+G94R,I-SNP
+),I-SNP
+,,O
+c.1022dupA,B-SNP
+,,I-SNP
+and,O
+c.970G,B-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+A324,I-SNP
+T,I-SNP
+),I-SNP
+.,O
+ , 
+Seven,O
+mutations,O
+were,O
+seen,O
+almost,O
+exclusively,O
+in,O
+black,O
+patients,O
+,,O
+including,O
+the,O
+previously,O
+reported,O
+c.2150G,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+G717V,I-SNP
+),I-SNP
+mutation,O
+,,O
+which,O
+was,O
+identified,O
+in,O
+12,O
+of,O
+29,O
+black,O
+patients,O
+.,O
+ , 
+Two,O
+mutations,O
+were,O
+seen,O
+only,O
+in,O
+Asian,O
+patients,O
+.,O
+ , 
+Some,O
+frequently,O
+identified,O
+mutations,O
+were,O
+not,O
+population,O
+-,O
+specific,O
+and,O
+were,O
+identified,O
+in,O
+patients,O
+of,O
+various,O
+ethnic,O
+backgrounds,O
+.,O
+ , 
+Some,O
+of,O
+these,O
+mutations,O
+were,O
+found,O
+in,O
+mutation,O
+clusters,O
+in,O
+exons,O
+2,O
+,,O
+3,O
+,,O
+6,O
+,,O
+and,O
+11,O
+,,O
+suggesting,O
+a,O
+recurrent,O
+mutation,O
+.,O
+ , 
+#11509994
+Maple,O
+syrup,O
+urine,O
+disease,O
+:,O
+identification,O
+and,O
+carrier,O
+-,O
+frequency,O
+determination,O
+of,O
+a,O
+novel,O
+founder,O
+mutation,O
+in,O
+the,O
+Ashkenazi,O
+Jewish,O
+population,O
+.,O
+ , 
+Maple,O
+syrup,O
+urine,O
+disease,O
+(,O
+MSUD,O
+),O
+is,O
+a,O
+rare,O
+,,O
+autosomal,O
+recessive,O
+disorder,O
+of,O
+branched,O
+-,O
+chain,O
+amino,O
+acid,O
+metabolism,O
+.,O
+ , 
+We,O
+noted,O
+that,O
+a,O
+large,O
+proportion,O
+(,O
+10,O
+of,O
+34,O
+),O
+of,O
+families,O
+with,O
+MSUD,O
+that,O
+were,O
+followed,O
+in,O
+our,O
+clinic,O
+were,O
+of,O
+Ashkenazi,O
+Jewish,O
+(,O
+AJ,O
+),O
+descent,O
+,,O
+leading,O
+us,O
+to,O
+search,O
+for,O
+a,O
+common,O
+mutation,O
+within,O
+this,O
+group,O
+.,O
+ , 
+On,O
+the,O
+basis,O
+of,O
+genotyping,O
+data,O
+suggestive,O
+of,O
+a,O
+conserved,O
+haplotype,O
+at,O
+tightly,O
+linked,O
+markers,O
+on,O
+chromosome,O
+6q14,O
+,,O
+the,O
+BCKDHB,B-Gene
+gene,O
+encoding,O
+the,O
+E1beta,O
+subunit,O
+was,O
+sequenced,O
+.,O
+ , 
+Three,O
+novel,O
+mutations,O
+were,O
+identified,O
+in,O
+seven,O
+unrelated,O
+AJ,O
+patients,O
+with,O
+MSUD,O
+.,O
+ , 
+The,O
+locations,O
+of,O
+the,O
+affected,O
+residues,O
+in,O
+the,O
+crystal,O
+structure,O
+of,O
+the,O
+E1beta,O
+subunit,O
+suggested,O
+possible,O
+mechanisms,O
+for,O
+the,O
+deleterious,O
+effects,O
+of,O
+these,O
+mutations,O
+.,O
+ , 
+Large,O
+-,O
+scale,O
+population,O
+screening,O
+of,O
+AJ,O
+individuals,O
+for,O
+R183P,B-SNP
+,,I-SNP
+the,O
+mutation,O
+present,O
+in,O
+six,O
+of,O
+seven,O
+patients,O
+,,O
+revealed,O
+that,O
+the,O
+carrier,O
+frequency,O
+of,O
+the,O
+mutant,O
+allele,O
+was,O
+approximately,O
+1/113,O
+;,O
+the,O
+patient,O
+not,O
+carrying,O
+R183P,B-SNP
+had,O
+a,O
+previously,O
+described,O
+homozygous,O
+mutation,O
+in,O
+the,O
+gene,O
+encoding,O
+the,O
+E2,O
+subunit,O
+.,O
+ , 
+These,O
+findings,O
+suggested,O
+that,O
+a,O
+limited,O
+number,O
+of,O
+mutations,O
+might,O
+underlie,O
+MSUD,O
+in,O
+the,O
+AJ,O
+population,O
+,,O
+potentially,O
+facilitating,O
+prenatal,O
+diagnosis,O
+and,O
+carrier,O
+detection,O
+of,O
+MSUD,O
+in,O
+this,O
+group,O
+.,O
+ , 
+#19836009
+Homozygous,O
+mutations,O
+in,O
+ADAMTS10,B-Gene
+and,O
+ADAMTS17,B-Gene
+cause,O
+lenticular,O
+myopia,O
+,,O
+ectopia,O
+lentis,O
+,,O
+glaucoma,O
+,,O
+spherophakia,O
+,,O
+and,O
+short,O
+stature,O
+.,O
+ , 
+Weill,O
+-,O
+Marchesani,O
+syndrome,O
+(,O
+WMS,O
+),O
+is,O
+a,O
+well,O
+-,O
+characterized,O
+disorder,O
+in,O
+which,O
+patients,O
+develop,O
+eye,O
+and,O
+skeletal,O
+abnormalities,O
+.,O
+ , 
+Autosomal,O
+-,O
+recessive,O
+and,O
+autosomal,O
+-,O
+dominant,O
+forms,O
+of,O
+WMS,O
+are,O
+caused,O
+by,O
+mutations,O
+in,O
+ADAMTS10,B-Gene
+and,O
+FBN1,B-Gene
+genes,O
+,,O
+respectively,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+on,O
+13,O
+patients,O
+from,O
+seven,O
+unrelated,O
+families,O
+from,O
+the,O
+Arabian,O
+Peninsula,O
+.,O
+ , 
+These,O
+patients,O
+have,O
+a,O
+constellation,O
+of,O
+features,O
+that,O
+fall,O
+within,O
+the,O
+WMS,O
+spectrum,O
+and,O
+follow,O
+an,O
+autosomal,O
+-,O
+recessive,O
+mode,O
+of,O
+inheritance,O
+.,O
+ , 
+Individuals,O
+who,O
+came,O
+from,O
+two,O
+families,O
+and,O
+met,O
+the,O
+diagnostic,O
+criteria,O
+for,O
+WMS,O
+were,O
+each,O
+found,O
+to,O
+have,O
+a,O
+different,O
+homozygous,O
+missense,O
+mutation,O
+in,O
+ADAMTS10,B-Gene
+.,I-Gene
+ , 
+Linkage,O
+analysis,O
+and,O
+direct,O
+sequencing,O
+of,O
+candidate,O
+genes,O
+in,O
+another,O
+two,O
+families,O
+and,O
+a,O
+sporadic,O
+case,O
+with,O
+phenotypes,O
+best,O
+described,O
+as,O
+WMS,O
+-,O
+like,O
+led,O
+to,O
+the,O
+identification,O
+of,O
+three,O
+homozygous,O
+mutations,O
+in,O
+the,O
+closely,O
+related,O
+ADAMTS17,B-Gene
+gene,O
+.,O
+ , 
+Our,O
+clinical,O
+and,O
+genetic,O
+findings,O
+suggest,O
+that,O
+ADAMTS17,B-Gene
+plays,O
+a,O
+role,O
+in,O
+crystalline,O
+lens,O
+zonules,O
+and,O
+connective,O
+tissue,O
+formation,O
+and,O
+that,O
+mutations,O
+in,O
+ADAMTS17,B-Gene
+are,O
+sufficient,O
+to,O
+produce,O
+some,O
+of,O
+the,O
+main,O
+features,O
+typically,O
+described,O
+in,O
+WMS,O
+.,O
+ , 
+#7668286
+Arylamine,B-Gene
+N,I-Gene
+-,I-Gene
+acetyltransferase,I-Gene
+(,B-Gene
+NAT2,I-Gene
+),I-Gene
+mutations,O
+and,O
+their,O
+allelic,O
+linkage,O
+in,O
+unrelated,O
+Caucasian,O
+individuals,O
+:,O
+correlation,O
+with,O
+phenotypic,O
+activity,O
+.,O
+ , 
+The,O
+polymorphic,O
+arylamine,B-Gene
+N,I-Gene
+-,I-Gene
+acetyltransferase,I-Gene
+(,B-Gene
+NAT2,I-Gene
+;,I-Gene
+EC,O
+2.3.1.5,O
+),O
+is,O
+supposed,O
+to,O
+be,O
+a,O
+susceptibility,O
+factor,O
+for,O
+several,O
+drug,O
+side,O
+effects,O
+and,O
+certain,O
+malignancies,O
+.,O
+ , 
+A,O
+group,O
+of,O
+844,O
+unrelated,O
+German,O
+subjects,O
+was,O
+genotyped,O
+for,O
+their,O
+acetylation,O
+type,O
+,,O
+and,O
+563,O
+of,O
+them,O
+were,O
+also,O
+phenotyped,O
+.,O
+ , 
+Seven,O
+mutations,O
+of,O
+the,O
+NAT2,B-Gene
+gene,O
+were,O
+evaluated,O
+by,O
+allele,O
+-,O
+specific,O
+PCR,O
+(,O
+mutation,O
+341C,B-SNP
+to,I-SNP
+T,I-SNP
+),I-SNP
+and,O
+PCR,O
+-,O
+RFLP,O
+for,O
+mutations,O
+at,O
+nt,O
+positions,O
+191,O
+,,O
+282,O
+,,O
+481,O
+,,O
+590,O
+,,O
+803,O
+,,O
+and,O
+857,O
+.,O
+ , 
+From,O
+the,O
+mutation,O
+pattern,O
+eight,O
+different,O
+alleles,O
+,,O
+including,O
+the,O
+wild,O
+type,O
+coding,O
+for,O
+rapid,O
+acetylation,O
+and,O
+seven,O
+alleles,O
+coding,O
+for,O
+slow,O
+phenotype,O
+,,O
+were,O
+determined,O
+.,O
+ , 
+Four,O
+hundred,O
+ninety,O
+-,O
+seven,O
+subjects,O
+had,O
+a,O
+genotype,O
+of,O
+slow,O
+acetylation,O
+(,O
+58.9,O
+%,O
+;,O
+95,O
+%,O
+confidence,O
+limits,O
+55.5%-62.2,O
+%,O
+),O
+.,O
+ , 
+Phenotypic,O
+acetylation,O
+capacity,O
+was,O
+expressed,O
+as,O
+the,O
+ratio,O
+of,O
+5,O
+-,O
+acetylamino-6,O
+-,O
+formylamino-3,O
+-,O
+methyluracil,O
+and,O
+1,O
+-,O
+methylxanthine,O
+in,O
+urine,O
+after,O
+caffeine,O
+intake,O
+.,O
+ , 
+Some,O
+6.7,O
+%,O
+of,O
+the,O
+cases,O
+deviated,O
+in,O
+genotype,O
+and,O
+phenotype,O
+,,O
+but,O
+sequencing,O
+DNA,O
+of,O
+these,O
+probands,O
+revealed,O
+no,O
+new,O
+mutations,O
+.,O
+ , 
+Furthermore,O
+,,O
+linkage,O
+pattern,O
+of,O
+the,O
+mutations,O
+was,O
+always,O
+confirmed,O
+,,O
+as,O
+tested,O
+in,O
+533,O
+subjects,O
+.,O
+ , 
+In,O
+vivo,O
+acetylation,O
+capacity,O
+of,O
+homozygous,O
+wild,O
+-,O
+type,O
+subjects,O
+(,O
+NAT2,O
+*,O
+4/*4,O
+),O
+was,O
+significantly,O
+higher,O
+than,O
+in,O
+heterozygous,O
+genotypes,O
+(,O
+P,O
+=,O
+.001,O
+),O
+.,O
+ , 
+All,O
+mutant,O
+alleles,O
+showed,O
+low,O
+in,O
+vivo,O
+acetylation,O
+capacities,O
+,,O
+including,O
+the,O
+previously,O
+not,O
+-,O
+yet,O
+-,O
+defined,O
+alleles,O
+*,O
+5A,O
+,,O
+*,O
+5C,O
+,,O
+and,O
+*,O
+13,O
+.,O
+ , 
+Moreover,O
+,,O
+distinct,O
+slow,O
+genotypes,O
+differed,O
+significantly,O
+among,O
+each,O
+other,O
+,,O
+as,O
+reflected,O
+in,O
+lower,O
+acetylation,O
+capacity,O
+of,O
+*,O
+6A,O
+,,O
+*,O
+7B,O
+,,O
+and,O
+*,O
+13,O
+alleles,O
+than,O
+the,O
+group,O
+of,O
+*,O
+5,O
+alleles,O
+.,O
+ , 
+The,O
+study,O
+demonstrated,O
+differential,O
+phenotypic,O
+activity,O
+of,O
+various,O
+NAT2,B-Gene
+genes,O
+and,O
+gives,O
+a,O
+solid,O
+basis,O
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+clinical,O
+and,O
+molecular,O
+-,O
+epidemiological,O
+investigations,O
+.,O
+ , 
+#8178820
+Detection,O
+of,O
+mutations,O
+of,O
+the,O
+RB1,B-Gene
+gene,O
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+retinoblastoma,O
+patients,O
+by,O
+using,O
+exon,O
+-,O
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+-,O
+exon,O
+PCR,O
+-,O
+SSCP,O
+analysis,O
+.,O
+ , 
+Most,O
+sporadic,O
+cases,O
+of,O
+retinoblastoma,O
+,,O
+malignant,O
+eye,O
+tumor,O
+of,O
+children,O
+,,O
+may,O
+require,O
+the,O
+identification,O
+of,O
+a,O
+mutation,O
+of,O
+the,O
+retinoblastoma,O
+gene,O
+(,B-Gene
+RB1,I-Gene
+gene,O
+),O
+for,O
+precise,O
+genetic,O
+counseling,O
+.,O
+ , 
+We,O
+established,O
+a,O
+mutation,O
+detection,O
+system,O
+of,O
+and,O
+screened,O
+for,O
+the,O
+RB1,B-Gene
+gene,O
+mutation,O
+in,O
+24,O
+patients,O
+with,O
+retinoblastoma--12,O
+bilateral,O
+patients,O
+and,O
+12,O
+unilateral,O
+patients,O
+.,O
+ , 
+Mutation,O
+analysis,O
+was,O
+performed,O
+by,O
+PCR,O
+-,O
+mediated,O
+SSCP,O
+analysis,O
+in,O
+the,O
+entire,O
+coding,O
+region,O
+and,O
+promoter,O
+region,O
+,,O
+as,O
+an,O
+initial,O
+screening,O
+method,O
+,,O
+followed,O
+by,O
+direct,O
+genomic,O
+sequencing,O
+.,O
+ , 
+Possible,O
+oncogenic,O
+mutations,O
+were,O
+identified,O
+in,O
+14,O
+(,O
+58,O
+%,O
+),O
+of,O
+24,O
+tumors,O
+,,O
+of,O
+which,O
+6,O
+were,O
+single,O
+base,O
+substitutions,O
+,,O
+4,O
+were,O
+small,O
+deletions,O
+,,O
+3,O
+were,O
+small,O
+insertions,O
+,,O
+and,O
+1,O
+was,O
+a,O
+complex,O
+alteration,O
+due,O
+to,O
+deletion,O
+-,O
+insertion,O
+.,O
+ , 
+A,O
+constitutional,O
+somatic,O
+mosaicism,O
+was,O
+suggested,O
+in,O
+one,O
+bilateral,O
+patient,O
+.,O
+ , 
+A,O
+majority,O
+(,O
+57,O
+%,O
+),O
+of,O
+mutations,O
+were,O
+found,O
+in,O
+E1A,B-Gene
+binding,O
+domains,O
+,,O
+and,O
+all,O
+were,O
+presumed,O
+to,O
+truncate,O
+the,O
+normal,O
+gene,O
+products,O
+.,O
+ , 
+The,O
+mutation,O
+analysis,O
+presented,O
+here,O
+may,O
+provide,O
+a,O
+basis,O
+for,O
+the,O
+screening,O
+system,O
+of,O
+RB1,B-Gene
+gene,O
+mutations,O
+in,O
+retinoblastoma,O
+patients,O
+.,O
+ , 
+#1550114
+Early,O
+British,O
+discoveries,O
+in,O
+human,O
+genetics,O
+:,O
+contributions,O
+of,O
+R.A.,O
+Fisher,O
+and,O
+J.B.S.,O
+Haldane,O
+to,O
+the,O
+development,O
+of,O
+blood,O
+groups,O
+.,O
+ , 
+#17436244
+Hypomorphic,O
+mutations,O
+in,O
+the,O
+gene,O
+encoding,O
+a,O
+key,O
+Fanconi,B-Gene
+anemia,I-Gene
+protein,I-Gene
+,,I-Gene
+FANCD2,B-Gene
+,,I-Gene
+sustain,O
+a,O
+significant,O
+group,O
+of,O
+FA,O
+-,O
+D2,O
+patients,O
+with,O
+severe,O
+phenotype,O
+.,O
+ , 
+FANCD2,B-Gene
+is,O
+an,O
+evolutionarily,O
+conserved,O
+Fanconi,O
+anemia,O
+(,O
+FA,O
+),O
+gene,O
+that,O
+plays,O
+a,O
+key,O
+role,O
+in,O
+DNA,O
+double,O
+-,O
+strand,O
+-,O
+type,O
+damage,O
+responses,O
+.,O
+ , 
+Using,O
+complementation,O
+assays,O
+and,O
+immunoblotting,O
+,,O
+a,O
+consortium,O
+of,O
+American,O
+and,O
+European,O
+groups,O
+assigned,O
+29,O
+patients,O
+with,O
+FA,O
+from,O
+23,O
+families,O
+and,O
+4,O
+additional,O
+unrelated,O
+patients,O
+to,O
+complementation,O
+group,O
+FA,O
+-,O
+D2,O
+.,O
+ , 
+This,O
+amounts,O
+to,O
+3%-6,O
+%,O
+of,O
+FA,O
+-,O
+affected,O
+patients,O
+registered,O
+in,O
+various,O
+data,O
+sets,O
+.,O
+ , 
+Malformations,O
+are,O
+frequent,O
+in,O
+FA,O
+-,O
+D2,O
+patients,O
+,,O
+and,O
+hematological,O
+manifestations,O
+appear,O
+earlier,O
+and,O
+progress,O
+more,O
+rapidly,O
+when,O
+compared,O
+with,O
+all,O
+other,O
+patients,O
+combined,O
+(,O
+FA,O
+-,O
+non,O
+-,O
+D2,O
+),O
+in,O
+the,O
+International,O
+Fanconi,O
+Anemia,O
+Registry,O
+.,O
+ , 
+FANCD2,B-Gene
+is,O
+flanked,O
+by,O
+two,O
+pseudogenes,O
+.,O
+ , 
+Mutation,O
+analysis,O
+revealed,O
+the,O
+expected,O
+total,O
+of,O
+66,O
+mutated,O
+alleles,O
+,,O
+34,O
+of,O
+which,O
+result,O
+in,O
+aberrant,O
+splicing,O
+patterns,O
+.,O
+ , 
+Many,O
+mutations,O
+are,O
+recurrent,O
+and,O
+have,O
+ethnic,O
+associations,O
+and,O
+shared,O
+allelic,O
+haplotypes,O
+.,O
+ , 
+There,O
+were,O
+no,O
+biallelic,O
+null,O
+mutations,O
+;,O
+residual,O
+FANCD2,B-Gene
+protein,O
+of,O
+both,O
+isotypes,O
+was,O
+observed,O
+in,O
+all,O
+available,O
+patient,O
+cell,O
+lines,O
+.,O
+ , 
+These,O
+analyses,O
+suggest,O
+that,O
+,,O
+unlike,O
+the,O
+knockout,O
+mouse,O
+model,O
+,,O
+total,O
+absence,O
+of,O
+FANCD2,B-Gene
+does,O
+not,O
+exist,O
+in,O
+FA,O
+-,O
+D2,O
+patients,O
+,,O
+because,O
+of,O
+constraints,O
+on,O
+viable,O
+combinations,O
+of,O
+FANCD2,B-Gene
+mutations,O
+.,O
+ , 
+Although,O
+hypomorphic,O
+mutations,O
+arie,O
+involved,O
+,,O
+clinically,O
+,,O
+these,O
+patients,O
+have,O
+a,O
+relatively,O
+severe,O
+form,O
+of,O
+FA,O
+.,O
+ , 
+#10841811
+Segregation,O
+analysis,O
+of,O
+esophageal,O
+cancer,O
+in,O
+a,O
+moderately,O
+high,O
+-,O
+incidence,O
+area,O
+of,O
+northern,O
+China,O
+.,O
+ , 
+In,O
+order,O
+to,O
+explore,O
+the,O
+mode,O
+of,O
+inheritance,O
+of,O
+esophageal,O
+cancer,O
+in,O
+a,O
+moderately,O
+high,O
+-,O
+incidence,O
+area,O
+of,O
+northern,O
+China,O
+,,O
+we,O
+conducted,O
+a,O
+pedigree,O
+survey,O
+on,O
+225,O
+patients,O
+affected,O
+by,O
+esophageal,O
+cancer,O
+in,O
+Yangquan,O
+,,O
+Shanxi,O
+Province,O
+.,O
+ , 
+Segregation,O
+analysis,O
+was,O
+performed,O
+using,O
+the,O
+REGTL,O
+program,O
+of,O
+S.A.G.E.,O
+ , 
+The,O
+results,O
+showed,O
+that,O
+Mendelian,O
+autosomal,O
+recessive,O
+inheritance,O
+of,O
+a,O
+major,O
+gene,O
+that,O
+influences,O
+susceptibility,O
+to,O
+esophageal,O
+cancer,O
+provided,O
+the,O
+best,O
+fit,O
+to,O
+the,O
+data,O
+.,O
+ , 
+In,O
+the,O
+best,O
+-,O
+fitting,O
+recessive,O
+model,O
+,,O
+the,O
+frequency,O
+of,O
+the,O
+disease,O
+allele,O
+was.2039,O
+.,O
+ , 
+There,O
+was,O
+a,O
+significant,O
+sex,O
+effect,O
+on,O
+susceptibility,O
+to,O
+the,O
+disease,O
+.,O
+ , 
+The,O
+maximum,O
+cumulative,O
+probability,O
+of,O
+esophageal,O
+cancer,O
+among,O
+males,O
+with,O
+the,O
+AA,O
+genotype,O
+was,O
+100,O
+%,O
+,,O
+but,O
+,,O
+among,O
+females,O
+,,O
+it,O
+was,O
+63.5,O
+%,O
+.,O
+ , 
+The,O
+mean,O
+age,O
+at,O
+onset,O
+for,O
+both,O
+men,O
+and,O
+women,O
+was,O
+62,O
+years,O
+.,O
+ , 
+The,O
+age,O
+-,O
+dependent,O
+penetrances,O
+for,O
+males,O
+with,O
+the,O
+AA,O
+genotype,O
+by,O
+the,O
+ages,O
+of,O
+60,O
+and,O
+80,O
+years,O
+were,O
+41.6,O
+%,O
+and,O
+95.2,O
+%,O
+,,O
+respectively,O
+,,O
+whereas,O
+,,O
+for,O
+females,O
+,,O
+they,O
+were,O
+26.4,O
+%,O
+and,O
+60.5,O
+%,O
+,,O
+respectively,O
+.,O
+ , 
+Incorporating,O
+environmental,O
+risk,O
+factors,O
+-,O
+such,O
+as,O
+cigarette,O
+smoking,O
+,,O
+pipe,O
+smoking,O
+,,O
+alcohol,O
+drinking,O
+,,O
+eating,O
+hot,O
+food,O
+,,O
+and,O
+eating,O
+pickled,O
+vegetables,O
+-,O
+into,O
+the,O
+models,O
+did,O
+not,O
+provide,O
+significant,O
+improvement,O
+of,O
+the,O
+fit,O
+of,O
+the,O
+models,O
+to,O
+these,O
+data,O
+.,O
+ , 
+The,O
+results,O
+suggest,O
+a,O
+major,O
+locus,O
+underlying,O
+susceptibility,O
+to,O
+esophageal,O
+cancer,O
+with,O
+sex,O
+-,O
+specific,O
+penetrance,O
+.,O
+ , 
+#19836010
+Mutations,O
+in,O
+LTBP4,B-Gene
+cause,O
+a,O
+syndrome,O
+of,O
+impaired,O
+pulmonary,O
+,,O
+gastrointestinal,O
+,,O
+genitourinary,O
+,,O
+musculoskeletal,O
+,,O
+and,O
+dermal,O
+development,O
+.,O
+ , 
+We,O
+report,O
+recessive,O
+mutations,O
+in,O
+the,O
+gene,O
+for,O
+the,O
+latent,B-Gene
+transforming,I-Gene
+growth,I-Gene
+factor,I-Gene
+-,I-Gene
+beta,I-Gene
+binding,I-Gene
+protein,I-Gene
+4,I-Gene
+(,B-Gene
+LTBP4,I-Gene
+),I-Gene
+in,O
+four,O
+unrelated,O
+patients,O
+with,O
+a,O
+human,O
+syndrome,O
+disrupting,O
+pulmonary,O
+,,O
+gastrointestinal,O
+,,O
+urinary,O
+,,O
+musculoskeletal,O
+,,O
+craniofacial,O
+,,O
+and,O
+dermal,O
+development,O
+.,O
+ , 
+All,O
+patients,O
+had,O
+severe,O
+respiratory,O
+distress,O
+,,O
+with,O
+cystic,O
+and,O
+atelectatic,O
+changes,O
+in,O
+the,O
+lungs,O
+complicated,O
+by,O
+tracheomalacia,O
+and,O
+diaphragmatic,O
+hernia,O
+.,O
+ , 
+Three,O
+of,O
+the,O
+four,O
+patients,O
+died,O
+of,O
+respiratory,O
+failure,O
+.,O
+ , 
+Cardiovascular,O
+lesions,O
+were,O
+mild,O
+,,O
+limited,O
+to,O
+pulmonary,O
+artery,O
+stenosis,O
+and,O
+patent,O
+foramen,O
+ovale,O
+.,O
+ , 
+Gastrointestinal,O
+malformations,O
+included,O
+diverticulosis,O
+,,O
+enlargement,O
+,,O
+tortuosity,O
+,,O
+and,O
+stenosis,O
+at,O
+various,O
+levels,O
+of,O
+the,O
+intestinal,O
+tract,O
+.,O
+ , 
+The,O
+urinary,O
+tract,O
+was,O
+affected,O
+by,O
+diverticulosis,O
+and,O
+hydronephrosis,O
+.,O
+ , 
+Joint,O
+laxity,O
+and,O
+low,O
+muscle,O
+tone,O
+contributed,O
+to,O
+musculoskeletal,O
+problems,O
+compounded,O
+by,O
+postnatal,O
+growth,O
+delay,O
+.,O
+ , 
+Craniofacial,O
+features,O
+included,O
+microretrognathia,O
+,,O
+flat,O
+midface,O
+,,O
+receding,O
+forehead,O
+,,O
+and,O
+wide,O
+fontanelles,O
+.,O
+ , 
+All,O
+patients,O
+had,O
+cutis,O
+laxa,O
+.,O
+ , 
+Four,O
+of,O
+the,O
+five,O
+identified,O
+LTBP4,B-Gene
+mutations,O
+led,O
+to,O
+premature,O
+termination,O
+of,O
+translation,O
+and,O
+destabilization,O
+of,O
+the,O
+LTBP4,B-Gene
+mRNA,O
+.,O
+ , 
+Impaired,O
+synthesis,O
+and,O
+lack,O
+of,O
+deposition,O
+of,O
+LTBP4,B-Gene
+into,O
+the,O
+extracellular,O
+matrix,O
+(,O
+ECM,O
+),O
+caused,O
+increased,O
+transforming,B-Gene
+growth,I-Gene
+factor,I-Gene
+-,I-Gene
+beta,I-Gene
+(,B-Gene
+TGF,I-Gene
+-,I-Gene
+beta,I-Gene
+),I-Gene
+activity,O
+in,O
+cultured,O
+fibroblasts,O
+and,O
+defective,O
+elastic,O
+fiber,O
+assembly,O
+in,O
+all,O
+tissues,O
+affected,O
+by,O
+the,O
+disease,O
+.,O
+ , 
+These,O
+molecular,O
+defects,O
+were,O
+associated,O
+with,O
+blocked,O
+alveolarization,O
+and,O
+airway,O
+collapse,O
+in,O
+the,O
+lung,O
+.,O
+ , 
+Our,O
+results,O
+show,O
+that,O
+coupling,O
+of,O
+TGF,B-Gene
+-,I-Gene
+beta,I-Gene
+signaling,O
+and,O
+ECM,O
+assembly,O
+is,O
+essential,O
+for,O
+proper,O
+development,O
+and,O
+is,O
+achieved,O
+in,O
+multiple,O
+human,O
+organ,O
+systems,O
+by,O
+multifunctional,O
+proteins,O
+such,O
+as,O
+LTBP4,B-Gene
+.,I-Gene
+ , 
+#14872408
+Linkage,O
+analysis,O
+of,O
+extremely,O
+discordant,O
+and,O
+concordant,O
+sibling,O
+pairs,O
+identifies,O
+quantitative,O
+trait,O
+loci,O
+influencing,O
+variation,O
+in,O
+human,O
+menopausal,O
+age,O
+.,O
+ , 
+Age,O
+at,O
+natural,O
+menopause,O
+may,O
+be,O
+used,O
+as,O
+parameter,O
+for,O
+evaluating,O
+the,O
+rate,O
+of,O
+ovarian,O
+aging,O
+.,O
+ , 
+Environmental,O
+factors,O
+determine,O
+only,O
+a,O
+small,O
+part,O
+of,O
+the,O
+large,O
+variation,O
+in,O
+menopausal,O
+age,O
+.,O
+ , 
+Studies,O
+have,O
+shown,O
+that,O
+genetic,O
+factors,O
+are,O
+likely,O
+to,O
+be,O
+involved,O
+in,O
+variation,O
+in,O
+menopausal,O
+age,O
+.,O
+ , 
+To,O
+identify,O
+quantitative,O
+-,O
+trait,O
+loci,O
+for,O
+this,O
+trait,O
+,,O
+we,O
+performed,O
+a,O
+genomewide,O
+linkage,O
+study,O
+with,O
+age,O
+at,O
+natural,O
+menopause,O
+as,O
+a,O
+continuous,O
+quantitative,O
+phenotype,O
+in,O
+Dutch,O
+sister,O
+pairs,O
+,,O
+through,O
+use,O
+of,O
+a,O
+selective,O
+sampling,O
+scheme,O
+.,O
+ , 
+A,O
+total,O
+of,O
+165,O
+families,O
+were,O
+ascertained,O
+using,O
+extreme,O
+selected,O
+sampling,O
+and,O
+were,O
+genotyped,O
+for,O
+417,O
+markers,O
+.,O
+ , 
+Data,O
+were,O
+analyzed,O
+by,O
+Haseman,O
+-,O
+Elston,O
+regression,O
+and,O
+by,O
+an,O
+adjusted,O
+variance,O
+-,O
+components,O
+analysis,O
+.,O
+ , 
+Subgroup,O
+analyses,O
+for,O
+early,O
+and,O
+late,O
+menopausal,O
+age,O
+were,O
+conducted,O
+by,O
+Haseman,O
+-,O
+Elston,O
+regression,O
+.,O
+ , 
+In,O
+the,O
+adjusted,O
+variance,O
+-,O
+components,O
+analysis,O
+,,O
+12,O
+chromosomes,O
+had,O
+a,O
+LOD,O
+score,O
+of,O
+>,O
+or,O
+=,O
+1.0,O
+.,O
+ , 
+Two,O
+chromosomal,O
+regions,O
+showed,O
+suggestive,O
+linkage,O
+:,O
+9q21.3,O
+(,O
+LOD,O
+score,O
+2.6,O
+),O
+and,O
+Xp21.3,O
+(,O
+LOD,O
+score,O
+3.1,O
+),O
+.,O
+ , 
+Haseman,O
+-,O
+Elston,O
+regression,O
+showed,O
+rather,O
+similar,O
+locations,O
+of,O
+the,O
+peaks,O
+but,O
+yielded,O
+lower,O
+LOD,O
+scores,O
+.,O
+ , 
+A,O
+permutation,O
+test,O
+to,O
+obtain,O
+empirical,O
+P,O
+values,O
+resulted,O
+in,O
+a,O
+significant,O
+peak,O
+on,O
+the,O
+X,O
+chromosome,O
+.,O
+ , 
+To,O
+our,O
+knowledge,O
+,,O
+this,O
+is,O
+the,O
+first,O
+study,O
+to,O
+attempt,O
+to,O
+identify,O
+loci,O
+responsible,O
+for,O
+variability,O
+in,O
+menopausal,O
+age,O
+and,O
+in,O
+which,O
+several,O
+chromosomal,O
+regions,O
+were,O
+identified,O
+with,O
+suggestive,O
+and,O
+significant,O
+linkage,O
+.,O
+ , 
+Although,O
+the,O
+finding,O
+of,O
+the,O
+region,O
+on,O
+the,O
+X,O
+chromosome,O
+comes,O
+as,O
+no,O
+surprise,O
+,,O
+because,O
+of,O
+its,O
+widespread,O
+involvement,O
+in,O
+premature,O
+ovarian,O
+failure,O
+,,O
+the,O
+definition,O
+of,O
+which,O
+particular,O
+gene,O
+is,O
+involved,O
+is,O
+of,O
+great,O
+interest,O
+.,O
+ , 
+The,O
+region,O
+on,O
+chromosome,O
+9,O
+deserves,O
+further,O
+consideration,O
+.,O
+ , 
+Both,O
+findings,O
+require,O
+independent,O
+confirmation,O
+.,O
+ , 
+#11519010
+Evidence,O
+of,O
+linkage,O
+with,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
+in,O
+DRB1,O
+*,O
+15,O
+-,O
+negative,O
+families,O
+with,O
+multiple,O
+sclerosis,O
+.,O
+ , 
+The,O
+importance,O
+of,O
+the,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
+locus,O
+to,O
+multiple,O
+sclerosis,O
+(,O
+MS,O
+),O
+susceptibility,O
+was,O
+assessed,O
+in,O
+542,O
+sib,O
+pairs,O
+with,O
+MS,O
+and,O
+in,O
+their,O
+families,O
+.,O
+ , 
+By,O
+genotyping,O
+1,978,O
+individuals,O
+for,O
+HLA,B-Gene
+-,I-Gene
+DRB1,I-Gene
+alleles,O
+,,O
+we,O
+confirmed,O
+the,O
+well,O
+-,O
+established,O
+association,O
+of,O
+MS,O
+with,O
+HLA,B-Gene
+-,I-Gene
+DRB1,I-Gene
+*,I-Gene
+15,O
+(,B-Gene
+HLA,I-Gene
+-,I-Gene
+DRB1,I-Gene
+*,I-Gene
+1501,O
+and,O
+HLA,B-Gene
+-,I-Gene
+DRB5,I-Gene
+*,I-Gene
+0101,O
+),O
+,,O
+by,O
+the,O
+transmission,O
+/,O
+disequilibrium,O
+test,O
+(,O
+chi2=138.3,O
+;,O
+P<.0001,O
+),O
+.,O
+ , 
+We,O
+obtained,O
+significant,O
+evidence,O
+of,O
+linkage,O
+throughout,O
+the,O
+whole,O
+data,O
+set,O
+(,O
+mlod=4.09,O
+;,O
+59.9,O
+%,O
+sharing,O
+),O
+.,O
+ , 
+Surprisingly,O
+,,O
+similar,O
+sharing,O
+was,O
+also,O
+observed,O
+in,O
+58,O
+families,O
+in,O
+which,O
+both,O
+parents,O
+lacked,O
+the,O
+DRB1,B-Gene
+*,I-Gene
+15,O
+allele,O
+(,O
+mlod=1.56,O
+;,O
+62.7,O
+%,O
+sharing,O
+;,O
+P=.0081,O
+),O
+.,O
+ , 
+Our,O
+findings,O
+suggest,O
+that,O
+the,O
+notion,O
+that,O
+HLA,B-Gene
+-,I-Gene
+DRB1,I-Gene
+*,I-Gene
+15,O
+is,O
+the,O
+sole,O
+major,O
+-,O
+histocompatibility,O
+-,O
+complex,O
+determinant,O
+of,O
+susceptibility,O
+in,O
+northern,O
+-,O
+European,O
+populations,O
+with,O
+MS,O
+may,O
+be,O
+incorrect,O
+.,O
+ , 
+It,O
+remains,O
+possible,O
+that,O
+the,O
+association,O
+of,O
+MS,O
+with,O
+HLA,B-Gene
+-,I-Gene
+DRB1,I-Gene
+*,I-Gene
+15,O
+is,O
+due,O
+to,O
+linkage,O
+disequilibrium,O
+with,O
+a,O
+nearby,O
+locus,O
+and/or,O
+to,O
+the,O
+presence,O
+of,O
+disease,O
+-,O
+influencing,O
+allele(s,O
+),O
+in,O
+DRB1,B-Gene
+*,I-Gene
+15,O
+-,O
+negative,O
+haplotypes,O
+.,O
+ , 
+#18304497
+Splice,O
+mutation,O
+in,O
+the,O
+iron,B-Gene
+-,I-Gene
+sulfur,I-Gene
+cluster,I-Gene
+scaffold,I-Gene
+protein,I-Gene
+ISCU,B-Gene
+causes,O
+myopathy,O
+with,O
+exercise,O
+intolerance,O
+.,O
+ , 
+A,O
+myopathy,O
+with,O
+severe,O
+exercise,O
+intolerance,O
+and,O
+myoglobinuria,O
+has,O
+been,O
+described,O
+in,O
+patients,O
+from,O
+northern,O
+Sweden,O
+,,O
+with,O
+associated,O
+deficiencies,O
+of,O
+succinate,O
+dehydrogenase,O
+and,O
+aconitase,O
+in,O
+skeletal,O
+muscle,O
+.,O
+ , 
+We,O
+identified,O
+the,O
+gene,O
+for,O
+the,O
+iron,O
+-,O
+sulfur,O
+cluster,O
+scaffold,O
+protein,O
+ISCU,B-Gene
+as,O
+a,O
+candidate,O
+within,O
+a,O
+region,O
+of,O
+shared,O
+homozygosity,O
+among,O
+patients,O
+with,O
+this,O
+disease,O
+.,O
+ , 
+We,O
+found,O
+a,O
+single,O
+mutation,O
+in,O
+ISCU,B-Gene
+that,O
+likely,O
+strengthens,O
+a,O
+weak,O
+splice,O
+acceptor,O
+site,O
+,,O
+with,O
+consequent,O
+exon,O
+retention,O
+.,O
+ , 
+A,O
+marked,O
+reduction,O
+of,O
+ISCU,B-Gene
+mRNA,O
+and,O
+mitochondrial,O
+ISCU,B-Gene
+protein,O
+in,O
+patient,O
+muscle,O
+was,O
+associated,O
+with,O
+a,O
+decrease,O
+in,O
+the,O
+iron,B-Gene
+regulatory,I-Gene
+protein,I-Gene
+IRP1,B-Gene
+and,O
+intracellular,O
+iron,O
+overload,O
+in,O
+skeletal,O
+muscle,O
+,,O
+consistent,O
+with,O
+a,O
+muscle,O
+-,O
+specific,O
+alteration,O
+of,O
+iron,O
+homeostasis,O
+in,O
+this,O
+disease,O
+.,O
+ , 
+ISCU,B-Gene
+interacts,O
+with,O
+the,O
+Friedreich,O
+ataxia,O
+gene,O
+product,O
+frataxin,O
+in,O
+iron,O
+-,O
+sulfur,O
+cluster,O
+biosynthesis,O
+.,O
+ , 
+Our,O
+results,O
+therefore,O
+extend,O
+the,O
+range,O
+of,O
+known,O
+human,O
+diseases,O
+that,O
+are,O
+caused,O
+by,O
+defects,O
+in,O
+iron,O
+-,O
+sulfur,O
+cluster,O
+biogenesis,O
+.,O
+ , 
+#9463308
+Susceptibility,O
+to,O
+relapsing,O
+-,O
+progressive,O
+multiple,O
+sclerosis,O
+is,O
+associated,O
+with,O
+inheritance,O
+of,O
+genes,O
+linked,O
+to,O
+the,O
+variable,O
+region,O
+of,O
+the,O
+TcR,O
+beta,O
+locus,O
+:,O
+use,O
+of,O
+affected,O
+family,O
+-,O
+based,O
+controls,O
+.,O
+ , 
+We,O
+tested,O
+the,O
+hypothesis,O
+that,O
+susceptibility,O
+to,O
+relapsing,O
+-,O
+progressive,O
+(,O
+RP,O
+),O
+(,O
+but,O
+not,O
+to,O
+relapsing,O
+-,O
+remitting,O
+[,O
+RR,O
+],O
+),O
+multiple,O
+sclerosis,O
+(,O
+MS,O
+),O
+is,O
+associated,O
+with,O
+a,O
+gene,O
+linked,O
+to,O
+the,O
+TcR,O
+beta,O
+-,O
+chain,O
+variable,O
+region,O
+delimited,O
+by,O
+the,O
+Vbeta8,O
+-,O
+BamHI,O
+and,O
+Vbeta11,O
+-,O
+BamHI,O
+RFLP,O
+alleles,O
+in,O
+DRw15,O
++,O
+MS,O
+patients,O
+,,O
+using,O
+a,O
+contingency,O
+-,O
+table,O
+test,O
+of,O
+patient,O
+data,O
+and,O
+affected,O
+family,O
+-,O
+based,O
+controls,O
+.,O
+ , 
+Control,O
+alleles,O
+and,O
+haplotypes,O
+were,O
+composed,O
+of,O
+parental,O
+marker,O
+alleles,O
+and,O
+haplotypes,O
+not,O
+transmitted,O
+to,O
+the,O
+affected,O
+child,O
+,,O
+in,O
+90,O
+simplex,O
+and,O
+31,O
+multiplex,O
+families,O
+from,O
+British,O
+Columbia,O
+.,O
+ , 
+A,O
+total,O
+of,O
+6,164,O
+alleles,O
+at,O
+11,O
+loci,O
+were,O
+segregated,O
+through,O
+families,O
+of,O
+probands,O
+with,O
+RP,O
+MS,O
+or,O
+RR,O
+MS,O
+.,O
+ , 
+The,O
+Vbeta8,O
+-,O
+Vbeta11,O
+subhaplotype,O
+frequencies,O
+in,O
+the,O
+DRw15,O
++,O
+RP,O
+MS,O
+(,O
+but,O
+not,O
+RR,O
+MS,O
+),O
+patients,O
+differed,O
+from,O
+control,O
+frequencies,O
+,,O
+because,O
+of,O
+an,O
+increase,O
+of,O
+the,O
+2,O
+-,O
+1,O
+subhaplotype,O
+(,O
+P=.02,O
+),O
+.,O
+ , 
+Vbeta8,O
+-,O
+BamHI,O
+and,O
+Vbeta11,O
+-,O
+BamHI,O
+allele,O
+frequencies,O
+(,O
+P=.05,O
+and,O
+.009,O
+,,O
+respectively,O
+),O
+in,O
+the,O
+DRw15,O
++,O
+RP,O
+MS,O
+(,O
+but,O
+not,O
+RR,O
+MS,O
+),O
+patients,O
+differed,O
+from,O
+control,O
+frequencies,O
+.,O
+ , 
+The,O
+Vbeta1,O
+-,O
+Vbeta8,O
+subhaplotype,O
+frequencies,O
+in,O
+the,O
+DRw15-,O
+RP,O
+MS,O
+(,O
+but,O
+not,O
+RR,O
+MS,O
+),O
+patients,O
+differed,O
+from,O
+control,O
+frequencies,O
+(,O
+P=.03,O
+),O
+,,O
+with,O
+a,O
+significantly,O
+increased,O
+frequency,O
+of,O
+the,O
+1,O
+-,O
+1,O
+subhaplotype,O
+(,O
+P=.01,O
+;,O
+RR=7.1,O
+),O
+in,O
+RP,O
+MS,O
+versus,O
+RR,O
+MS,O
+patients,O
+.,O
+ , 
+Susceptibility,O
+to,O
+RP,O
+MS,O
+is,O
+associated,O
+both,O
+with,O
+a,O
+recessive,O
+inheritance,O
+of,O
+a,O
+gene,O
+linked,O
+to,O
+the,O
+3,O
+',O
+(,O
+Vbeta11,O
+),O
+end,O
+of,O
+the,O
+2,O
+-,O
+1,O
+subhaplotype,O
+defined,O
+by,O
+the,O
+Vbeta8,O
+-,O
+BamHI,O
+and,O
+Vbeta11,O
+-,O
+BamHI,O
+alleles,O
+in,O
+DRw15,O
++,O
+patients,O
+and,O
+with,O
+a,O
+gene,O
+,,O
+located,O
+on,O
+the,O
+1,O
+-,O
+1,O
+subhaplotype,O
+,,O
+defined,O
+by,O
+the,O
+Vbeta1,O
+-,O
+TaqI,O
+and,O
+Vbeta8,O
+-,O
+MspI,O
+alleles,O
+of,O
+the,O
+TcR,O
+beta,O
+-,O
+chain,O
+complex,O
+in,O
+DRw15-,O
+patients,O
+.,O
+ , 
+#7509237
+Complex,O
+mutation,O
+4114,B-SNP
+ , 
+ATA-->TT,B-SNP
+in,O
+exon,O
+22,O
+of,O
+the,O
+cystic,O
+fibrosis,O
+gene,O
+CFTR,B-Gene
+.,I-Gene
+ , 
+#9792408
+A,O
+frequent,O
+TG,O
+deletion,O
+near,O
+the,O
+polyadenylation,O
+signal,O
+of,O
+the,O
+human,O
+HEXB,B-Gene
+gene,O
+:,O
+occurrence,O
+of,O
+an,O
+irregular,O
+DNA,O
+structure,O
+and,O
+conserved,O
+nucleotide,O
+sequence,O
+motif,O
+in,O
+the,O
+3,O
+',O
+untranslated,O
+region,O
+.,O
+ , 
+While,O
+screening,O
+for,O
+new,O
+mutations,O
+in,O
+the,O
+HEXB,B-Gene
+gene,O
+,,O
+which,O
+encodes,O
+the,O
+beta,O
+-,O
+subunit,O
+of,O
+beta,B-Gene
+-,I-Gene
+hexosaminidase,I-Gene
+,,I-Gene
+a,O
+TG,O
+deletion,O
+(,B-SNP
+deltaTG,I-SNP
+),I-SNP
+was,I-SNP
+found,I-SNP
+in,I-SNP
+the,I-SNP
+3,I-SNP
+',I-SNP
+untranslated,I-SNP
+region,I-SNP
+(,I-SNP
+3'UTR,I-SNP
+),I-SNP
+of,I-SNP
+the,I-SNP
+gene,I-SNP
+,,I-SNP
+7,I-SNP
+bp,I-SNP
+upstream,I-SNP
+from,I-SNP
+the,I-SNP
+polyadenylation,I-SNP
+signal,I-SNP
+.,I-SNP
+ , 
+Examination,O
+of,O
+DNA,O
+samples,O
+of,O
+145,O
+unrelated,O
+Argentinean,O
+individuals,O
+from,O
+different,O
+racial,O
+backgrounds,O
+showed,O
+that,O
+the,O
+deltaTG,O
+allele,O
+was,O
+present,O
+with,O
+a,O
+frequency,O
+of,O
+approximately,O
+0.1,O
+,,O
+compared,O
+with,O
+the,O
+wild,O
+-,O
+type,O
+(,O
+WT,O
+),O
+allele,O
+.,O
+ , 
+The,O
+deletion,O
+was,O
+not,O
+associated,O
+with,O
+infantile,O
+or,O
+variant,O
+forms,O
+of,O
+Sandhoff,O
+disease,O
+when,O
+present,O
+in,O
+combination,O
+with,O
+a,O
+deleterious,O
+allele,O
+.,O
+ , 
+Total,O
+Hex,B-Gene
+and,O
+Hex,B-Gene
+B,I-Gene
+enzymatic,O
+activities,O
+measured,O
+in,O
+individuals,O
+heterozygous,O
+for,O
+deltaTG,O
+and,O
+a,O
+null,O
+allele,O
+,,O
+IVS-2,B-SNP
++,I-SNP
+1G-->A,I-SNP
+(,O
+G-->A,O
+),O
+,,O
+were,O
+approximately,O
+30,O
+%,O
+lower,O
+than,O
+the,O
+activities,O
+of,O
+G-->A,O
+/,O
+WT,O
+individuals,O
+.,O
+ , 
+Analysis,O
+of,O
+the,O
+HEXB,B-Gene
+mRNA,O
+from,O
+leukocytes,O
+of,O
+deltaTG,O
+/,O
+WT,O
+individuals,O
+by,O
+RT,O
+-,O
+PCR,O
+of,O
+the,O
+3'UTR,O
+showed,O
+that,O
+the,O
+deltaTG,O
+allele,O
+is,O
+present,O
+at,O
+lower,O
+level,O
+than,O
+the,O
+WT,O
+allele,O
+.,O
+ , 
+By,O
+polyacrylamide,O
+gel,O
+electrophoresis,O
+,,O
+it,O
+was,O
+determined,O
+that,O
+a,O
+PCR,O
+fragment,O
+containing,O
+the,O
++,O
+TG,O
+version,O
+of,O
+the,O
+3'UTR,O
+of,O
+the,O
+HEXB,O
+gene,O
+had,O
+an,O
+irregular,O
+structure,O
+.,O
+ , 
+On,O
+inspection,O
+of,O
+genes,O
+containing,O
+a,O
+TG,O
+dinucleotide,O
+upstream,O
+from,O
+the,O
+polyadenylation,O
+signal,O
+we,O
+found,O
+that,O
+this,O
+dinucleotide,O
+was,O
+part,O
+of,O
+a,O
+conserved,O
+sequence,O
+(,O
+TGTTTT,O
+),O
+immersed,O
+in,O
+a,O
+A,O
+/,O
+T,O
+-,O
+rich,O
+region,O
+.,O
+ , 
+This,O
+sequence,O
+arrangement,O
+was,O
+present,O
+in,O
+more,O
+than,O
+40,O
+%,O
+analyzed,O
+eukaryotic,O
+mRNAs,O
+,,O
+including,O
+in,O
+the,O
+human,O
+,,O
+mouse,O
+and,O
+cat,O
+HEXB,O
+genes,O
+.,O
+ , 
+The,O
+significance,O
+of,O
+the,O
+TG,O
+deletion,O
+in,O
+reference,O
+to,O
+Sandhoff,O
+disease,O
+as,O
+well,O
+as,O
+the,O
+possible,O
+functional,O
+role,O
+of,O
+the,O
+consensus,O
+sequence,O
+and,O
+the,O
+DNA,O
+structure,O
+of,O
+the,O
+3'UTR,O
+are,O
+considered,O
+.,O
+ , 
+#17879353
+Multiple,O
+endocrine,O
+neoplasia,O
+type,O
+1,O
+(,O
+MEN1,O
+):,O
+analysis,O
+of,O
+1336,O
+mutations,O
+reported,O
+in,O
+the,O
+first,O
+decade,O
+following,O
+identification,O
+of,O
+the,O
+gene,O
+.,O
+ , 
+Multiple,O
+endocrine,O
+neoplasia,O
+type,O
+1,O
+(,O
+MEN1,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+disorder,O
+characterized,O
+by,O
+the,O
+occurrence,O
+of,O
+tumors,O
+of,O
+the,O
+parathyroids,O
+,,O
+pancreas,O
+,,O
+and,O
+anterior,O
+pituitary,O
+.,O
+ , 
+The,O
+MEN1,B-Gene
+gene,O
+,,O
+which,O
+was,O
+identified,O
+in,O
+1997,O
+,,O
+consists,O
+of,O
+10,O
+exons,O
+that,O
+encode,O
+a,O
+610,O
+-,O
+amino,O
+acid,O
+protein,O
+referred,O
+to,O
+as,O
+menin,B-Gene
+.,I-Gene
+ , 
+Menin,B-Gene
+is,O
+predominantly,O
+a,O
+nuclear,O
+protein,O
+that,O
+has,O
+roles,O
+in,O
+transcriptional,O
+regulation,O
+,,O
+genome,O
+stability,O
+,,O
+cell,O
+division,O
+,,O
+and,O
+proliferation,O
+.,O
+ , 
+Germline,O
+mutations,O
+usually,O
+result,O
+in,O
+MEN1,O
+or,O
+occasionally,O
+in,O
+an,O
+allelic,O
+variant,O
+referred,O
+to,O
+as,O
+familial,O
+isolated,O
+hyperparathyroidism,O
+(,O
+FIHP,O
+),O
+.,O
+ , 
+MEN1,O
+tumors,O
+frequently,O
+have,O
+loss,O
+of,O
+heterozygosity,O
+(,O
+LOH,O
+),O
+of,O
+the,O
+MEN1,B-Gene
+locus,O
+,,O
+which,O
+is,O
+consistent,O
+with,O
+a,O
+tumor,O
+suppressor,O
+role,O
+of,O
+MEN1,B-Gene
+.,I-Gene
+ , 
+Furthermore,O
+,,O
+somatic,O
+abnormalities,O
+of,O
+MEN1,B-Gene
+have,O
+been,O
+reported,O
+in,O
+MEN1,O
+and,O
+non,O
+-,O
+MEN1,O
+endocrine,O
+tumors,O
+.,O
+ , 
+The,O
+clinical,O
+aspects,O
+and,O
+molecular,O
+genetics,O
+of,O
+MEN1,B-Gene
+are,O
+reviewed,O
+together,O
+with,O
+the,O
+reported,O
+1,336,O
+mutations,O
+.,O
+ , 
+The,O
+majority,O
+(,O
+>,O
+70,O
+%,O
+),O
+of,O
+these,O
+mutations,O
+are,O
+predicted,O
+to,O
+lead,O
+to,O
+truncated,O
+forms,O
+of,O
+menin,O
+.,O
+ , 
+The,O
+mutations,O
+are,O
+scattered,O
+throughout,O
+the>9,O
+-,O
+kb,O
+genomic,O
+sequence,O
+of,O
+the,O
+MEN1,B-Gene
+gene,O
+.,O
+ , 
+Four,O
+,,O
+which,O
+consist,O
+of,O
+c.249_252delGTCT,B-SNP
+(,O
+deletion,O
+at,O
+codons,O
+83,O
+-,O
+84,O
+),O
+,,O
+c.1546_1547insC,B-SNP
+(,O
+insertion,O
+at,O
+codon,O
+516,O
+),O
+,,O
+c.1378C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+Arg460Ter,I-SNP
+),I-SNP
+,,O
+and,O
+c.628_631delACAG,B-SNP
+(,O
+deletion,O
+at,O
+codons,O
+210,O
+-,O
+211,O
+),O
+have,O
+been,O
+reported,O
+to,O
+occur,O
+frequently,O
+in,O
+4.5,O
+%,O
+,,O
+2.7,O
+%,O
+,,O
+2.6,O
+%,O
+,,O
+and,O
+2.5,O
+%,O
+of,O
+families,O
+,,O
+respectively,O
+.,O
+ , 
+However,O
+,,O
+a,O
+comparison,O
+of,O
+the,O
+clinical,O
+features,O
+in,O
+patients,O
+and,O
+their,O
+families,O
+with,O
+the,O
+same,O
+mutations,O
+reveals,O
+an,O
+absence,O
+of,O
+phenotype,O
+-,O
+genotype,O
+correlations,O
+.,O
+ , 
+The,O
+majority,O
+of,O
+MEN1,B-Gene
+mutations,O
+are,O
+likely,O
+to,O
+disrupt,O
+the,O
+interactions,O
+of,O
+menin,O
+with,O
+other,O
+proteins,O
+and,O
+thereby,O
+alter,O
+critical,O
+events,O
+in,O
+cell,O
+cycle,O
+regulation,O
+and,O
+proliferation,O
+.,O
+ , 
+#12618959
+Autosomal,O
+recessive,O
+HEM,O
+/,O
+Greenberg,O
+skeletal,O
+dysplasia,O
+is,O
+caused,O
+by,O
+3,O
+beta,O
+-,O
+hydroxysterol,O
+delta,O
+14,O
+-,O
+reductase,O
+deficiency,O
+due,O
+to,O
+mutations,O
+in,O
+the,O
+lamin,B-Gene
+B,I-Gene
+receptor,I-Gene
+gene,O
+.,O
+ , 
+Hydrops,O
+-,O
+ectopic,O
+calcification-"moth,O
+-,O
+eaten,O
+",O
+(,O
+HEM,O
+),O
+or,O
+Greenberg,O
+skeletal,O
+dysplasia,O
+ , 
+is,O
+an,O
+autosomal,O
+recessive,O
+chondrodystrophy,O
+with,O
+a,O
+lethal,O
+course,O
+,,O
+characterized,O
+by,O
+fetal,O
+hydrops,O
+,,O
+short,O
+limbs,O
+,,O
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+abnormal,O
+chondro,O
+-,O
+osseous,O
+calcification,O
+.,O
+ , 
+We,O
+found,O
+elevated,O
+levels,O
+of,O
+cholesta-8,14,O
+-,O
+dien-3beta,O
+-,O
+ol,O
+in,O
+cultured,O
+skin,O
+fibroblasts,O
+of,O
+an,O
+18,O
+-,O
+wk,O
+-,O
+old,O
+fetus,O
+with,O
+HEM,O
+,,O
+compatible,O
+with,O
+a,O
+deficiency,O
+of,O
+the,O
+cholesterol,O
+biosynthetic,O
+enzyme,O
+3beta,B-Gene
+-,I-Gene
+hydroxysterol,I-Gene
+delta(14)-reductase,I-Gene
+.,I-Gene
+ , 
+Sequence,O
+analysis,O
+of,O
+two,O
+candidate,O
+genes,O
+encoding,O
+putative,O
+human,B-Gene
+sterol,I-Gene
+delta(14)-reductases,I-Gene
+(,B-Gene
+TM7SF2,I-Gene
+and,O
+LBR,B-Gene
+),I-Gene
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+1599,B-SNP
+-,I-SNP
+1605TCTTCTA-->CTAGAAG,I-SNP
+substitution,O
+in,O
+exon,O
+13,O
+of,O
+the,O
+LBR,B-Gene
+gene,O
+encoding,O
+the,O
+lamin,O
+B,O
+receptor,O
+,,O
+which,O
+results,O
+in,O
+a,O
+truncated,O
+protein,O
+.,O
+ , 
+Functional,O
+complementation,O
+of,O
+the,O
+HEM,O
+cells,O
+by,O
+transfection,O
+with,O
+control,O
+LBR,O
+cDNA,O
+confirmed,O
+that,O
+LBR,B-Gene
+encoded,O
+the,O
+defective,O
+sterol,O
+delta(14)-reductase,O
+.,O
+ , 
+Mutations,O
+in,O
+LBR,B-Gene
+recently,O
+have,O
+been,O
+reported,O
+also,O
+to,O
+cause,O
+Pelger,O
+-,O
+Huët,O
+anomaly,O
+,,O
+an,O
+autosomal,O
+dominant,O
+trait,O
+characterized,O
+by,O
+hypolobulated,O
+nuclei,O
+and,O
+abnormal,O
+chromatin,O
+structure,O
+in,O
+granulocytes,O
+.,O
+ , 
+The,O
+fact,O
+that,O
+the,O
+healthy,O
+mother,O
+of,O
+the,O
+fetus,O
+showed,O
+hypolobulated,O
+nuclei,O
+in,O
+60,O
+%,O
+of,O
+her,O
+granulocytes,O
+confirms,O
+that,O
+classic,O
+Pelger,O
+-,O
+Huët,O
+anomaly,O
+represents,O
+the,O
+heterozygous,O
+state,O
+of,O
+3beta,B-Gene
+-,I-Gene
+hydroxysterol,I-Gene
+delta(14)-reductase,I-Gene
+deficiency,O
+.,O
+ , 
+#11333381
+Niemann,O
+-,O
+Pick,O
+C1,O
+disease,O
+:,O
+correlations,O
+between,O
+NPC1,B-Gene
+mutations,O
+,,O
+levels,O
+of,O
+NPC1,B-Gene
+protein,O
+,,O
+and,O
+ , 
+phenotypes,O
+emphasize,O
+the,O
+functional,O
+significance,O
+of,O
+the,O
+putative,O
+sterol,O
+-,O
+sensing,O
+domain,O
+and,O
+of,O
+the,O
+cysteine,O
+-,O
+rich,O
+luminal,O
+loop,O
+.,O
+ , 
+To,O
+obtain,O
+more,O
+information,O
+of,O
+the,O
+functional,O
+domains,O
+of,O
+the,O
+NPC1,B-Gene
+protein,O
+,,O
+the,O
+mutational,O
+spectrum,O
+and,O
+the,O
+level,O
+of,O
+immunoreactive,O
+protein,O
+were,O
+investigated,O
+in,O
+skin,O
+fibroblasts,O
+from,O
+30,O
+unrelated,O
+patients,O
+with,O
+Niemann,O
+-,O
+Pick,O
+C1,O
+disease,O
+.,O
+ , 
+Nine,O
+of,O
+them,O
+were,O
+characterized,O
+by,O
+mild,O
+alterations,O
+of,O
+cellular,O
+cholesterol,O
+transport,O
+(,O
+the,O
+",O
+variant,O
+",O
+biochemical,O
+phenotype,O
+),O
+.,O
+ , 
+The,O
+mutations,O
+showed,O
+a,O
+wide,O
+distribution,O
+to,O
+nearly,O
+all,O
+NPC1,B-Gene
+domains,O
+,,O
+with,O
+a,O
+cluster,O
+(,O
+11/32,O
+),O
+in,O
+a,O
+conserved,O
+NPC1,B-Gene
+cysteine,O
+-,O
+rich,O
+luminal,O
+loop,O
+.,O
+ , 
+Homozygous,O
+mutations,O
+in,O
+14,O
+patients,O
+and,O
+a,O
+phenotypically,O
+defined,O
+allele,O
+,,O
+combined,O
+with,O
+a,O
+new,O
+mutation,O
+,,O
+in,O
+a,O
+further,O
+10,O
+patients,O
+allowed,O
+genotype,O
+/,O
+phenotype,O
+correlations,O
+.,O
+ , 
+Premature,O
+-,O
+termination,O
+-,O
+codon,O
+mutations,O
+,,O
+the,O
+three,O
+missense,O
+mutations,O
+in,O
+the,O
+sterol,O
+-,O
+sensing,O
+domain,O
+(,O
+SSD,O
+),O
+,,O
+and,O
+A1054,B-SNP
+T,I-SNP
+in,O
+the,O
+cysteine,O
+-,O
+rich,O
+luminal,O
+loop,O
+all,O
+occurred,O
+in,O
+patients,O
+with,O
+infantile,O
+neurological,O
+onset,O
+and,O
+",O
+classic,O
+",O
+(,O
+severe,O
+),O
+cholesterol,O
+-,O
+trafficking,O
+alterations,O
+.,O
+ , 
+By,O
+western,O
+blot,O
+,,O
+NPC1,B-Gene
+protein,O
+was,O
+undetectable,O
+in,O
+the,O
+SSD,O
+missense,O
+mutations,O
+studied,O
+(,B-SNP
+L724P,I-SNP
+and,O
+Q775P,B-SNP
+),I-SNP
+and,O
+essentially,O
+was,O
+absent,O
+in,O
+the,O
+A1054,B-SNP
+T,I-SNP
+missense,O
+allele,O
+.,O
+ , 
+Our,O
+results,O
+thus,O
+enhance,O
+the,O
+functional,O
+significance,O
+of,O
+the,O
+SSD,O
+and,O
+demonstrate,O
+a,O
+correlation,O
+between,O
+the,O
+absence,O
+of,O
+NPC1,B-Gene
+protein,O
+and,O
+the,O
+most,O
+severe,O
+neurological,O
+form,O
+.,O
+ , 
+In,O
+the,O
+remaining,O
+missense,O
+mutations,O
+studied,O
+,,O
+corresponding,O
+to,O
+other,O
+disease,O
+presentations,O
+(,O
+including,O
+two,O
+adults,O
+with,O
+nonneurological,O
+disease,O
+),O
+,,O
+NPC1,B-Gene
+protein,O
+was,O
+present,O
+in,O
+significant,O
+amounts,O
+of,O
+normal,O
+size,O
+,,O
+without,O
+clear,O
+-,O
+cut,O
+correlation,O
+with,O
+either,O
+the,O
+clinical,O
+phenotype,O
+or,O
+the,O
+",O
+classic"/"variant,O
+",O
+biochemical,O
+phenotype,O
+.,O
+ , 
+Missense,O
+mutations,O
+in,O
+the,O
+cysteine,O
+-,O
+rich,O
+luminal,O
+loop,O
+resulted,O
+in,O
+a,O
+wide,O
+array,O
+of,O
+clinical,O
+and,O
+biochemical,O
+phenotypes,O
+.,O
+ , 
+Remarkably,O
+,,O
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+five,O
+mutant,O
+alleles,O
+(,B-SNP
+I943,I-SNP
+M,I-SNP
+,,I-SNP
+V950,B-SNP
+M,I-SNP
+,,I-SNP
+G986S,B-SNP
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+G992R,B-SNP
+,,I-SNP
+and,O
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+recurrent,O
+P1007A,B-SNP
+),I-SNP
+definitively,O
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+with,O
+the,O
+",O
+variant,O
+",O
+phenotype,O
+clustered,O
+within,O
+this,O
+loop,O
+,,O
+providing,O
+new,O
+insight,O
+on,O
+the,O
+functional,O
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+of,O
+the,O
+latter,O
+domain,O
+.,O
+ , 
+#22770979
+Presence,O
+of,O
+multiple,O
+independent,O
+effects,O
+in,O
+risk,O
+loci,O
+of,O
+common,O
+complex,O
+human,O
+diseases,O
+.,O
+ , 
+Many,O
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+loci,O
+and,O
+SNPs,O
+associated,O
+with,O
+many,O
+common,O
+complex,O
+human,O
+diseases,O
+and,O
+traits,O
+are,O
+now,O
+identified,O
+.,O
+ , 
+The,O
+total,O
+genetic,O
+variance,O
+explained,O
+by,O
+these,O
+loci,O
+for,O
+a,O
+trait,O
+or,O
+disease,O
+,,O
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+,,O
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+often,O
+been,O
+very,O
+small,O
+.,O
+ , 
+Much,O
+of,O
+the,O
+",O
+missing,O
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+",O
+has,O
+been,O
+revealed,O
+to,O
+be,O
+hidden,O
+in,O
+the,O
+genome,O
+among,O
+the,O
+large,O
+number,O
+of,O
+variants,O
+with,O
+small,O
+effects,O
+.,O
+ , 
+Several,O
+recent,O
+studies,O
+have,O
+reported,O
+the,O
+presence,O
+of,O
+multiple,O
+independent,O
+SNPs,O
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+genetic,O
+heterogeneity,O
+in,O
+trait,O
+-,O
+associated,O
+loci,O
+.,O
+ , 
+It,O
+is,O
+therefore,O
+reasonable,O
+to,O
+speculate,O
+that,O
+such,O
+a,O
+phenomenon,O
+could,O
+be,O
+common,O
+among,O
+loci,O
+known,O
+to,O
+be,O
+associated,O
+with,O
+a,O
+complex,O
+trait,O
+or,O
+disease,O
+.,O
+ , 
+For,O
+testing,O
+this,O
+hypothesis,O
+,,O
+a,O
+total,O
+of,O
+117,O
+loci,O
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+to,O
+be,O
+associated,O
+with,O
+rheumatoid,O
+arthritis,O
+(,O
+RA,O
+),O
+,,O
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+(,O
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+),O
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+(,O
+T1D,O
+),O
+,,O
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+type,O
+2,O
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+(,O
+T2D,O
+),O
+were,O
+selected,O
+.,O
+ , 
+The,O
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+of,O
+multiple,O
+independent,O
+effects,O
+was,O
+assessed,O
+in,O
+the,O
+case,O
+-,O
+control,O
+samples,O
+genotyped,O
+by,O
+the,O
+Wellcome,O
+Trust,O
+Case,O
+Control,O
+Consortium,O
+study,O
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+imputed,O
+with,O
+SNP,O
+genotype,O
+information,O
+from,O
+the,O
+HapMap,O
+Project,O
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+the,O
+1000,O
+Genomes,O
+Project,O
+.,O
+ , 
+Eleven,O
+loci,O
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+evidence,O
+of,O
+multiple,O
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+were,O
+identified,O
+in,O
+the,O
+study,O
+,,O
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+the,O
+number,O
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+expected,O
+to,O
+increase,O
+at,O
+larger,O
+sample,O
+sizes,O
+and,O
+improved,O
+statistical,O
+power,O
+.,O
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+The,O
+variance,O
+explained,O
+by,O
+the,O
+multiple,O
+effects,O
+in,O
+a,O
+locus,O
+was,O
+much,O
+higher,O
+than,O
+the,O
+variance,O
+explained,O
+by,O
+the,O
+single,O
+reported,O
+SNP,O
+effect,O
+.,O
+ , 
+The,O
+results,O
+thus,O
+significantly,O
+improve,O
+our,O
+understanding,O
+of,O
+the,O
+allelic,O
+structure,O
+of,O
+these,O
+individual,O
+disease,O
+-,O
+associated,O
+loci,O
+,,O
+as,O
+well,O
+as,O
+our,O
+knowledge,O
+of,O
+the,O
+general,O
+genetic,O
+mechanisms,O
+of,O
+common,O
+complex,O
+traits,O
+and,O
+diseases,O
+.,O
+ , 
+#22290723
+Association,O
+of,O
+glycosylated,O
+hemoglobin,O
+with,O
+the,O
+gene,O
+encoding,O
+CDKAL1,B-Gene
+in,O
+the,O
+Korean,O
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+Resource,O
+(,O
+KARE,O
+),O
+study,O
+.,O
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+Genome,O
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+associations,O
+with,O
+glycosylated,O
+hemoglobin,O
+,,O
+which,O
+reflects,O
+the,O
+long,O
+-,O
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+glycemia,O
+,,O
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+examined,O
+using,O
+two,O
+independent,O
+cohorts,O
+of,O
+the,O
+Korea,O
+Association,O
+Resource,O
+(,O
+KARE,O
+),O
+consortium,O
+.,O
+ , 
+We,O
+first,O
+identified,O
+sequence,O
+variants,O
+within,O
+a,O
+linkage,O
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+block,O
+(,O
+r(2,O
+),O
+>,O
+0.98,O
+),O
+in,O
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+intron,O
+5,O
+of,O
+cyclin,B-Gene
+-,I-Gene
+dependent,I-Gene
+kinase,I-Gene
+5,I-Gene
+regulatory,I-Gene
+subunit,I-Gene
+-,I-Gene
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+protein,I-Gene
+1,I-Gene
+-,I-Gene
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+1,I-Gene
+(,B-Gene
+CDKAL1,I-Gene
+),I-Gene
+gene,O
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+4,275,O
+normoglycemic,O
+subjects,O
+of,O
+Cohort,O
+1,O
+(,O
+P,O
+<,O
+2.5,O
+×,O
+10(-8,O
+),O
+),O
+.,O
+ , 
+The,O
+association,O
+was,O
+replicated,O
+in,O
+3,782,O
+normoglycemic,O
+subjects,O
+of,O
+Cohort,O
+2,O
+.,O
+ , 
+Furthermore,O
+,,O
+the,O
+sequence,O
+variants,O
+were,O
+also,O
+associated,O
+with,O
+glucose,O
+levels,O
+after,O
+oral,O
+glucose,O
+tolerance,O
+test,O
+.,O
+ , 
+Especially,O
+,,O
+a,O
+strong,O
+association,O
+with,O
+1,O
+h,O
+glucose,O
+(,O
+P,O
+=,O
+1.3,O
+×,O
+10(-11,O
+),O
+),O
+led,O
+us,O
+to,O
+interpreting,O
+that,O
+CDKAL1,B-Gene
+might,O
+influence,O
+the,O
+level,O
+of,O
+glycosylated,O
+hemoglobin,O
+by,O
+affecting,O
+1,O
+h,O
+glucose,O
+level,O
+.,O
+ , 
+Ultimately,O
+,,O
+accumulated,O
+effects,O
+on,O
+the,O
+glycosylated,O
+hemoglobin,O
+level,O
+by,O
+the,O
+genetic,O
+variation,O
+of,O
+CDKAL1,B-Gene
+might,O
+affect,O
+susceptibility,O
+to,O
+type,O
+2,O
+diabetes,O
+mellitus,O
+.,O
+ , 
+#9199548
+Genetics,O
+of,O
+narcolepsy,O
+and,O
+other,O
+sleep,O
+disorders,O
+.,O
+ , 
+#11309680
+Identification,O
+of,O
+a,O
+new,O
+candidate,O
+locus,O
+for,O
+uric,O
+acid,O
+nephrolithiasis,O
+.,O
+ , 
+Renal,O
+stone,O
+formation,O
+is,O
+a,O
+common,O
+multifactorial,O
+disorder,O
+,,O
+of,O
+unknown,O
+etiology,O
+,,O
+with,O
+an,O
+established,O
+genetic,O
+contribution,O
+.,O
+ , 
+Lifetime,O
+risk,O
+for,O
+nephrolithiasis,O
+is,O
+approximately,O
+10,O
+%,O
+in,O
+Western,O
+populations,O
+,,O
+and,O
+uric,O
+acid,O
+stones,O
+account,O
+for,O
+5%-10,O
+%,O
+of,O
+all,O
+stones,O
+,,O
+depending,O
+on,O
+climatic,O
+,,O
+dietary,O
+,,O
+and,O
+ethnic,O
+differences,O
+.,O
+ , 
+We,O
+studied,O
+a,O
+small,O
+,,O
+isolated,O
+founder,O
+population,O
+in,O
+Sardinia,O
+,,O
+characterized,O
+by,O
+an,O
+increased,O
+prevalence,O
+of,O
+uric,O
+acid,O
+stones,O
+,,O
+and,O
+performed,O
+a,O
+genomewide,O
+search,O
+in,O
+a,O
+deep,O
+-,O
+rooted,O
+pedigree,O
+comprising,O
+many,O
+members,O
+who,O
+formed,O
+uric,O
+acid,O
+renal,O
+stones,O
+.,O
+ , 
+The,O
+pedigree,O
+was,O
+created,O
+by,O
+tracing,O
+common,O
+ancestors,O
+of,O
+affected,O
+individuals,O
+through,O
+a,O
+genealogical,O
+database,O
+based,O
+on,O
+archival,O
+records,O
+kept,O
+by,O
+the,O
+parish,O
+church,O
+since,O
+1640,O
+.,O
+ , 
+This,O
+genealogical,O
+information,O
+was,O
+used,O
+as,O
+the,O
+basis,O
+for,O
+the,O
+study,O
+strategy,O
+,,O
+involving,O
+screening,O
+for,O
+alleles,O
+shared,O
+among,O
+affected,O
+individuals,O
+,,O
+originating,O
+from,O
+common,O
+ancestors,O
+,,O
+and,O
+utilization,O
+of,O
+large,O
+pedigrees,O
+to,O
+obtain,O
+greater,O
+power,O
+for,O
+linkage,O
+detection,O
+.,O
+ , 
+We,O
+performed,O
+multistep,O
+linkage,O
+and,O
+allele,O
+-,O
+sharing,O
+analyses,O
+.,O
+ , 
+In,O
+the,O
+initial,O
+stage,O
+,,O
+382,O
+markers,O
+were,O
+typed,O
+in,O
+14,O
+closely,O
+related,O
+affected,O
+subjects,O
+;,O
+interesting,O
+regions,O
+were,O
+subsequently,O
+investigated,O
+in,O
+the,O
+whole,O
+sample,O
+.,O
+ , 
+We,O
+identified,O
+two,O
+chromosomal,O
+regions,O
+that,O
+may,O
+harbor,O
+loci,O
+with,O
+susceptibility,O
+genes,O
+for,O
+uric,O
+acid,O
+stones,O
+.,O
+ , 
+The,O
+strongest,O
+evidence,O
+was,O
+observed,O
+on,O
+10q21,O
+-,O
+q22,O
+,,O
+where,O
+a,O
+LOD,O
+score,O
+of,O
+3.07,O
+was,O
+obtained,O
+for,O
+D10S1652,B-SNP
+under,O
+an,O
+affected,O
+-,O
+only,O
+dominant,O
+model,O
+,,O
+and,O
+a,O
+LOD,O
+score,O
+of,O
+3.90,O
+was,O
+obtained,O
+using,O
+a,O
+dominant,O
+pseudomarker,O
+assignment,O
+.,O
+ , 
+The,O
+localization,O
+was,O
+supported,O
+also,O
+by,O
+multipoint,O
+allele,O
+-,O
+sharing,O
+statistics,O
+and,O
+by,O
+haplotype,O
+analysis,O
+of,O
+familial,O
+cases,O
+and,O
+of,O
+unrelated,O
+affected,O
+subjects,O
+collected,O
+from,O
+the,O
+isolate,O
+.,O
+ , 
+In,O
+the,O
+second,O
+region,O
+on,O
+20q13.1,O
+-,O
+13.3,O
+,,O
+multipoint,O
+nonparametric,O
+scores,O
+yielded,O
+suggestive,O
+evidence,O
+in,O
+a,O
+approximately,O
+20,O
+-,O
+cM,O
+region,O
+,,O
+and,O
+further,O
+analysis,O
+is,O
+needed,O
+to,O
+confirm,O
+and,O
+fine,O
+-,O
+map,O
+this,O
+putative,O
+locus,O
+.,O
+ , 
+Replication,O
+studies,O
+are,O
+required,O
+to,O
+investigate,O
+the,O
+involvement,O
+of,O
+these,O
+regions,O
+in,O
+the,O
+genetic,O
+contribution,O
+to,O
+uric,O
+acid,O
+stone,O
+formation,O
+.,O
+ , 
+#21394829
+WAVe,O
+:,O
+web,O
+analysis,O
+of,O
+the,O
+variome,O
+.,O
+ , 
+DNA,O
+sequence,O
+variation,O
+is,O
+the,O
+underlying,O
+basis,O
+of,O
+common,O
+human,O
+traits,O
+and,O
+rarer,O
+single,O
+-,O
+gene,O
+disorders,O
+.,O
+ , 
+Understanding,O
+the,O
+variome,O
+,,O
+the,O
+variants,O
+in,O
+an,O
+individual,O
+'s,O
+genome,O
+,,O
+is,O
+essential,O
+to,O
+enable,O
+the,O
+ultimate,O
+goals,O
+of,O
+personalized,O
+medicine,O
+.,O
+ , 
+This,O
+critical,O
+research,O
+field,O
+has,O
+grown,O
+dramatically,O
+in,O
+recent,O
+years,O
+,,O
+mostly,O
+due,O
+to,O
+the,O
+spread,O
+and,O
+development,O
+of,O
+genotyping,O
+technologies,O
+.,O
+ , 
+Despite,O
+these,O
+activities,O
+being,O
+promoted,O
+by,O
+the,O
+Human,O
+Genome,O
+Variation,O
+Society,O
+and,O
+projects,O
+such,O
+as,O
+the,O
+Human,O
+Variome,O
+Project,O
+or,O
+the,O
+European,O
+GEN2PHEN,O
+Project,O
+,,O
+variome,O
+data,O
+-,O
+integration,O
+systems,O
+are,O
+far,O
+from,O
+being,O
+widely,O
+used,O
+in,O
+the,O
+research,O
+community,O
+workflow,O
+.,O
+ , 
+Most,O
+of,O
+ongoing,O
+research,O
+is,O
+focused,O
+on,O
+improving,O
+locus,O
+-,O
+specific,O
+databases,O
+.,O
+ , 
+Although,O
+the,O
+quality,O
+and,O
+manual,O
+curation,O
+of,O
+LSDBs,O
+adds,O
+true,O
+value,O
+to,O
+this,O
+domain,O
+,,O
+they,O
+are,O
+often,O
+narrow,O
+,,O
+heterogeneous,O
+,,O
+and,O
+independent,O
+systems,O
+.,O
+ , 
+This,O
+hampers,O
+data,O
+harmonization,O
+and,O
+interoperability,O
+between,O
+systems,O
+,,O
+stifling,O
+the,O
+aggregation,O
+of,O
+data,O
+from,O
+LSDBs,O
+and,O
+related,O
+data,O
+sources,O
+.,O
+ , 
+A,O
+new,O
+platform,O
+entitled,O
+Web,O
+Analysis,O
+of,O
+the,O
+Variome,O
+,,O
+WAVe,O
+,,O
+is,O
+introduced,O
+.,O
+ , 
+It,O
+offers,O
+direct,O
+and,O
+programmatic,O
+access,O
+to,O
+multiple,O
+locus,O
+-,O
+specific,O
+databases,O
+,,O
+with,O
+the,O
+integration,O
+of,O
+genetic,O
+variation,O
+datasets,O
+and,O
+enrichment,O
+with,O
+relevant,O
+information,O
+.,O
+ , 
+WAVe,O
+'s,O
+agile,O
+and,O
+innovative,O
+Web,O
+interface,O
+is,O
+accessible,O
+at,O
+http://bioinformatics.ua.pt/WAVe,O
+.,O
+ , 
+#15526234
+Sex,O
+-,O
+specific,O
+genetic,O
+architecture,O
+of,O
+whole,O
+blood,O
+serotonin,O
+levels,O
+.,O
+ , 
+Recently,O
+,,O
+a,O
+quantitative,O
+-,O
+trait,O
+locus,O
+(,O
+QTL,O
+),O
+for,O
+whole,O
+blood,O
+serotonin,O
+level,O
+was,O
+identified,O
+in,O
+a,O
+genomewide,O
+linkage,O
+and,O
+association,O
+study,O
+in,O
+a,O
+founder,O
+population,O
+.,O
+ , 
+Because,O
+serotonin,O
+level,O
+is,O
+a,O
+sexually,O
+dimorphic,O
+trait,O
+,,O
+in,O
+the,O
+present,O
+study,O
+,,O
+we,O
+evaluated,O
+the,O
+sex,O
+-,O
+specific,O
+genetic,O
+architecture,O
+of,O
+whole,O
+blood,O
+serotonin,O
+level,O
+in,O
+the,O
+same,O
+population,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+use,O
+an,O
+extended,O
+homozygosity,O
+-,O
+by,O
+-,O
+descent,O
+linkage,O
+method,O
+that,O
+is,O
+suitable,O
+for,O
+large,O
+complex,O
+pedigrees,O
+.,O
+ , 
+Although,O
+both,O
+males,O
+and,O
+females,O
+have,O
+high,O
+broad,O
+heritability,O
+(,O
+H2=0.99,O
+),O
+,,O
+females,O
+have,O
+a,O
+higher,O
+additive,O
+component,O
+(,O
+h2=0.63,O
+in,O
+females,O
+;,O
+h2=0.27,O
+in,O
+males,O
+),O
+.,O
+ , 
+Furthermore,O
+,,O
+the,O
+serotonin,O
+QTL,O
+on,O
+17q,O
+that,O
+was,O
+identified,O
+previously,O
+in,O
+this,O
+population,O
+,,O
+integrin,B-Gene
+beta,I-Gene
+3,I-Gene
+(,B-Gene
+ITGB3,I-Gene
+),I-Gene
+,,O
+and,O
+a,O
+novel,O
+locus,O
+on,O
+2q,O
+influence,O
+serotonin,O
+levels,O
+only,O
+in,O
+males,O
+,,O
+whereas,O
+linkage,O
+to,O
+a,O
+region,O
+on,O
+chromosome,O
+6q,O
+is,O
+specific,O
+to,O
+females,O
+.,O
+ , 
+Both,O
+sexes,O
+contribute,O
+to,O
+linkage,O
+signals,O
+on,O
+12q,O
+and,O
+16p,O
+.,O
+ , 
+There,O
+were,O
+,,O
+overall,O
+,,O
+more,O
+associations,O
+meeting,O
+criteria,O
+for,O
+suggestive,O
+significance,O
+in,O
+males,O
+than,O
+in,O
+females,O
+,,O
+including,O
+those,O
+of,O
+ITGB3,B-Gene
+and,O
+the,O
+serotonin,B-Gene
+transporter,I-Gene
+gene,O
+(,B-Gene
+5HTT,I-Gene
+),I-Gene
+.,O
+ , 
+This,O
+analysis,O
+is,O
+consistent,O
+with,O
+heritable,O
+sexual,O
+dimorphism,O
+in,O
+whole,O
+blood,O
+serotonin,O
+levels,O
+resulting,O
+from,O
+the,O
+effects,O
+of,O
+a,O
+combination,O
+of,O
+sex,O
+-,O
+specific,O
+and,O
+sex,O
+-,O
+independent,O
+loci,O
+.,O
+ , 
+#8304341
+Isolation,O
+of,O
+novel,O
+non,O
+-,O
+HLA,O
+gene,O
+fragments,O
+from,O
+the,O
+hemochromatosis,O
+region,O
+(,O
+6p21.3,O
+),O
+by,O
+cDNA,O
+hybridization,O
+selection,O
+.,O
+ , 
+It,O
+has,O
+previously,O
+been,O
+shown,O
+that,O
+cDNA,O
+hybridization,O
+selection,O
+can,O
+identify,O
+and,O
+recover,O
+novel,O
+genes,O
+from,O
+large,O
+cloned,O
+genomic,O
+DNA,O
+such,O
+as,O
+cosmids,O
+or,O
+YACs,O
+.,O
+ , 
+In,O
+an,O
+effort,O
+to,O
+identify,O
+candidate,O
+genes,O
+for,O
+hemochromatosis,O
+,,O
+this,O
+technique,O
+was,O
+applied,O
+to,O
+a,O
+320,O
+-,O
+kb,O
+YAC,O
+containing,O
+the,O
+HLA,B-Gene
+-,I-Gene
+A,I-Gene
+gene,O
+.,O
+ , 
+A,O
+short,O
+fragment,O
+cDNA,O
+library,O
+derived,O
+from,O
+human,O
+duodenum,O
+was,O
+selected,O
+with,O
+the,O
+YAC,O
+DNA,O
+.,O
+ , 
+Ten,O
+novel,O
+gene,O
+fragments,O
+were,O
+isolated,O
+,,O
+characterized,O
+,,O
+and,O
+localized,O
+on,O
+the,O
+physical,O
+map,O
+of,O
+the,O
+YAC,O
+.,O
+ , 
+#18381613
+A,O
+multicenter,O
+study,O
+on,O
+the,O
+prevalence,O
+and,O
+spectrum,O
+of,O
+mutations,O
+in,O
+the,O
+otoferlin,B-Gene
+gene,I-Gene
+(,B-Gene
+OTOF,I-Gene
+),I-Gene
+in,O
+subjects,O
+with,O
+nonsyndromic,O
+hearing,O
+impairment,O
+and,O
+auditory,O
+neuropathy,O
+.,O
+ , 
+Autosomal,O
+recessive,O
+nonsyndromic,O
+hearing,O
+impairment,O
+(,O
+NSHI,O
+),O
+is,O
+a,O
+heterogeneous,O
+condition,O
+,,O
+for,O
+which,O
+53,O
+genetic,O
+loci,O
+have,O
+been,O
+reported,O
+,,O
+and,O
+29,O
+genes,O
+have,O
+been,O
+identified,O
+to,O
+date,O
+.,O
+ , 
+One,O
+of,O
+these,O
+,,O
+OTOF,O
+,,O
+encodes,O
+otoferlin,O
+,,O
+a,O
+membrane,O
+-,O
+anchored,O
+calcium,O
+-,O
+binding,O
+protein,O
+that,O
+plays,O
+a,O
+role,O
+in,O
+the,O
+exocytosis,O
+of,O
+synaptic,O
+vesicles,O
+at,O
+the,O
+auditory,O
+inner,O
+hair,O
+cell,O
+ribbon,O
+synapse,O
+.,O
+ , 
+We,O
+have,O
+investigated,O
+the,O
+prevalence,O
+and,O
+spectrum,O
+of,O
+deafness,O
+-,O
+causing,O
+mutations,O
+in,O
+the,O
+OTOF,B-Gene
+gene,O
+.,O
+ , 
+Cohorts,O
+of,O
+708,O
+Spanish,O
+,,O
+83,O
+Colombian,O
+,,O
+and,O
+30,O
+Argentinean,O
+unrelated,O
+subjects,O
+with,O
+autosomal,O
+recessive,O
+NSHI,O
+were,O
+screened,O
+for,O
+the,O
+common,O
+p.,B-SNP
+Gln829X,I-SNP
+mutation,O
+.,O
+ , 
+In,O
+compound,O
+heterozygotes,O
+,,O
+the,O
+second,O
+mutant,O
+allele,O
+was,O
+identified,O
+by,O
+DNA,O
+sequencing,O
+.,O
+ , 
+In,O
+total,O
+,,O
+23,O
+Spanish,O
+,,O
+two,O
+Colombian,O
+and,O
+two,O
+Argentinean,O
+subjects,O
+were,O
+shown,O
+to,O
+carry,O
+two,O
+mutant,O
+alleles,O
+of,O
+OTOF,O
+.,O
+ , 
+Of,O
+these,O
+,,O
+one,O
+Colombian,O
+and,O
+13,O
+Spanish,O
+subjects,O
+presented,O
+with,O
+auditory,O
+neuropathy,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+a,O
+cohort,O
+of,O
+20,O
+unrelated,O
+subjects,O
+with,O
+a,O
+diagnosis,O
+of,O
+auditory,O
+neuropathy,O
+,,O
+from,O
+several,O
+countries,O
+,,O
+was,O
+screened,O
+for,O
+mutations,O
+in,O
+OTOF,O
+by,O
+DNA,O
+sequencing,O
+.,O
+ , 
+A,O
+total,O
+of,O
+11,O
+of,O
+these,O
+subjects,O
+were,O
+shown,O
+to,O
+carry,O
+two,O
+mutant,O
+alleles,O
+of,O
+OTOF,B-Gene
+.,I-Gene
+ , 
+In,O
+total,O
+,,O
+18,O
+pathogenic,O
+and,O
+four,O
+neutral,O
+novel,O
+alleles,O
+of,O
+the,O
+OTOF,B-Gene
+gene,O
+were,O
+identified,O
+.,O
+ , 
+Haplotype,O
+analysis,O
+for,O
+markers,O
+close,O
+to,O
+OTOF,B-Gene
+suggests,O
+a,O
+common,O
+founder,O
+for,O
+the,O
+novel,O
+c.2905_2923delinsCTCCGAGCGCA,B-SNP
+mutation,O
+,,O
+frequently,O
+found,O
+in,O
+Argentina,O
+.,O
+ , 
+Our,O
+results,O
+confirm,O
+that,O
+mutation,O
+of,O
+the,O
+OTOF,B-Gene
+gene,O
+correlates,O
+with,O
+a,O
+phenotype,O
+of,O
+prelingual,O
+,,O
+profound,O
+NSHI,O
+,,O
+and,O
+indicate,O
+that,O
+OTOF,B-Gene
+mutations,O
+are,O
+a,O
+major,O
+cause,O
+of,O
+inherited,O
+auditory,O
+neuropathy,O
+.,O
+ , 
+#11644969
+Ethical,O
+guidelines,O
+for,O
+enzyme,O
+therapy,O
+in,O
+neuronopathic,O
+Gaucher,O
+disease,O
+.,O
+ , 
+#8533785
+No,O
+difference,O
+in,O
+the,O
+parental,O
+origin,O
+of,O
+susceptibility,O
+HLA,O
+class,O
+II,O
+haplotypes,O
+among,O
+Norwegian,O
+patients,O
+with,O
+insulin,O
+-,O
+dependent,O
+diabetes,O
+mellitus,O
+.,O
+ , 
+#12145749
+Order,O
+of,O
+intron,O
+removal,O
+influences,O
+multiple,O
+splice,O
+outcomes,O
+,,O
+including,O
+a,O
+two,O
+-,O
+exon,O
+skip,O
+,,O
+in,O
+a,O
+COL5A1,B-Gene
+acceptor,O
+-,O
+site,O
+mutation,O
+that,O
+results,O
+in,O
+abnormal,O
+pro,O
+-,O
+alpha1(V,O
+),O
+N,O
+-,O
+propeptides,O
+and,O
+Ehlers,O
+-,O
+Danlos,O
+syndrome,O
+type,O
+I.,O
+Ehlers,O
+-,O
+Danlos,O
+syndrome,O
+(,O
+EDS,O
+),O
+type,O
+I,O
+(,O
+the,O
+classical,O
+variety,O
+),O
+is,O
+a,O
+dominantly,O
+inherited,O
+,,O
+genetically,O
+heterogeneous,O
+connective,O
+-,O
+tissue,O
+disorder,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+COL5A1,B-Gene
+and,O
+COL5A2,B-Gene
+genes,O
+,,O
+which,O
+encode,O
+type,O
+V,O
+collagen,O
+,,O
+have,O
+been,O
+identified,O
+in,O
+several,O
+individuals,O
+.,O
+ , 
+Most,O
+mutations,O
+affect,O
+either,O
+the,O
+triple,O
+-,O
+helical,O
+domain,O
+of,O
+the,O
+protein,O
+or,O
+the,O
+expression,O
+of,O
+one,O
+COL5A1,B-Gene
+allele,O
+.,O
+ , 
+We,O
+identified,O
+a,O
+novel,O
+splice,O
+-,O
+acceptor,O
+mutation,O
+(,B-SNP
+IVS4,I-SNP
+-,I-SNP
+2A-->G,I-SNP
+),I-SNP
+in,O
+the,O
+N,O
+-,O
+propeptide,O
+-,O
+encoding,O
+region,O
+of,O
+COL5A1,B-Gene
+,,I-Gene
+in,O
+one,O
+patient,O
+with,O
+EDS,O
+type,O
+I.,O
+ , 
+The,O
+outcome,O
+of,O
+this,O
+mutation,O
+was,O
+complex,O
+:,O
+ , 
+In,O
+the,O
+major,O
+product,O
+,,O
+both,O
+exons,O
+5,O
+and,O
+6,O
+were,O
+skipped,O
+;,O
+other,O
+products,O
+included,O
+a,O
+small,O
+amount,O
+in,O
+which,O
+only,O
+exon,O
+5,O
+was,O
+skipped,O
+and,O
+an,O
+even,O
+smaller,O
+amount,O
+in,O
+which,O
+cryptic,O
+acceptor,O
+sites,O
+within,O
+exon,O
+5,O
+were,O
+used,O
+.,O
+ , 
+All,O
+products,O
+were,O
+in,O
+frame,O
+.,O
+ , 
+Pro,O
+-,O
+alpha1(V,O
+),O
+chains,O
+with,O
+abnormal,O
+N,O
+-,O
+propeptides,O
+were,O
+secreted,O
+and,O
+were,O
+incorporated,O
+into,O
+extracellular,O
+matrix,O
+,,O
+and,O
+the,O
+mutation,O
+resulted,O
+in,O
+dramatic,O
+alterations,O
+in,O
+collagen,O
+fibril,O
+structure,O
+.,O
+ , 
+The,O
+two,O
+-,O
+exon,O
+skip,O
+occurred,O
+in,O
+transcripts,O
+in,O
+which,O
+intron,O
+5,O
+was,O
+removed,O
+rapidly,O
+relative,O
+to,O
+introns,O
+4,O
+and,O
+6,O
+,,O
+leaving,O
+a,O
+large,O
+(,O
+270,O
+nt,O
+),O
+composite,O
+exon,O
+that,O
+can,O
+be,O
+skipped,O
+in,O
+its,O
+entirety,O
+.,O
+ , 
+The,O
+transcripts,O
+in,O
+which,O
+only,O
+exon,O
+5,O
+was,O
+skipped,O
+were,O
+derived,O
+from,O
+those,O
+in,O
+which,O
+intron,O
+6,O
+was,O
+removed,O
+prior,O
+to,O
+intron,O
+5,O
+.,O
+ , 
+The,O
+use,O
+of,O
+cryptic,O
+acceptor,O
+sites,O
+in,O
+exon,O
+5,O
+occurred,O
+in,O
+transcripts,O
+in,O
+which,O
+intron,O
+4,O
+was,O
+removed,O
+subsequent,O
+to,O
+introns,O
+5,O
+and,O
+6,O
+.,O
+ , 
+These,O
+findings,O
+suggest,O
+that,O
+the,O
+order,O
+of,O
+intron,O
+removal,O
+plays,O
+an,O
+important,O
+role,O
+in,O
+the,O
+outcome,O
+of,O
+splice,O
+-,O
+site,O
+mutations,O
+and,O
+provide,O
+a,O
+model,O
+that,O
+explains,O
+why,O
+multiple,O
+products,O
+derive,O
+from,O
+a,O
+mutation,O
+at,O
+a,O
+single,O
+splice,O
+site,O
+.,O
+ , 
+#16960803
+Satb2,B-Gene
+haploinsufficiency,O
+phenocopies,O
+2q32,O
+-,O
+q33,O
+deletions,O
+,,O
+whereas,O
+loss,O
+suggests,O
+a,O
+fundamental,O
+role,O
+in,O
+the,O
+coordination,O
+of,O
+jaw,O
+development,O
+.,O
+ , 
+The,O
+recent,O
+identification,O
+of,O
+SATB2,B-Gene
+as,O
+a,O
+candidate,O
+gene,O
+responsible,O
+for,O
+the,O
+craniofacial,O
+dysmorphologies,O
+associated,O
+with,O
+deletions,O
+and,O
+translocations,O
+at,O
+2q32,O
+-,O
+q33,O
+,,O
+one,O
+of,O
+only,O
+three,O
+regions,O
+of,O
+the,O
+genome,O
+for,O
+which,O
+haploinsufficiency,O
+has,O
+been,O
+significantly,O
+associated,O
+with,O
+isolated,O
+cleft,O
+palate,O
+,,O
+led,O
+us,O
+to,O
+investigate,O
+the,O
+in,O
+vivo,O
+functions,O
+of,O
+murine,O
+Satb2,B-Gene
+.,I-Gene
+ , 
+We,O
+find,O
+that,O
+,,O
+similar,O
+to,O
+the,O
+way,O
+in,O
+which,O
+SATB2,B-Gene
+is,O
+perceived,O
+to,O
+act,O
+in,O
+humans,O
+,,O
+craniofacial,O
+defects,O
+due,O
+to,O
+haploinsufficiency,O
+of,O
+Satb2,B-Gene
+,,I-Gene
+including,O
+cleft,O
+palate,O
+(,O
+in,O
+approximately,O
+25,O
+%,O
+of,O
+cases,O
+),O
+,,O
+phenocopy,O
+those,O
+seen,O
+with,O
+2q32,O
+-,O
+q33,O
+deletions,O
+and,O
+translocations,O
+in,O
+humans,O
+.,O
+ , 
+Full,O
+functional,O
+loss,O
+of,O
+Satb2,B-Gene
+results,O
+in,O
+amplification,O
+of,O
+these,O
+defects,O
+and,O
+leads,O
+both,O
+to,O
+increased,O
+apoptosis,O
+in,O
+the,O
+craniofacial,O
+mesenchyme,O
+where,O
+Satb2,B-Gene
+is,O
+usually,O
+expressed,O
+and,O
+to,O
+changes,O
+in,O
+the,O
+pattern,O
+of,O
+expression,O
+of,O
+three,O
+genes,O
+implicated,O
+in,O
+the,O
+regulation,O
+of,O
+craniofacial,O
+development,O
+in,O
+humans,O
+and,O
+mice,O
+:,O
+Pax9,B-Gene
+,,I-Gene
+Alx4,B-Gene
+,,I-Gene
+and,O
+Msx1,B-Gene
+.,I-Gene
+ , 
+The,O
+Satb2,O
+-,O
+dosage,O
+sensitivity,O
+in,O
+craniofacial,O
+development,O
+is,O
+conspicuous,O
+--,O
+along,O
+with,O
+its,O
+control,O
+of,O
+cell,O
+survival,O
+,,O
+pattern,O
+of,O
+expression,O
+,,O
+and,O
+reversible,O
+functional,O
+modification,O
+by,O
+SUMOylation,O
+,,O
+it,O
+suggests,O
+that,O
+Satb2,B-Gene
+/,I-Gene
+SATB2,I-Gene
+function,O
+in,O
+craniofacial,O
+development,O
+may,O
+prove,O
+to,O
+be,O
+more,O
+profound,O
+than,O
+has,O
+been,O
+anticipated,O
+previously,O
+.,O
+ , 
+Because,O
+jaw,O
+development,O
+is,O
+Satb2,O
+-,O
+dosage,O
+sensitive,O
+,,O
+the,O
+regulators,O
+of,O
+Satb2,B-Gene
+expression,O
+and,O
+posttranslational,O
+modification,O
+become,O
+of,O
+critical,O
+importance,O
+both,O
+ontogenetically,O
+and,O
+evolutionarily,O
+,,O
+especially,O
+since,O
+such,O
+regulators,O
+plausibly,O
+play,O
+undetected,O
+roles,O
+in,O
+jaw,O
+and,O
+palate,O
+development,O
+and,O
+in,O
+the,O
+etiology,O
+of,O
+craniofacial,O
+malformations,O
+.,O
+ , 
+#17357082
+Identification,O
+of,O
+a,O
+novel,O
+risk,O
+locus,O
+for,O
+progressive,O
+supranuclear,O
+palsy,O
+by,O
+a,O
+pooled,O
+genomewide,O
+scan,O
+of,O
+500,288,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+.,O
+ , 
+To,O
+date,O
+,,O
+only,O
+the,O
+H1,O
+MAPT,B-Gene
+haplotype,O
+has,O
+been,O
+consistently,O
+associated,O
+with,O
+risk,O
+of,O
+developing,O
+the,O
+neurodegenerative,O
+disease,O
+progressive,O
+supranuclear,O
+palsy,O
+(,O
+PSP,O
+),O
+.,O
+ , 
+We,O
+hypothesized,O
+that,O
+additional,O
+genetic,O
+loci,O
+may,O
+be,O
+involved,O
+in,O
+conferring,O
+risk,O
+of,O
+PSP,O
+that,O
+could,O
+be,O
+identified,O
+through,O
+a,O
+pooling,O
+-,O
+based,O
+genomewide,O
+association,O
+study,O
+of,O
+>,O
+500,000,O
+SNPs,O
+.,O
+ , 
+Candidate,O
+SNPs,O
+with,O
+large,O
+differences,O
+in,O
+allelic,O
+frequency,O
+were,O
+identified,O
+by,O
+ranking,O
+all,O
+SNPs,O
+by,O
+their,O
+probe,O
+-,O
+intensity,O
+difference,O
+between,O
+cohorts,O
+.,O
+ , 
+The,O
+MAPT,B-Gene
+H1,O
+haplotype,O
+was,O
+strongly,O
+detected,O
+by,O
+this,O
+methodology,O
+,,O
+as,O
+was,O
+a,O
+second,O
+major,O
+locus,O
+on,O
+chromosome,O
+11p12,O
+-,O
+p11,O
+that,O
+showed,O
+evidence,O
+of,O
+association,O
+at,O
+allelic,O
+(,O
+P<.001,O
+),O
+,,O
+genotypic,O
+(,O
+P<.001,O
+),O
+,,O
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+haplotypic,O
+(,O
+P<.001,O
+),O
+levels,O
+and,O
+was,O
+narrowed,O
+to,O
+a,O
+single,O
+haplotype,O
+block,O
+containing,O
+the,O
+DNA,B-Gene
+damage,I-Gene
+-,I-Gene
+binding,I-Gene
+protein,I-Gene
+2,I-Gene
+(,B-Gene
+DDB2,I-Gene
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+and,O
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+acid,I-Gene
+phosphatase,I-Gene
+2,I-Gene
+(,B-Gene
+ACP2,I-Gene
+),I-Gene
+genes,O
+.,O
+ , 
+Since,O
+DNA,O
+damage,O
+and,O
+lysosomal,O
+dysfunction,O
+have,O
+been,O
+implicated,O
+in,O
+aging,O
+and,O
+neurodegenerative,O
+processes,O
+,,O
+both,O
+genes,O
+are,O
+viable,O
+candidates,O
+for,O
+conferring,O
+risk,O
+of,O
+disease,O
+.,O
+ , 
+#12619118
+Germline,O
+TP53,B-Gene
+mutations,O
+and,O
+Li,O
+-,O
+Fraumeni,O
+syndrome,O
+.,O
+ , 
+There,O
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+now,O
+reports,O
+of,O
+nearly,O
+250,O
+independent,O
+germline,O
+TP53,B-Gene
+(,B-Gene
+p53,I-Gene
+),I-Gene
+mutations,O
+in,O
+over,O
+100,O
+publications,O
+.,O
+ , 
+Such,O
+mutations,O
+are,O
+typically,O
+associated,O
+with,O
+Li,O
+-,O
+Fraumeni,O
+or,O
+Li,O
+-,O
+Fraumeni,O
+-,O
+like,O
+syndrome,O
+,,O
+although,O
+many,O
+have,O
+been,O
+identified,O
+in,O
+cohorts,O
+of,O
+patients,O
+with,O
+tumors,O
+considered,O
+to,O
+be,O
+typical,O
+of,O
+LFS,O
+.,O
+ , 
+In,O
+general,O
+,,O
+the,O
+spectrum,O
+of,O
+mutations,O
+that,O
+has,O
+been,O
+detected,O
+in,O
+the,O
+germline,O
+reflects,O
+that,O
+found,O
+in,O
+tumors,O
+,,O
+although,O
+there,O
+are,O
+some,O
+notable,O
+exceptions,O
+in,O
+certain,O
+tumor,O
+types,O
+.,O
+ , 
+Detailed,O
+knowledge,O
+of,O
+the,O
+pedigrees,O
+allows,O
+a,O
+comprehensive,O
+analysis,O
+of,O
+genotype,O
+-,O
+phenotype,O
+correlations,O
+and,O
+an,O
+understanding,O
+of,O
+the,O
+tumors,O
+that,O
+are,O
+associated,O
+with,O
+germline,O
+TP53,B-Gene
+mutations,O
+.,O
+ , 
+This,O
+review,O
+will,O
+discuss,O
+the,O
+spectrum,O
+of,O
+mutations,O
+and,O
+the,O
+methods,O
+for,O
+mutation,O
+detection,O
+,,O
+the,O
+tumors,O
+associated,O
+with,O
+inheritance,O
+of,O
+a,O
+germline,O
+mutation,O
+,,O
+and,O
+some,O
+of,O
+the,O
+ethical,O
+and,O
+clinical,O
+problems,O
+in,O
+patients,O
+with,O
+a,O
+germline,O
+TP53,B-Gene
+mutation,O
+.,O
+ , 
+#1301950
+Detection,O
+of,O
+sequence,O
+variants,O
+in,O
+the,O
+gene,O
+for,O
+human,O
+type,B-Gene
+II,I-Gene
+procollagen,I-Gene
+(,B-Gene
+COL2A1,I-Gene
+),I-Gene
+by,O
+direct,O
+sequencing,O
+of,O
+polymerase,O
+chain,O
+reaction,O
+-,O
+amplified,O
+genomic,O
+DNA,O
+.,O
+ , 
+The,O
+direct,O
+sequencing,O
+of,O
+the,O
+human,O
+type,B-Gene
+II,I-Gene
+procollagen,I-Gene
+(,B-Gene
+COL2A1,I-Gene
+),I-Gene
+gene,O
+from,O
+polymerase,O
+chain,O
+reaction,O
+(,O
+PCR)-amplified,O
+genomic,O
+DNA,O
+is,O
+described,O
+.,O
+ , 
+Thirty,O
+-,O
+two,O
+regions,O
+of,O
+the,O
+COL2A1,O
+gene,O
+were,O
+asymmetrically,O
+amplified,O
+with,O
+intron,O
+primers,O
+which,O
+were,O
+specifically,O
+chosen,O
+to,O
+amplify,O
+a,O
+region,O
+spanning,O
+500,O
+to,O
+800,O
+bp,O
+of,O
+sequence,O
+encoding,O
+one,O
+or,O
+more,O
+exons,O
+and,O
+their,O
+accompanying,O
+intervening,O
+sequences,O
+.,O
+ , 
+Primers,O
+for,O
+dideoxynucleotide,O
+sequencing,O
+of,O
+the,O
+PCR,O
+products,O
+were,O
+then,O
+designed,O
+to,O
+provide,O
+complete,O
+exon,O
+sequence,O
+information,O
+and,O
+to,O
+insure,O
+that,O
+intron,O
+:,O
+exon,O
+splice,O
+junction,O
+sequence,O
+data,O
+would,O
+be,O
+obtained,O
+.,O
+ , 
+Amplification,O
+and,O
+sequencing,O
+reactions,O
+were,O
+performed,O
+on,O
+an,O
+automated,O
+workstation,O
+to,O
+facilitate,O
+the,O
+handling,O
+of,O
+multiple,O
+DNA,O
+templates,O
+.,O
+ , 
+The,O
+procedure,O
+allowed,O
+efficient,O
+sequencing,O
+of,O
+over,O
+25,000,O
+bp,O
+of,O
+each,O
+allele,O
+of,O
+the,O
+COL2A1,O
+gene,O
+per,O
+diploid,O
+genome,O
+.,O
+ , 
+We,O
+used,O
+this,O
+method,O
+for,O
+the,O
+comparative,O
+analyses,O
+of,O
+COL2A1,B-Gene
+sequences,O
+in,O
+DNA,O
+isolated,O
+from,O
+the,O
+blood,O
+of,O
+42,O
+unrelated,O
+individuals,O
+and,O
+we,O
+identified,O
+21,O
+neutral,O
+sequence,O
+variants,O
+in,O
+the,O
+gene,O
+.,O
+ , 
+The,O
+sequence,O
+variations,O
+were,O
+confirmed,O
+by,O
+independent,O
+assays,O
+,,O
+including,O
+restriction,O
+enzyme,O
+digestion,O
+.,O
+ , 
+The,O
+sequence,O
+variants,O
+described,O
+here,O
+will,O
+be,O
+important,O
+for,O
+identifying,O
+haplotypes,O
+of,O
+the,O
+type,B-Gene
+II,I-Gene
+procollagen,I-Gene
+gene,O
+that,O
+will,O
+be,O
+useful,O
+in,O
+defining,O
+a,O
+genetic,O
+etiology,O
+for,O
+diseases,O
+of,O
+cartilaginous,O
+tissues,O
+.,O
+ , 
+#18308288
+Genome,O
+-,O
+wide,O
+high,O
+-,O
+density,O
+SNP,O
+-,O
+based,O
+linkage,O
+analysis,O
+of,O
+infantile,O
+hypertrophic,O
+pyloric,O
+stenosis,O
+identifies,O
+loci,O
+on,O
+chromosomes,O
+11q14,O
+-,O
+q22,O
+and,O
+Xq23,O
+.,O
+ , 
+Infantile,O
+hypertrophic,O
+pyloric,O
+stenosis,O
+(,O
+IHPS,O
+),O
+has,O
+an,O
+incidence,O
+of,O
+1,O
+-,O
+8,O
+per,O
+1000,O
+live,O
+births,O
+and,O
+is,O
+inherited,O
+as,O
+a,O
+complex,O
+sex,O
+-,O
+modified,O
+multifactorial,O
+trait,O
+with,O
+a,O
+striking,O
+male,O
+preponderance,O
+.,O
+ , 
+Syndromic,O
+and,O
+monogenic,O
+forms,O
+exist,O
+,,O
+and,O
+two,O
+loci,O
+have,O
+been,O
+identified,O
+.,O
+ , 
+Infants,O
+present,O
+with,O
+vomiting,O
+due,O
+to,O
+gastric,O
+-,O
+outlet,O
+obstruction,O
+caused,O
+by,O
+hypertrophy,O
+of,O
+the,O
+smooth,O
+muscle,O
+of,O
+the,O
+pylorus,O
+.,O
+ , 
+A,O
+genome,O
+-,O
+wide,O
+SNP,O
+-,O
+based,O
+high,O
+-,O
+density,O
+linkage,O
+scan,O
+was,O
+carried,O
+out,O
+on,O
+81,O
+IHPS,O
+pedigrees,O
+.,O
+ , 
+Nonparametric,O
+and,O
+parametric,O
+linkage,O
+analysis,O
+identified,O
+loci,O
+on,O
+chromosomes,O
+11q14,O
+-,O
+q22,O
+(,O
+Z(max,O
+),O
+=,O
+3.9,O
+,,O
+p,O
+<,O
+0.0001,O
+;,O
+HLOD(max,O
+),O
+=,O
+3.4,O
+,,O
+alpha,O
+=,O
+0.34,O
+),O
+and,O
+Xq23,O
+(,O
+Z(max,O
+),O
+=,O
+4.3,O
+,,O
+p,O
+<,O
+0.00001,O
+;,O
+HLOD(max,O
+),O
+=,O
+4.8,O
+,,O
+alpha,O
+=,O
+0.56,O
+),O
+.,O
+ , 
+The,O
+two,O
+linked,O
+chromosomal,O
+regions,O
+each,O
+harbor,O
+functional,O
+candidate,O
+genes,O
+that,O
+are,O
+members,O
+of,O
+the,O
+canonical,O
+transient,O
+receptor,O
+potential,O
+(,B-Gene
+TRPC,I-Gene
+),I-Gene
+family,O
+of,O
+ion,O
+channels,O
+and,O
+have,O
+a,O
+potential,O
+role,O
+in,O
+smooth,O
+-,O
+muscle,O
+control,O
+and,O
+hypertrophy,O
+.,O
+ , 
+#8829663
+Two,O
+novel,O
+(,B-SNP
+1098insA,I-SNP
+and,O
+Y313H,B-SNP
+),I-SNP
+and,O
+one,O
+rare,O
+(,B-SNP
+R359Q,I-SNP
+),I-SNP
+mutations,O
+detected,O
+in,O
+exon,O
+8,O
+of,O
+the,O
+beta,B-Gene
+-,I-Gene
+glucocerebrosidase,I-Gene
+gene,O
+in,O
+Gaucher,O
+'s,O
+disease,O
+patients,O
+.,O
+ , 
+#16358216
+A,O
+novel,O
+framework,O
+for,O
+sib,O
+pair,O
+linkage,O
+analysis,O
+.,O
+ , 
+Sib,O
+pair,O
+linkage,O
+analysis,O
+of,O
+a,O
+dichotomous,O
+trait,O
+is,O
+a,O
+popular,O
+method,O
+for,O
+narrowing,O
+the,O
+search,O
+for,O
+genes,O
+that,O
+influence,O
+complex,O
+diseases,O
+.,O
+ , 
+Although,O
+the,O
+pedigree,O
+structures,O
+are,O
+uncomplicated,O
+and,O
+the,O
+underlying,O
+genetic,O
+principles,O
+straightforward,O
+,,O
+a,O
+surprising,O
+degree,O
+of,O
+complexity,O
+is,O
+involved,O
+in,O
+implementing,O
+a,O
+sib,O
+pair,O
+study,O
+and,O
+interpreting,O
+the,O
+results,O
+.,O
+ , 
+Ascertainment,O
+may,O
+be,O
+based,O
+on,O
+affected,O
+,,O
+discordant,O
+,,O
+or,O
+unaffected,O
+sib,O
+pairs,O
+,,O
+as,O
+well,O
+as,O
+on,O
+pairs,O
+defined,O
+by,O
+threshold,O
+values,O
+for,O
+quantitative,O
+traits,O
+,,O
+such,O
+as,O
+extreme,O
+discordant,O
+sib,O
+pairs,O
+.,O
+ , 
+To,O
+optimize,O
+power,O
+,,O
+various,O
+domain,O
+restrictions,O
+and,O
+null,O
+hypotheses,O
+have,O
+been,O
+proposed,O
+for,O
+each,O
+of,O
+these,O
+designs,O
+,,O
+yielding,O
+a,O
+wide,O
+array,O
+of,O
+choices,O
+for,O
+the,O
+analyst,O
+.,O
+ , 
+To,O
+begin,O
+,,O
+we,O
+systematically,O
+classify,O
+the,O
+major,O
+sources,O
+of,O
+discretion,O
+in,O
+sib,O
+pair,O
+linkage,O
+analysis,O
+.,O
+ , 
+Then,O
+,,O
+we,O
+extend,O
+the,O
+work,O
+of,O
+Kruglyak,O
+and,O
+Lander,O
+(,O
+1995,O
+),O
+,,O
+to,O
+bring,O
+the,O
+various,O
+forms,O
+into,O
+a,O
+unified,O
+framework,O
+and,O
+to,O
+facilitate,O
+a,O
+more,O
+general,O
+approach,O
+to,O
+the,O
+analysis,O
+.,O
+ , 
+Finally,O
+,,O
+we,O
+describe,O
+a,O
+new,O
+,,O
+freely,O
+available,O
+computer,O
+program,O
+,,O
+Splat,O
+(,O
+Sib,O
+Pair,O
+Linkage,O
+Analysis,O
+Testing,O
+),O
+,,O
+that,O
+can,O
+perform,O
+any,O
+sib,O
+pair,O
+statistical,O
+test,O
+currently,O
+in,O
+use,O
+,,O
+as,O
+well,O
+as,O
+any,O
+user,O
+-,O
+defined,O
+test,O
+yet,O
+to,O
+be,O
+proposed,O
+.,O
+ , 
+Splat,O
+uses,O
+the,O
+expectation,O
+maximization,O
+algorithm,O
+to,O
+calculate,O
+maximum,O
+-,O
+likelihood,O
+estimates,O
+of,O
+sharing,O
+(,O
+subject,O
+to,O
+user,O
+-,O
+specified,O
+conditions,O
+),O
+and,O
+then,O
+plots,O
+LOD,O
+scores,O
+versus,O
+chromosomal,O
+position,O
+.,O
+ , 
+It,O
+includes,O
+a,O
+novel,O
+grid,O
+-,O
+scanning,O
+capability,O
+that,O
+enables,O
+simultaneous,O
+visualization,O
+of,O
+multiple,O
+test,O
+statistics,O
+.,O
+ , 
+This,O
+can,O
+lead,O
+to,O
+further,O
+insight,O
+into,O
+the,O
+genetic,O
+basis,O
+of,O
+the,O
+disease,O
+process,O
+under,O
+consideration,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+phenotype,O
+definitions,O
+can,O
+be,O
+modified,O
+without,O
+the,O
+recalculation,O
+of,O
+inheritance,O
+vectors,O
+,,O
+thereby,O
+providing,O
+considerable,O
+flexibility,O
+for,O
+exploratory,O
+analysis,O
+.,O
+ , 
+The,O
+application,O
+of,O
+Splat,O
+will,O
+be,O
+illustrated,O
+with,O
+data,O
+from,O
+studies,O
+on,O
+the,O
+genetics,O
+of,O
+diabetic,O
+nephropathy,O
+.,O
+ , 
+#12673802
+Oculopharyngeal,O
+muscular,O
+dystrophy,O
+(,O
+OPMD,O
+),O
+due,O
+to,O
+a,O
+small,O
+duplication,O
+in,O
+the,O
+PABPN1,B-Gene
+gene,O
+.,O
+ , 
+Oculopharyngeal,O
+muscular,O
+dystrophy,O
+(,O
+OPMD,O
+),O
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+a,O
+late,O
+onset,O
+autosomal,O
+dominant,O
+muscle,O
+disorder,O
+.,O
+ , 
+The,O
+OPMD,O
+-,O
+locus,O
+has,O
+been,O
+mapped,O
+to,O
+chromosome,O
+14q11.2,O
+-,O
+q13,O
+.,O
+ , 
+The,O
+polyadenylate,B-Gene
+binding,I-Gene
+protein,I-Gene
+nuclear,I-Gene
+1,I-Gene
+(,B-Gene
+PABPN1,I-Gene
+;,I-Gene
+PABP2,B-Gene
+),I-Gene
+gene,O
+has,O
+been,O
+identified,O
+as,O
+the,O
+mutated,O
+gene,O
+.,O
+ , 
+The,O
+mutation,O
+consists,O
+of,O
+a,O
+short,O
+meiotically,O
+stable,O
+trinucleotide,O
+repeat,O
+in,O
+the,O
+first,O
+exon,O
+of,O
+PABPN1,B-Gene
+gene,O
+.,O
+ , 
+We,O
+have,O
+investigated,O
+Dutch,O
+OPMD,O
+patients,O
+from,O
+four,O
+unrelated,O
+families,O
+and,O
+identified,O
+a,O
+new,O
+mutation,O
+in,O
+two,O
+of,O
+the,O
+four,O
+families,O
+.,O
+ , 
+Instead,O
+of,O
+a,O
+repeat,O
+expansion,O
+we,O
+found,O
+a,O
+duplication,O
+in,O
+the,O
+first,O
+exon,O
+of,O
+the,O
+PABPN1,B-Gene
+gene,O
+(,B-SNP
+c.27_28ins12,I-SNP
+,,I-SNP
+p.11_12insAAAA,B-SNP
+),I-SNP
+.,O
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+The,O
+identification,O
+of,O
+this,O
+new,O
+mutation,O
+supports,O
+the,O
+theory,O
+of,O
+unequal,O
+crossing,O
+-,O
+over,O
+as,O
+molecular,O
+mechanism,O
+causing,O
+the,O
+mutation,O
+in,O
+the,O
+PABPN1,B-Gene
+gene,O
+responsible,O
+for,O
+OPMD,O
+,,O
+and,O
+not,O
+the,O
+slippage,O
+model,O
+.,O
+ , 
+#8488836
+Rapid,O
+prenatal,O
+diagnosis,O
+of,O
+chromosomal,O
+aneuploidies,O
+by,O
+fluorescence,O
+in,O
+situ,O
+hybridization,O
+:,O
+clinical,O
+experience,O
+with,O
+4,500,O
+specimens,O
+.,O
+ , 
+Detection,O
+of,O
+chromosome,O
+aneuploidies,O
+in,O
+uncultured,O
+amniocytes,O
+is,O
+possible,O
+using,O
+fluorescence,O
+in,O
+situ,O
+hybridization,O
+(,O
+FISH,O
+),O
+.,O
+ , 
+We,O
+herein,O
+describe,O
+the,O
+results,O
+of,O
+the,O
+first,O
+clinical,O
+program,O
+which,O
+utilized,O
+FISH,O
+for,O
+the,O
+rapid,O
+detection,O
+of,O
+chromosome,O
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+in,O
+uncultured,O
+amniocytes,O
+.,O
+ , 
+FISH,O
+was,O
+performed,O
+on,O
+physician,O
+request,O
+,,O
+as,O
+an,O
+adjunct,O
+to,O
+cytogenetics,O
+in,O
+4,500,O
+patients,O
+.,O
+ , 
+Region,O
+-,O
+specific,O
+DNA,O
+probes,O
+to,O
+chromosomes,O
+13,O
+,,O
+18,O
+,,O
+21,O
+,,O
+X,O
+,,O
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+Y,O
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+to,O
+determine,O
+ploidy,O
+by,O
+analysis,O
+of,O
+signal,O
+number,O
+in,O
+hybridized,O
+nuclei,O
+.,O
+ , 
+A,O
+sample,O
+was,O
+considered,O
+to,O
+be,O
+euploid,O
+when,O
+all,O
+autosomal,O
+probes,O
+generated,O
+two,O
+hybridization,O
+signals,O
+and,O
+when,O
+a,O
+normal,O
+sex,O
+chromosome,O
+pattern,O
+was,O
+observed,O
+in,O
+greater,O
+than,O
+or,O
+equal,O
+to,O
+80,O
+%,O
+of,O
+hybridized,O
+nuclei,O
+.,O
+ , 
+A,O
+sample,O
+was,O
+considered,O
+to,O
+be,O
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+when,O
+greater,O
+than,O
+or,O
+equal,O
+to,O
+70,O
+%,O
+of,O
+hybridized,O
+nuclei,O
+displayed,O
+the,O
+same,O
+abnormal,O
+hybridization,O
+pattern,O
+for,O
+a,O
+specific,O
+probe,O
+.,O
+ , 
+Of,O
+the,O
+attempted,O
+analyses,O
+,,O
+90.2,O
+%,O
+met,O
+these,O
+criteria,O
+and,O
+were,O
+reported,O
+as,O
+informative,O
+to,O
+referring,O
+physicians,O
+within,O
+2,O
+d,O
+of,O
+receipt,O
+.,O
+ , 
+Based,O
+on,O
+these,O
+reporting,O
+parameters,O
+,,O
+the,O
+overall,O
+detection,O
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+73.3,O
+%,O
+(,O
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+),O
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+informative,O
+results,O
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+aneuploidies,O
+of,O
+93.9,O
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+(,O
+107/114,O
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+.,O
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+Compared,O
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+cytogenetics,O
+,,O
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+accuracy,O
+of,O
+all,O
+informative,O
+FISH,O
+results,O
+,,O
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+aneuploid,O
+,,O
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+99.8,O
+%,O
+,,O
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+specificity,O
+was,O
+99.9,O
+%,O
+.,O
+ , 
+In,O
+those,O
+pregnancies,O
+where,O
+fetal,O
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+had,O
+been,O
+observed,O
+by,O
+ultrasound,O
+,,O
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+physicians,O
+requested,O
+FISH,O
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+cytogenetics,O
+at,O
+a,O
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+higher,O
+rate,O
+than,O
+they,O
+requested,O
+cytogenetics,O
+alone,O
+.,O
+ , 
+The,O
+current,O
+prenatal,O
+FISH,O
+protocol,O
+is,O
+not,O
+designed,O
+to,O
+detect,O
+all,O
+chromosome,O
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+and,O
+should,O
+only,O
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+This,O
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+#10521296
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+two,O
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+founder,O
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+.,O
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+Hypertrophic,O
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+(,O
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+the,O
+cardiac,O
+sarcomere,O
+,,O
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+Mutation,O
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+global,O
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+mutations,O
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+the,O
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+of,O
+founder,O
+effects,O
+within,O
+populations,O
+.,O
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+We,O
+have,O
+investigated,O
+whether,O
+this,O
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+true,O
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+African,O
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+,,O
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+-,O
+European,O
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+beta,B-Gene
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+cTnT,I-Gene
+),I-Gene
+,,O
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+MyBPC)-and,I-Gene
+two,O
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+Arg403Trp,I-SNP
+and,O
+Arg249Gln,B-SNP
+),I-SNP
+.,O
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+Here,O
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+report,O
+three,O
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+novel,O
+mutations,O
+-,B-SNP
+Gln499Lys,I-SNP
+in,O
+betaMHC,B-Gene
+and,O
+Val896Met,B-SNP
+and,O
+Deltac756,B-SNP
+in,O
+MyBPC,B-Gene
+-,I-Gene
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+the,O
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+betaMHC,B-Gene
+Arg719Gln,B-SNP
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+ , 
+Seven,O
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+nine,O
+HCM,O
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+mutations,O
+arose,O
+independently,O
+;,O
+no,O
+conclusions,O
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+two,O
+.,O
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+However,O
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+detected,O
+in,O
+another,O
+one,O
+,,O
+eight,O
+,,O
+and,O
+four,O
+probands,O
+,,O
+respectively,O
+,,O
+and,O
+haplotype,O
+analysis,O
+in,O
+families,O
+carrying,O
+these,O
+recurring,O
+mutations,O
+inferred,O
+their,O
+origin,O
+from,O
+three,O
+common,O
+ancestors,O
+.,O
+ , 
+The,O
+milder,O
+phenotype,O
+of,O
+the,O
+betaMHC,B-Gene
+mutations,O
+may,O
+account,O
+for,O
+the,O
+presence,O
+of,O
+these,O
+founder,O
+effects,O
+,,O
+whereas,O
+population,O
+dynamics,O
+alone,O
+may,O
+have,O
+overridden,O
+the,O
+reproductive,O
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+incurred,O
+by,O
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+lethal,O
+,,O
+cTnT,O
+Arg92Trp,B-SNP
+mutation,O
+.,O
+ , 
+#18179885
+Independent,O
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+two,O
+lactase,O
+-,O
+persistence,O
+alleles,O
+into,O
+human,O
+populations,O
+reflects,O
+different,O
+history,O
+of,O
+adaptation,O
+to,O
+milk,O
+culture,O
+.,O
+ , 
+The,O
+T(-13910,O
+),O
+variant,O
+located,O
+in,O
+the,O
+enhancer,O
+element,O
+of,O
+the,O
+lactase,B-Gene
+(,B-Gene
+LCT,I-Gene
+),I-Gene
+gene,O
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+with,O
+lactase,O
+persistence,O
+(,O
+LP,O
+),O
+in,O
+Eurasian,O
+populations,O
+whereas,O
+the,O
+variant,O
+is,O
+almost,O
+nonexistent,O
+among,O
+Sub,O
+-,O
+Saharan,O
+African,O
+populations,O
+,,O
+showing,O
+high,O
+prevalence,O
+of,O
+LP,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+identification,O
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+two,O
+new,O
+mutations,O
+among,O
+Saudis,O
+,,O
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+known,O
+for,O
+the,O
+high,O
+prevalence,O
+of,O
+LP,O
+.,O
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+We,O
+confirmed,O
+the,O
+absence,O
+of,O
+the,O
+European,O
+T(-13910,O
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+:,O
+T,B-SNP
+/,I-SNP
+G(-13915,I-SNP
+),I-SNP
+within,O
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+-13910,O
+enhancer,O
+region,O
+and,O
+a,O
+synonymous,O
+SNP,O
+in,O
+the,O
+exon,O
+17,O
+of,O
+the,O
+MCM6,B-Gene
+gene,O
+T,B-SNP
+/,I-SNP
+C(-3712,I-SNP
+),I-SNP
+,,I-SNP
+-3712,O
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+from,O
+the,O
+LCT,B-Gene
+gene,O
+.,O
+ , 
+The,O
+compound,O
+allele,O
+is,O
+driven,O
+to,O
+a,O
+high,O
+prevalence,O
+among,O
+Middle,O
+East,O
+population(s,O
+),O
+.,O
+ , 
+Our,O
+functional,O
+analyses,O
+in,O
+vitro,O
+showed,O
+that,O
+both,O
+SNPs,O
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+the,O
+compound,O
+allele,O
+,,O
+located,O
+10,O
+kb,O
+apart,O
+,,O
+are,O
+required,O
+for,O
+the,O
+enhancer,O
+effect,O
+,,O
+most,O
+probably,O
+mediated,O
+through,O
+the,O
+binding,O
+of,O
+the,O
+hepatic,B-Gene
+nuclear,I-Gene
+factor,I-Gene
+1,I-Gene
+alpha,I-Gene
+(,B-Gene
+HNF1,I-Gene
+alpha,I-Gene
+),I-Gene
+.,O
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+High,O
+selection,O
+coefficient,O
+(,O
+s,O
+),O
+approximately,O
+0.04,O
+for,O
+LP,O
+phenotype,O
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+found,O
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+both,O
+T(-13910,O
+),O
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+the,O
+compound,O
+allele,O
+.,O
+ , 
+The,O
+European,O
+T(-13910,O
+),O
+and,O
+the,O
+earlier,O
+identified,O
+East,O
+African,O
+G(-13907,O
+),O
+ , 
+LP,O
+allele,O
+share,O
+the,O
+same,O
+ancestral,O
+background,O
+and,O
+most,O
+likely,O
+the,O
+same,O
+history,O
+,,O
+probably,O
+related,O
+to,O
+the,O
+same,O
+cattle,O
+domestication,O
+event,O
+.,O
+ , 
+In,O
+contrast,O
+,,O
+the,O
+compound,O
+Arab,O
+allele,O
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+a,O
+different,O
+,,O
+highly,O
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+ancestral,O
+haplotype,O
+,,O
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+that,O
+these,O
+two,O
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+global,O
+LP,O
+alleles,O
+have,O
+arisen,O
+independently,O
+,,O
+the,O
+latter,O
+perhaps,O
+in,O
+response,O
+to,O
+camel,O
+milk,O
+consumption,O
+.,O
+ , 
+These,O
+results,O
+support,O
+the,O
+convergent,O
+evolution,O
+of,O
+the,O
+LP,O
+in,O
+diverse,O
+populations,O
+,,O
+most,O
+probably,O
+reflecting,O
+different,O
+histories,O
+of,O
+adaptation,O
+to,O
+milk,O
+culture,O
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+#15365989
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+(,O
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+Mutations,O
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+as,O
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+(,O
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+early,O
+disease,O
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+.,O
+ , 
+However,O
+,,O
+based,O
+on,O
+linkage,O
+data,O
+,,O
+mutations,O
+in,O
+other,O
+genes,O
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+to,O
+the,O
+genetic,O
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+of,O
+early,O
+-,O
+onset,O
+PD,O
+(,O
+EOPD,O
+),O
+.,O
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+Recently,O
+,,O
+two,O
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+in,O
+the,O
+DJ1,B-Gene
+gene,O
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+described,O
+as,O
+a,O
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+cause,O
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+EOPD,O
+(,B-Gene
+PARK7,I-Gene
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+.,O
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+Analyzing,O
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+PARK7,B-Gene
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+DJ1,I-Gene
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+104,O
+EOPD,O
+patients,O
+,,O
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+identified,O
+a,O
+third,O
+mutation,O
+,,O
+c.192G,B-SNP
+>,I-SNP
+C,I-SNP
+(,B-SNP
+p.,I-SNP
+E64D,I-SNP
+),I-SNP
+,,O
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+EOPD,O
+in,O
+a,O
+patient,O
+of,O
+Turkish,O
+ancestry,O
+and,O
+characterized,O
+the,O
+functional,O
+significance,O
+of,O
+this,O
+amino,O
+acid,O
+substitution,O
+.,O
+ , 
+In,O
+the,O
+patient,O
+,,O
+a,O
+substantial,O
+reduction,O
+of,O
+dopamine,O
+uptake,O
+transporter,O
+(,O
+DAT,O
+),O
+binding,O
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+in,O
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+striatum,O
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+[,O
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+18)F]FP,O
+-,O
+CIT,O
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+PET,O
+,,O
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+His,O
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+E64D,B-SNP
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+compared,O
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+a,O
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+by,O
+crystallography,O
+that,O
+the,O
+E64D,B-SNP
+mutation,O
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+not,O
+alter,O
+the,O
+structure,O
+of,O
+the,O
+DJ1,B-Gene
+protein,O
+,,O
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+we,O
+observe,O
+a,O
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+towards,O
+decreased,O
+levels,O
+of,O
+the,O
+mutant,O
+protein,O
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+overexpressed,O
+in,O
+HEK293,O
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+COS7,O
+cells,O
+.,O
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+Using,O
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+homogenous,O
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+L166P,B-SNP
+mutation,O
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+#15776395
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+As,O
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+search,O
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+genes,O
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+(,O
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+),O
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+IL2RA,B-Gene
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+Tag,O
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+These,O
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+disease,O
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+#8477263
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+determine,O
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+spectrum,O
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+Among,O
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+In,O
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+#8554049
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+In,O
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+paper,O
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+a,O
+set,O
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+Rh,O
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+DNA,O
+markers,O
+and,O
+derived,O
+a,O
+comprehensive,O
+map,O
+for,O
+the,O
+RH,O
+locus,O
+.,O
+ , 
+It,O
+was,O
+found,O
+that,O
+the,O
+SphI,O
+fragments,O
+encompassing,O
+exons,O
+4,O
+-,O
+7,O
+of,O
+the,O
+Rh,O
+genes,O
+occur,O
+in,O
+four,O
+banding,O
+patterns,O
+or,O
+frameworks,O
+that,O
+correspond,O
+to,O
+the,O
+distribution,O
+and,O
+segregation,O
+of,O
+the,O
+common,O
+Rh,O
+haplotypes,O
+.,O
+ , 
+This,O
+linkage,O
+disequilibrium,O
+allowed,O
+a,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+and,O
+direct,O
+determination,O
+of,O
+Rh,O
+zygosity,O
+related,O
+to,O
+the,O
+Rh,O
+-,O
+positive,O
+or,O
+Rh,O
+-,O
+negative,O
+status,O
+(,O
+D,O
+/,O
+D,O
+,,O
+D,O
+/,O
+d,O
+,,O
+and,O
+d,O
+/,O
+d,O
+),O
+.,O
+ , 
+Studies,O
+on,O
+the,O
+occurrence,O
+of,O
+SphI,O
+RFLPs,O
+in,O
+a,O
+number,O
+of,O
+rare,O
+Rh,O
+variants,O
+indicated,O
+that,O
+Rh,O
+phenotypic,O
+diversity,O
+has,O
+taken,O
+place,O
+on,O
+different,O
+haplotype,O
+backgrounds,O
+and,O
+has,O
+arisen,O
+by,O
+diverse,O
+genetic,O
+mechanisms,O
+.,O
+ , 
+The,O
+molecular,O
+definition,O
+of,O
+Rh,O
+haplotypes,O
+by,O
+SphI,O
+RFLP,O
+frameworks,O
+should,O
+provide,O
+a,O
+useful,O
+procedure,O
+for,O
+genetic,O
+counseling,O
+and,O
+prenatal,O
+assessment,O
+of,O
+Rh,O
+alloimmunization,O
+.,O
+ , 
+#17503332
+Type,O
+2,O
+diabetes,O
+TCF7L2,B-Gene
+risk,O
+genotypes,O
+alter,O
+birth,O
+weight,O
+:,O
+a,O
+study,O
+of,O
+24,053,O
+individuals,O
+.,O
+ , 
+The,O
+role,O
+of,O
+genes,O
+in,O
+normal,O
+birth,O
+-,O
+weight,O
+variation,O
+is,O
+poorly,O
+understood,O
+,,O
+and,O
+it,O
+has,O
+been,O
+suggested,O
+that,O
+the,O
+genetic,O
+component,O
+of,O
+fetal,O
+growth,O
+is,O
+small,O
+.,O
+ , 
+Type,O
+2,O
+diabetes,O
+genes,O
+may,O
+influence,O
+birth,O
+weight,O
+through,O
+maternal,O
+genotype,O
+,,O
+by,O
+increasing,O
+maternal,O
+glycemia,O
+in,O
+pregnancy,O
+,,O
+or,O
+through,O
+fetal,O
+genotype,O
+,,O
+by,O
+altering,O
+fetal,O
+insulin,O
+secretion,O
+.,O
+ , 
+We,O
+aimed,O
+to,O
+assess,O
+the,O
+role,O
+of,O
+the,O
+recently,O
+described,O
+type,O
+2,O
+diabetes,O
+gene,O
+TCF7L2,B-Gene
+in,O
+birth,O
+weight,O
+.,O
+ , 
+We,O
+genotyped,O
+the,O
+polymorphism,O
+rs7903146,O
+in,O
+15,709,O
+individuals,O
+whose,O
+birth,O
+weight,O
+was,O
+available,O
+from,O
+six,O
+studies,O
+and,O
+in,O
+8,344,O
+mothers,O
+from,O
+three,O
+studies,O
+.,O
+ , 
+Each,O
+fetal,O
+copy,O
+of,O
+the,O
+predisposing,O
+allele,O
+was,O
+associated,O
+with,O
+an,O
+18,O
+-,O
+g,O
+(,O
+95,O
+%,O
+confidence,O
+interval,O
+[,O
+CI,O
+],O
+7,O
+-,O
+29,O
+g,O
+),O
+increase,O
+in,O
+birth,O
+weight,O
+(,O
+P=.001,O
+),O
+and,O
+each,O
+maternal,O
+copy,O
+with,O
+a,O
+30,O
+-,O
+g,O
+(,O
+95,O
+%,O
+CI,O
+15,O
+-,O
+45,O
+g,O
+),O
+increase,O
+in,O
+offspring,O
+birth,O
+weight,O
+(,O
+P=2.8x10,O
+-,O
+5,O
+),O
+.,O
+ , 
+Stratification,O
+by,O
+fetal,O
+genotype,O
+suggested,O
+that,O
+the,O
+association,O
+was,O
+driven,O
+by,O
+maternal,O
+genotype,O
+(,O
+31,O
+-,O
+g,O
+[,O
+95,O
+%,O
+CI,O
+9,O
+-,O
+48,O
+g,O
+],O
+increase,O
+per,O
+allele,O
+;,O
+corrected,O
+P=.003,O
+),O
+.,O
+ , 
+Analysis,O
+of,O
+diabetes,O
+-,O
+related,O
+traits,O
+in,O
+10,314,O
+nondiabetic,O
+individuals,O
+suggested,O
+the,O
+most,O
+likely,O
+mechanism,O
+is,O
+that,O
+the,O
+risk,O
+allele,O
+reduces,O
+maternal,O
+insulin,O
+secretion,O
+(,O
+disposition,O
+index,O
+reduced,O
+by,O
+~0.15,O
+standard,O
+deviation,O
+;,O
+P=1x10,O
+-,O
+4,O
+),O
+,,O
+which,O
+results,O
+in,O
+increased,O
+maternal,O
+glycemia,O
+in,O
+pregnancy,O
+and,O
+hence,O
+increased,O
+offspring,O
+birth,O
+weight,O
+.,O
+ , 
+We,O
+combined,O
+information,O
+with,O
+the,O
+other,O
+common,O
+variant,O
+known,O
+to,O
+alter,O
+fetal,O
+growth,O
+,,O
+the,O
+-30G-->A,B-SNP
+polymorphism,O
+of,O
+glucokinase,O
+(,O
+rs1799884,O
+),O
+.,O
+ , 
+The,O
+4,O
+%,O
+of,O
+offspring,O
+born,O
+to,O
+mothers,O
+carrying,O
+three,O
+or,O
+four,O
+risk,O
+alleles,O
+were,O
+119,O
+g,O
+(,O
+95,O
+%,O
+CI,O
+62,O
+-,O
+172,O
+g,O
+),O
+heavier,O
+than,O
+were,O
+the,O
+32,O
+%,O
+born,O
+to,O
+mothers,O
+with,O
+none,O
+(,O
+for,O
+overall,O
+trend,O
+,,O
+P=2x10,O
+-,O
+7,O
+),O
+,,O
+comparable,O
+to,O
+the,O
+impact,O
+of,O
+maternal,O
+smoking,O
+during,O
+pregnancy,O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+we,O
+have,O
+identified,O
+the,O
+first,O
+type,O
+2,O
+diabetes,O
+-,O
+susceptibility,O
+allele,O
+to,O
+be,O
+reproducibly,O
+associated,O
+with,O
+birth,O
+weight,O
+.,O
+ , 
+Common,O
+gene,O
+variants,O
+can,O
+substantially,O
+influence,O
+normal,O
+birth,O
+-,O
+weight,O
+variation,O
+.,O
+ , 
+#8956055
+Identification,O
+of,O
+a,O
+novel,O
+R552O,B-SNP
+mutation,O
+in,O
+exon,O
+13,O
+of,O
+the,O
+beta,O
+-,O
+subunit,O
+of,O
+rod,B-Gene
+phosphodiesterase,I-Gene
+gene,O
+in,O
+a,O
+Spanish,O
+family,O
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+autosomal,O
+recessive,O
+retinitis,O
+pigmentosa,O
+.,O
+ , 
+#17847001
+Copy,O
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+variations,O
+measured,O
+by,O
+single,O
+-,O
+nucleotide,O
+-,O
+polymorphism,O
+oligonucleotide,O
+arrays,O
+in,O
+patients,O
+with,O
+mental,O
+retardation,O
+.,O
+ , 
+Whole,O
+-,O
+genome,O
+analysis,O
+using,O
+high,O
+-,O
+density,O
+single,O
+-,O
+nucleotide,O
+-,O
+polymorphism,O
+oligonucleotide,O
+arrays,O
+allows,O
+identification,O
+of,O
+microdeletions,O
+,,O
+microduplications,O
+,,O
+and,O
+uniparental,O
+disomies,O
+.,O
+ , 
+We,O
+studied,O
+67,O
+children,O
+with,O
+unexplained,O
+mental,O
+retardation,O
+with,O
+normal,O
+karyotypes,O
+,,O
+as,O
+assessed,O
+by,O
+G,O
+-,O
+banded,O
+chromosome,O
+analyses,O
+.,O
+ , 
+Their,O
+DNAs,O
+were,O
+analyzed,O
+with,O
+Affymetrix,O
+100,O
+K,O
+arrays,O
+.,O
+ , 
+We,O
+detected,O
+11,O
+copy,O
+-,O
+number,O
+variations,O
+that,O
+most,O
+likely,O
+are,O
+causative,O
+of,O
+mental,O
+retardation,O
+,,O
+because,O
+they,O
+either,O
+arose,O
+de,O
+novo,O
+(,O
+9,O
+cases,O
+),O
+and/or,O
+overlapped,O
+with,O
+known,O
+microdeletions,O
+(,O
+2,O
+cases,O
+),O
+.,O
+ , 
+The,O
+eight,O
+deletions,O
+and,O
+three,O
+duplications,O
+varied,O
+in,O
+size,O
+from,O
+200,O
+kb,O
+to,O
+7.5,O
+Mb,O
+.,O
+ , 
+Of,O
+the,O
+11,O
+copy,O
+-,O
+number,O
+variations,O
+,,O
+5,O
+were,O
+flanked,O
+by,O
+low,O
+-,O
+copy,O
+repeats,O
+.,O
+ , 
+Two,O
+of,O
+those,O
+,,O
+on,O
+chromosomes,O
+15q25.2,O
+and,O
+Xp22.31,O
+,,O
+have,O
+not,O
+been,O
+described,O
+before,O
+and,O
+have,O
+a,O
+high,O
+probability,O
+of,O
+being,O
+causative,O
+of,O
+new,O
+deletion,O
+and,O
+duplication,O
+syndromes,O
+,,O
+respectively,O
+.,O
+ , 
+In,O
+one,O
+patient,O
+,,O
+we,O
+found,O
+a,O
+deletion,O
+affecting,O
+only,O
+a,O
+single,O
+gene,O
+,,O
+MBD5,B-Gene
+,,I-Gene
+which,O
+codes,O
+for,O
+the,O
+methyl,B-Gene
+-,I-Gene
+CpG,I-Gene
+-,I-Gene
+binding,I-Gene
+domain,I-Gene
+protein,I-Gene
+5,I-Gene
+.,I-Gene
+ , 
+In,O
+addition,O
+to,O
+the,O
+67,O
+children,O
+,,O
+we,O
+investigated,O
+4,O
+mentally,O
+retarded,O
+children,O
+with,O
+apparent,O
+balanced,O
+translocations,O
+and,O
+detected,O
+four,O
+deletions,O
+at,O
+breakpoint,O
+regions,O
+ranging,O
+in,O
+size,O
+from,O
+1.1,O
+to,O
+14,O
+Mb,O
+.,O
+ , 
+#11462173
+p63,B-Gene
+Gene,O
+mutations,O
+in,O
+eec,O
+syndrome,O
+,,O
+limb,O
+-,O
+mammary,O
+syndrome,O
+,,O
+and,O
+isolated,O
+split,O
+hand,O
+-,O
+split,O
+foot,O
+malformation,O
+suggest,O
+a,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+.,O
+ , 
+p63,B-Gene
+mutations,O
+have,O
+been,O
+associated,O
+with,O
+EEC,O
+syndrome,O
+(,O
+ectrodactyly,O
+,,O
+ectodermal,O
+dysplasia,O
+,,O
+and,O
+cleft,O
+lip,O
+/,O
+palate,O
+),O
+,,O
+as,O
+well,O
+as,O
+with,O
+nonsyndromic,O
+split,O
+hand,O
+-,O
+split,O
+foot,O
+malformation,O
+(,O
+SHFM,O
+),O
+.,O
+ , 
+We,O
+performed,O
+p63,B-Gene
+mutation,O
+analysis,O
+in,O
+a,O
+sample,O
+of,O
+43,O
+individuals,O
+and,O
+families,O
+affected,O
+with,O
+EEC,O
+syndrome,O
+,,O
+in,O
+35,O
+individuals,O
+affected,O
+with,O
+SHFM,O
+,,O
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+in,O
+three,O
+families,O
+with,O
+the,O
+EEC,O
+-,O
+like,O
+condition,O
+limb,O
+-,O
+mammary,O
+syndrome,O
+(,O
+LMS,O
+),O
+,,O
+which,O
+is,O
+characterized,O
+by,O
+ectrodactyly,O
+,,O
+cleft,O
+palate,O
+,,O
+and,O
+mammary,O
+-,O
+gland,O
+abnormalities,O
+.,O
+ , 
+The,O
+results,O
+differed,O
+for,O
+these,O
+three,O
+conditions,O
+.,O
+ , 
+p63,B-Gene
+gene,O
+mutations,O
+were,O
+detected,O
+in,O
+almost,O
+all,O
+(,O
+40/43,O
+),O
+individuals,O
+affected,O
+with,O
+EEC,O
+syndrome,O
+.,O
+ , 
+Apart,O
+from,O
+a,O
+frameshift,O
+mutation,O
+in,O
+exon,O
+13,O
+,,O
+all,O
+other,O
+EEC,O
+mutations,O
+were,O
+missense,O
+,,O
+predominantly,O
+involving,O
+codons,O
+204,O
+,,O
+227,O
+,,O
+279,O
+,,O
+280,O
+,,O
+and,O
+304,O
+.,O
+ , 
+In,O
+contrast,O
+,,O
+p63,B-Gene
+mutations,O
+were,O
+detected,O
+in,O
+only,O
+a,O
+small,O
+proportion,O
+(,O
+4/35,O
+),O
+of,O
+patients,O
+with,O
+isolated,O
+SHFM,O
+.,O
+ , 
+p63,B-Gene
+mutations,O
+in,O
+SHFM,O
+included,O
+three,O
+novel,O
+mutations,O
+:,O
+a,O
+missense,O
+mutation,O
+(,B-SNP
+K193E,I-SNP
+),I-SNP
+,,O
+a,O
+nonsense,O
+mutation,O
+(,B-SNP
+Q634X,I-SNP
+),I-SNP
+,,O
+and,O
+a,O
+mutation,O
+in,O
+the,O
+3,O
+',O
+splice,O
+site,O
+for,O
+exon,O
+5,O
+.,O
+ , 
+The,O
+fourth,O
+SHFM,O
+mutation,O
+(,B-SNP
+R280H,I-SNP
+),I-SNP
+in,O
+this,O
+series,O
+was,O
+also,O
+found,O
+in,O
+a,O
+patient,O
+with,O
+classical,O
+EEC,O
+syndrome,O
+,,O
+suggesting,O
+partial,O
+overlap,O
+between,O
+the,O
+EEC,O
+and,O
+SHFM,O
+mutational,O
+spectra,O
+.,O
+ , 
+The,O
+original,O
+family,O
+with,O
+LMS,O
+(,O
+van,O
+Bokhoven,O
+et,O
+al,O
+.,O
+1999,O
+),O
+had,O
+no,O
+detectable,O
+p63,B-Gene
+mutation,O
+,,O
+although,O
+it,O
+clearly,O
+localizes,O
+to,O
+the,O
+p63,B-Gene
+locus,O
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+3q27,O
+.,O
+ , 
+In,O
+two,O
+other,O
+small,O
+kindreds,O
+affected,O
+with,O
+LMS,O
+,,O
+frameshift,O
+mutations,O
+were,O
+detected,O
+in,O
+exons,O
+13,O
+and,O
+14,O
+,,O
+respectively,O
+.,O
+ , 
+The,O
+combined,O
+data,O
+show,O
+that,O
+p63,B-Gene
+is,O
+the,O
+major,O
+gene,O
+for,O
+EEC,O
+syndrome,O
+,,O
+and,O
+that,O
+it,O
+makes,O
+a,O
+modest,O
+contribution,O
+to,O
+SHFM,O
+.,O
+ , 
+There,O
+appears,O
+to,O
+be,O
+a,O
+genotype,O
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+phenotype,O
+correlation,O
+,,O
+in,O
+that,O
+there,O
+is,O
+a,O
+specific,O
+pattern,O
+of,O
+missense,O
+mutations,O
+in,O
+EEC,O
+syndrome,O
+that,O
+are,O
+not,O
+generally,O
+found,O
+in,O
+SHFM,O
+or,O
+LMS,O
+.,O
+ , 
+#22770981
+HOXB1,B-Gene
+founder,O
+mutation,O
+in,O
+humans,O
+recapitulates,O
+the,O
+phenotype,O
+of,O
+Hoxb1-/-,O
+mice,O
+.,O
+ , 
+Members,O
+of,O
+the,O
+highly,O
+conserved,O
+homeobox,O
+(,O
+HOX,O
+),O
+gene,O
+family,O
+encode,O
+transcription,O
+factors,O
+that,O
+confer,O
+cellular,O
+and,O
+tissue,O
+identities,O
+along,O
+the,O
+antero,O
+-,O
+posterior,O
+axis,O
+of,O
+mice,O
+and,O
+humans,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+a,O
+founder,O
+homozygous,O
+missense,O
+mutation,O
+in,O
+HOXB1,B-Gene
+in,O
+two,O
+families,O
+from,O
+a,O
+conservative,O
+German,O
+American,O
+population,O
+.,O
+ , 
+The,O
+resulting,O
+phenotype,O
+includes,O
+bilateral,O
+facial,O
+palsy,O
+,,O
+hearing,O
+loss,O
+,,O
+and,O
+strabismus,O
+and,O
+correlates,O
+extensively,O
+with,O
+the,O
+previously,O
+reported,O
+Hoxb1(-/-,O
+),O
+mouse,O
+phenotype,O
+.,O
+ , 
+The,O
+missense,O
+variant,O
+is,O
+predicted,O
+to,O
+result,O
+in,O
+the,O
+substitution,O
+of,O
+a,O
+cysteine,O
+for,O
+an,O
+arginine,O
+at,O
+amino,O
+acid,O
+residue,O
+207,O
+(,B-SNP
+Arg207Cys,I-SNP
+),I-SNP
+,,O
+which,O
+corresponds,O
+to,O
+the,O
+highly,O
+conserved,O
+Arg5,O
+of,O
+the,O
+homeodomain,O
+.,O
+ , 
+Arg5,O
+interacts,O
+with,O
+thymine,O
+in,O
+the,O
+minor,O
+groove,O
+of,O
+DNA,O
+through,O
+hydrogen,O
+bonding,O
+and,O
+electrostatic,O
+attraction,O
+.,O
+ , 
+Molecular,O
+modeling,O
+and,O
+an,O
+in,O
+vitro,O
+DNA,O
+-,O
+protein,O
+binding,O
+assay,O
+predict,O
+that,O
+the,O
+mutation,O
+would,O
+disrupt,O
+these,O
+interactions,O
+,,O
+destabilize,O
+the,O
+HOXB1,O
+:,O
+PBX1,O
+:,O
+DNA,O
+complex,O
+,,O
+and,O
+alter,O
+HOXB1,B-Gene
+transcriptional,O
+activity,O
+.,O
+ , 
+#8080001
+Regression,O
+to,O
+the,O
+mean,O
+does,O
+not,O
+exclude,O
+anticipation,O
+and,O
+unstable,O
+DNA,O
+disease,O
+.,O
+ , 
+#9837820
+A,O
+common,O
+and,O
+recurrent,O
+13,O
+-,O
+bp,O
+deletion,O
+in,O
+the,O
+autoimmune,O
+regulator,O
+gene,O
+in,O
+British,O
+kindreds,O
+with,O
+autoimmune,O
+polyendocrinopathy,O
+type,O
+1,O
+.,O
+ , 
+Autoimmune,O
+polyendocrinopathy,O
+type,O
+1,O
+(,O
+APS1,O
+),O
+is,O
+an,O
+autosomal,O
+recessive,O
+disorder,O
+characterized,O
+by,O
+autoimmune,O
+hypoparathyroidism,O
+,,O
+autoimmune,O
+adrenocortical,O
+failure,O
+,,O
+and,O
+mucocutaneous,O
+candidiasis,O
+.,O
+ , 
+Recently,O
+,,O
+an,O
+autoimmune,O
+regulator,O
+gene,O
+(,B-Gene
+AIRE-1,I-Gene
+),I-Gene
+,,I-Gene
+which,O
+is,O
+located,O
+on,O
+chromosome,O
+21q22.3,O
+,,O
+has,O
+been,O
+identified,O
+,,O
+and,O
+mutations,O
+in,O
+European,O
+kindreds,O
+with,O
+APS1,O
+have,O
+been,O
+described,O
+.,O
+ , 
+We,O
+used,O
+SSCP,O
+analysis,O
+and,O
+direct,O
+DNA,O
+sequencing,O
+to,O
+screen,O
+the,O
+entire,O
+1,635,O
+-,O
+bp,O
+coding,O
+region,O
+of,O
+AIRE-1,B-Gene
+in,O
+12,O
+British,O
+families,O
+with,O
+APS1,O
+.,O
+ , 
+A,O
+13,O
+-,O
+bp,O
+deletion,O
+(,B-SNP
+964del13,I-SNP
+),I-SNP
+was,O
+found,O
+to,O
+account,O
+for,O
+17,O
+of,O
+the,O
+24,O
+possible,O
+mutant,O
+AIRE-1,B-Gene
+alleles,O
+,,O
+in,O
+our,O
+kindreds,O
+.,O
+ , 
+This,O
+mutation,O
+was,O
+found,O
+to,O
+occur,O
+de,O
+novo,O
+in,O
+one,O
+affected,O
+subject,O
+.,O
+ , 
+A,O
+common,O
+haplotype,O
+spanning,O
+the,O
+AIRE-1,B-Gene
+locus,O
+was,O
+found,O
+in,O
+chromosomes,O
+that,O
+carried,O
+the,O
+964del13,B-SNP
+mutation,O
+,,O
+suggesting,O
+a,O
+founder,O
+effect,O
+in,O
+our,O
+population,O
+.,O
+ , 
+One,O
+of,O
+576,O
+normal,O
+subjects,O
+was,O
+also,O
+a,O
+heterozygous,O
+carrier,O
+of,O
+the,O
+964del13,B-SNP
+mutation,O
+.,O
+ , 
+Six,O
+other,O
+point,O
+mutations,O
+were,O
+found,O
+in,O
+AIRE-1,B-Gene
+,,I-Gene
+including,O
+two,O
+1,O
+-,O
+bp,O
+deletions,O
+,,O
+three,O
+missense,O
+mutations,O
+(,B-SNP
+R15L,I-SNP
+,,I-SNP
+L28P,B-SNP
+,,I-SNP
+and,O
+Y90C,B-SNP
+),I-SNP
+,,O
+and,O
+a,O
+nonsense,O
+mutation,O
+(,B-SNP
+R257,I-SNP
+*,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+high,O
+frequency,O
+of,O
+the,O
+964del13,B-SNP
+allele,O
+and,O
+the,O
+clustering,O
+of,O
+the,O
+other,O
+AIRE-1,B-Gene
+mutations,O
+may,O
+allow,O
+rapid,O
+molecular,O
+screening,O
+for,O
+APS1,O
+in,O
+British,O
+kindreds,O
+.,O
+ , 
+Furthermore,O
+,,O
+the,O
+prevalence,O
+of,O
+the,O
+964del13,B-SNP
+AIRE-1,B-Gene
+mutation,O
+may,O
+have,O
+implications,O
+in,O
+the,O
+pathogenesis,O
+of,O
+the,O
+more,O
+common,O
+autoimmune,O
+endocrinopathies,O
+in,O
+our,O
+population,O
+.,O
+ , 
+#12587094
+Use,O
+of,O
+multivariate,O
+linkage,O
+analysis,O
+for,O
+dissection,O
+of,O
+a,O
+complex,O
+cognitive,O
+trait,O
+.,O
+ , 
+Replication,O
+of,O
+linkage,O
+results,O
+for,O
+complex,O
+traits,O
+has,O
+been,O
+exceedingly,O
+difficult,O
+,,O
+owing,O
+in,O
+part,O
+to,O
+the,O
+inability,O
+to,O
+measure,O
+the,O
+precise,O
+underlying,O
+phenotype,O
+,,O
+small,O
+sample,O
+sizes,O
+,,O
+genetic,O
+heterogeneity,O
+,,O
+and,O
+statistical,O
+methods,O
+employed,O
+in,O
+analysis,O
+.,O
+ , 
+Often,O
+,,O
+in,O
+any,O
+particular,O
+study,O
+,,O
+multiple,O
+correlated,O
+traits,O
+have,O
+been,O
+collected,O
+,,O
+yet,O
+these,O
+have,O
+been,O
+analyzed,O
+independently,O
+or,O
+,,O
+at,O
+most,O
+,,O
+in,O
+bivariate,O
+analyses,O
+.,O
+ , 
+Theoretical,O
+arguments,O
+suggest,O
+that,O
+full,O
+multivariate,O
+analysis,O
+of,O
+all,O
+available,O
+traits,O
+should,O
+offer,O
+more,O
+power,O
+to,O
+detect,O
+linkage,O
+;,O
+however,O
+,,O
+this,O
+has,O
+not,O
+yet,O
+been,O
+evaluated,O
+on,O
+a,O
+genomewide,O
+scale,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+conduct,O
+multivariate,O
+genomewide,O
+analyses,O
+of,O
+quantitative,O
+-,O
+trait,O
+loci,O
+that,O
+influence,O
+reading-,O
+and,O
+language,O
+-,O
+related,O
+measures,O
+in,O
+families,O
+affected,O
+with,O
+developmental,O
+dyslexia,O
+.,O
+ , 
+The,O
+results,O
+of,O
+these,O
+analyses,O
+are,O
+substantially,O
+clearer,O
+than,O
+those,O
+of,O
+previous,O
+univariate,O
+analyses,O
+of,O
+the,O
+same,O
+data,O
+set,O
+,,O
+helping,O
+to,O
+resolve,O
+a,O
+number,O
+of,O
+key,O
+issues,O
+.,O
+ , 
+These,O
+outcomes,O
+highlight,O
+the,O
+relevance,O
+of,O
+multivariate,O
+analysis,O
+for,O
+complex,O
+disorders,O
+for,O
+dissection,O
+of,O
+linkage,O
+results,O
+in,O
+correlated,O
+traits,O
+.,O
+ , 
+The,O
+approach,O
+employed,O
+here,O
+may,O
+aid,O
+positional,O
+cloning,O
+of,O
+susceptibility,O
+genes,O
+in,O
+a,O
+wide,O
+spectrum,O
+of,O
+complex,O
+traits,O
+.,O
+ , 
+#9150164
+A,O
+gene,O
+for,O
+autosomal,O
+dominant,O
+nonsyndromic,O
+hearing,O
+loss,O
+(,O
+DFNA12,O
+),O
+maps,O
+to,O
+chromosome,O
+11q22,O
+-,O
+24,O
+.,O
+ , 
+We,O
+performed,O
+linkage,O
+analysis,O
+in,O
+a,O
+Belgian,O
+family,O
+with,O
+autosomal,O
+dominant,O
+midfrequency,O
+hearing,O
+loss,O
+,,O
+which,O
+has,O
+a,O
+prelingual,O
+onset,O
+and,O
+a,O
+nonprogressive,O
+course,O
+in,O
+most,O
+patients,O
+.,O
+ , 
+We,O
+found,O
+LOD,O
+scores,O
+>,O
+6,O
+with,O
+markers,O
+on,O
+chromosome,O
+11q,O
+.,O
+ , 
+Analysis,O
+of,O
+key,O
+recombinants,O
+maps,O
+this,O
+deafness,O
+gene,O
+(,B-Gene
+DFNA12,I-Gene
+),I-Gene
+to,O
+a,O
+36,O
+-,O
+cM,O
+interval,O
+on,O
+chromosome,O
+11q22,O
+-,O
+24,O
+,,O
+between,O
+markers,O
+D11S4120,O
+and,O
+D11S912,O
+.,O
+ , 
+The,O
+critical,O
+regions,O
+for,O
+the,O
+recessive,O
+deafness,O
+locus,O
+DFNB2,B-Gene
+and,O
+the,O
+dominant,O
+locus,O
+DFNA11,B-Gene
+,,I-Gene
+which,O
+were,O
+previously,O
+localized,O
+to,O
+the,O
+long,O
+arm,O
+of,O
+chromosome,O
+11,O
+,,O
+do,O
+not,O
+overlap,O
+with,O
+the,O
+candidate,O
+interval,O
+of,O
+DFNA12,B-Gene
+.,I-Gene
+ , 
+#16941471
+Comprehensive,O
+NF1,O
+screening,O
+on,O
+cultured,O
+Schwann,O
+cells,O
+from,O
+neurofibromas,O
+.,O
+ , 
+Neurofibromatosis,O
+type,O
+1,O
+(,O
+NF1,O
+),O
+is,O
+mainly,O
+characterized,O
+by,O
+the,O
+occurrence,O
+of,O
+benign,O
+peripheral,O
+nerve,O
+sheath,O
+tumors,O
+or,O
+neurofibromas,O
+.,O
+ , 
+Thorough,O
+investigation,O
+of,O
+the,O
+somatic,O
+mutation,O
+spectrum,O
+has,O
+thus,O
+far,O
+been,O
+hampered,O
+by,O
+the,O
+large,O
+size,O
+of,O
+the,O
+NF1,O
+gene,O
+and,O
+the,O
+considerable,O
+proportion,O
+of,O
+NF1,O
+heterozygous,O
+cells,O
+within,O
+the,O
+tumors,O
+.,O
+ , 
+We,O
+developed,O
+an,O
+improved,O
+somatic,O
+mutation,O
+detection,O
+strategy,O
+on,O
+cultured,O
+Schwann,O
+cells,O
+derived,O
+from,O
+neurofibromas,O
+and,O
+investigated,O
+38,O
+tumors,O
+from,O
+nine,O
+NF1,O
+patients,O
+.,O
+ , 
+Twenty,O
+-,O
+nine,O
+somatic,O
+NF1,O
+lesions,O
+were,O
+detected,O
+which,O
+represents,O
+the,O
+highest,O
+NF1,O
+somatic,O
+mutation,O
+detection,O
+rate,O
+described,O
+so,O
+far,O
+(,O
+76,O
+%,O
+),O
+.,O
+ , 
+Furthermore,O
+,,O
+our,O
+data,O
+strongly,O
+suggest,O
+that,O
+the,O
+acquired,O
+second,O
+hit,O
+underlies,O
+reduced,O
+NF1,O
+expression,O
+in,O
+Schwann,O
+cell,O
+cultures,O
+.,O
+ , 
+Together,O
+,,O
+these,O
+data,O
+clearly,O
+illustrate,O
+that,O
+two,O
+inactivating,O
+NF1,O
+mutations,O
+,,O
+in,O
+a,O
+subpopulation,O
+of,O
+the,O
+Schwann,O
+cells,O
+,,O
+are,O
+required,O
+for,O
+neurofibroma,O
+formation,O
+in,O
+NF1,O
+tumorigenesis,O
+.,O
+ , 
+The,O
+observed,O
+somatic,O
+mutation,O
+spectrum,O
+shows,O
+that,O
+intragenic,O
+NF1,O
+mutations,O
+(,O
+26/29,O
+),O
+are,O
+most,O
+prevalent,O
+,,O
+particularly,O
+frameshift,O
+mutations,O
+(,O
+12/29,O
+,,O
+41,O
+%,O
+),O
+.,O
+ , 
+We,O
+hypothesize,O
+that,O
+this,O
+mutation,O
+signature,O
+might,O
+reflect,O
+slightly,O
+reduced,O
+DNA,O
+repair,O
+efficiency,O
+as,O
+a,O
+trigger,O
+for,O
+NF1,O
+somatic,O
+inactivation,O
+preceding,O
+tumorigenesis,O
+.,O
+ , 
+Joint,O
+analysis,O
+of,O
+the,O
+current,O
+and,O
+previously,O
+published,O
+NF1,O
+mutation,O
+data,O
+revealed,O
+a,O
+significant,O
+difference,O
+in,O
+the,O
+somatic,O
+mutation,O
+spectrum,O
+in,O
+patients,O
+with,O
+a,O
+NF1,O
+microdeletion,O
+vs.,O
+non,O
+-,O
+microdeletion,O
+patients,O
+with,O
+respect,O
+to,O
+the,O
+prevalence,O
+of,O
+loss,O
+of,O
+heterozygosity,O
+events,O
+(,O
+0/15,O
+vs.,O
+41/81,O
+),O
+.,O
+ , 
+Differences,O
+in,O
+somatic,O
+inactivation,O
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+might,O
+therefore,O
+exist,O
+between,O
+NF1,O
+microdeletion,O
+patients,O
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+the,O
+general,O
+NF1,O
+population,O
+.,O
+ , 
+#22265016
+RHBDF2,B-Gene
+mutations,O
+are,O
+associated,O
+with,O
+tylosis,O
+,,O
+a,O
+familial,O
+esophageal,O
+cancer,O
+syndrome,O
+.,O
+ , 
+Tylosis,O
+esophageal,O
+cancer,O
+(,O
+TOC,O
+),O
+is,O
+an,O
+autosomal,O
+-,O
+dominant,O
+syndrome,O
+characterized,O
+by,O
+palmoplantar,O
+keratoderma,O
+,,O
+oral,O
+precursor,O
+lesions,O
+,,O
+and,O
+a,O
+high,O
+lifetime,O
+risk,O
+of,O
+esophageal,O
+cancer,O
+.,O
+ , 
+We,O
+have,O
+previously,O
+localized,O
+the,O
+TOC,O
+locus,O
+to,O
+a,O
+small,O
+genomic,O
+interval,O
+within,O
+chromosomal,O
+region,O
+17q25,O
+.,O
+ , 
+Using,O
+a,O
+targeted,O
+capture,O
+array,O
+and,O
+next,O
+-,O
+generation,O
+sequencing,O
+,,O
+we,O
+have,O
+now,O
+identified,O
+missense,O
+mutations,O
+(,B-SNP
+c.557T,I-SNP
+>,I-SNP
+C,I-SNP
+ , 
+[,B-SNP
+p.,I-SNP
+Ile186Thr,I-SNP
+],I-SNP
+and,O
+c.566C,B-SNP
+>,I-SNP
+T,I-SNP
+ , 
+[,B-SNP
+p.,I-SNP
+Pro189Leu,I-SNP
+],I-SNP
+in,O
+RHBDF2,B-Gene
+,,I-Gene
+which,O
+encodes,O
+the,O
+inactive,O
+rhomboid,O
+protease,O
+RHBDF2,B-Gene
+(,O
+also,O
+known,O
+as,O
+iRhom2,B-Gene
+),I-Gene
+,,O
+as,O
+the,O
+underlying,O
+cause,O
+of,O
+TOC,O
+.,O
+ , 
+We,O
+show,O
+that,O
+the,O
+distribution,O
+of,O
+RHBDF2,B-Gene
+in,O
+tylotic,O
+skin,O
+is,O
+altered,O
+in,O
+comparison,O
+with,O
+that,O
+in,O
+normal,O
+skin,O
+,,O
+and,O
+immortalized,O
+tylotic,O
+keratinocytes,O
+have,O
+decreased,O
+levels,O
+of,O
+total,O
+epidermal,B-Gene
+growth,I-Gene
+factor,I-Gene
+receptor,I-Gene
+(,B-Gene
+EGFR,I-Gene
+),I-Gene
+and,O
+display,O
+an,O
+increased,O
+proliferative,O
+and,O
+migratory,O
+potential,O
+relative,O
+to,O
+normal,O
+cells,O
+,,O
+even,O
+when,O
+normal,O
+cells,O
+are,O
+stimulated,O
+with,O
+exogenous,O
+epidermal,O
+growth,O
+factor,O
+.,O
+ , 
+It,O
+would,O
+thus,O
+appear,O
+that,O
+EGFR,B-Gene
+signaling,O
+is,O
+dysregulated,O
+in,O
+tylotic,O
+cells,O
+.,O
+ , 
+Furthermore,O
+,,O
+we,O
+also,O
+show,O
+an,O
+altered,O
+localization,O
+of,O
+RHBDF2,B-Gene
+in,O
+both,O
+tylotic,O
+and,O
+sporadic,O
+squamous,O
+esophageal,O
+tumors,O
+.,O
+ , 
+The,O
+elucidation,O
+of,O
+a,O
+role,O
+of,O
+RHBDF2,B-Gene
+in,O
+growth,O
+-,O
+factor,O
+signaling,O
+in,O
+esophageal,O
+cancer,O
+will,O
+help,O
+to,O
+determine,O
+whether,O
+targeting,O
+this,O
+pathway,O
+in,O
+chemotherapy,O
+for,O
+this,O
+and,O
+other,O
+squamous,O
+cell,O
+carcinomas,O
+will,O
+be,O
+effective,O
+.,O
+ , 
+#7866409
+Mutation,O
+at,O
+the,O
+catalytic,O
+site,O
+(,B-SNP
+M519V,I-SNP
+),I-SNP
+in,O
+glycogen,O
+storage,O
+disease,O
+type,O
+II,O
+(,O
+Pompe,O
+disease,O
+),O
+.,O
+ , 
+#21882294
+SgD,O
+-,O
+CNV,O
+,,O
+a,O
+database,O
+for,O
+common,O
+and,O
+rare,O
+copy,O
+number,O
+variants,O
+in,O
+three,O
+Asian,O
+populations,O
+.,O
+ , 
+Copy,O
+number,O
+variants,O
+(,O
+CNVs,O
+),O
+extend,O
+our,O
+understanding,O
+of,O
+the,O
+genetic,O
+diversity,O
+in,O
+humans,O
+.,O
+ , 
+However,O
+,,O
+the,O
+distribution,O
+and,O
+characteristics,O
+of,O
+CNVs,O
+in,O
+Asian,O
+populations,O
+remain,O
+largely,O
+unexplored,O
+,,O
+especially,O
+for,O
+rare,O
+CNVs,O
+that,O
+have,O
+emerged,O
+as,O
+important,O
+genetic,O
+factors,O
+for,O
+complex,O
+traits,O
+.,O
+ , 
+In,O
+the,O
+present,O
+study,O
+,,O
+we,O
+performed,O
+an,O
+in,O
+-,O
+depth,O
+investigation,O
+of,O
+common,O
+and,O
+rare,O
+CNVs,O
+across,O
+8,148,O
+individuals,O
+from,O
+the,O
+three,O
+major,O
+Asian,O
+ethnic,O
+groups,O
+:,O
+Chinese,O
+(,O
+n,O
+=,O
+1,945,O
+),O
+,,O
+Malays,O
+(,O
+n,O
+=,O
+2,399,O
+),O
+,,O
+and,O
+Indians,O
+(,O
+n,O
+=,O
+2,217,O
+),O
+in,O
+Singapore,O
+,,O
+making,O
+this,O
+investigation,O
+the,O
+most,O
+comprehensive,O
+genome,O
+-,O
+wide,O
+survey,O
+of,O
+CNVs,O
+outside,O
+the,O
+European,O
+-,O
+ancestry,O
+populations,O
+to,O
+date,O
+.,O
+ , 
+We,O
+detected,O
+about,O
+16,O
+CNVs,O
+per,O
+individual,O
+and,O
+the,O
+ratio,O
+of,O
+loss,O
+to,O
+gain,O
+events,O
+is,O
+∼2:1,O
+.,O
+ , 
+The,O
+majority,O
+of,O
+the,O
+CNVs,O
+are,O
+of,O
+low,O
+frequency,O
+(,O
+<,O
+10,O
+%,O
+),O
+,,O
+and,O
+40,O
+%,O
+are,O
+rare,O
+(,O
+<,O
+1,O
+%,O
+),O
+.,O
+ , 
+In,O
+each,O
+population,O
+,,O
+∼20,O
+%,O
+of,O
+the,O
+CNVs,O
+are,O
+not,O
+previously,O
+catalogued,O
+in,O
+the,O
+Database,O
+of,O
+Genomic,O
+Variants,O
+(,O
+DGV,O
+),O
+.,O
+ , 
+Contrary,O
+to,O
+findings,O
+from,O
+European,O
+studies,O
+,,O
+the,O
+common,O
+CNVs,O
+(,O
+>,O
+5,O
+%,O
+),O
+in,O
+our,O
+populations,O
+are,O
+not,O
+well,O
+tagged,O
+by,O
+SNPs,O
+in,O
+Illumina,O
+1,O
+M,O
+and,O
+610,O
+K,O
+arrays,O
+,,O
+and,O
+most,O
+disease,O
+-,O
+associated,O
+common,O
+CNVs,O
+previously,O
+reported,O
+in,O
+Caucasians,O
+are,O
+rare,O
+in,O
+our,O
+populations,O
+.,O
+ , 
+We,O
+also,O
+report,O
+noticeable,O
+population,O
+differentiation,O
+in,O
+the,O
+CNV,O
+landscape,O
+of,O
+these,O
+Asian,O
+populations,O
+,,O
+with,O
+the,O
+greatest,O
+diversity,O
+seen,O
+between,O
+the,O
+Indians,O
+and,O
+the,O
+Chinese,O
+.,O
+ , 
+#9443866
+Ataxia,O
+-,O
+telangiectasia,O
+:,O
+identification,O
+and,O
+detection,O
+of,O
+founder,O
+-,O
+effect,O
+mutations,O
+in,O
+the,O
+ATM,B-Gene
+gene,O
+in,O
+ethnic,O
+populations,O
+.,O
+ , 
+To,O
+facilitate,O
+the,O
+evaluation,O
+of,O
+ATM,B-Gene
+heterozygotes,O
+for,O
+susceptibility,O
+to,O
+other,O
+diseases,O
+,,O
+such,O
+as,O
+breast,O
+cancer,O
+,,O
+we,O
+have,O
+attempted,O
+to,O
+define,O
+the,O
+most,O
+common,O
+mutations,O
+and,O
+their,O
+frequencies,O
+in,O
+ataxia,O
+-,O
+telangiectasia,O
+(,O
+A,O
+-,O
+T,O
+),O
+homozygotes,O
+from,O
+10,O
+ethnic,O
+populations,O
+.,O
+ , 
+Both,O
+genomic,O
+mutations,O
+and,O
+their,O
+effects,O
+on,O
+cDNA,O
+were,O
+characterized,O
+.,O
+ , 
+Protein,O
+-,O
+truncation,O
+testing,O
+of,O
+the,O
+entire,O
+ATM,B-Gene
+cDNA,O
+detected,O
+92,O
+(,O
+66,O
+%,O
+),O
+truncating,O
+mutations,O
+in,O
+140,O
+mutant,O
+alleles,O
+screened,O
+.,O
+ , 
+The,O
+haplotyping,O
+of,O
+patients,O
+with,O
+identical,O
+mutations,O
+indicates,O
+that,O
+almost,O
+all,O
+of,O
+these,O
+represent,O
+common,O
+ancestry,O
+and,O
+that,O
+very,O
+few,O
+spontaneously,O
+recurring,O
+ATM,B-Gene
+mutations,O
+exist,O
+.,O
+ , 
+Assays,O
+requiring,O
+minimal,O
+amounts,O
+of,O
+genomic,O
+DNA,O
+were,O
+designed,O
+to,O
+allow,O
+rapid,O
+screening,O
+for,O
+common,O
+ethnic,O
+mutations,O
+.,O
+ , 
+These,O
+rapid,O
+assays,O
+detected,O
+mutations,O
+in,O
+76,O
+%,O
+of,O
+Costa,O
+Rican,O
+patients,O
+(,O
+3,O
+),O
+,,O
+50,O
+%,O
+of,O
+Norwegian,O
+patients,O
+(,O
+1,O
+),O
+,,O
+25,O
+%,O
+of,O
+Polish,O
+patients,O
+(,O
+4,O
+),O
+,,O
+and,O
+14,O
+%,O
+of,O
+Italian,O
+patients,O
+(,O
+1,O
+),O
+,,O
+as,O
+well,O
+as,O
+in,O
+patients,O
+of,O
+Amish,O
+/,O
+Mennonite,O
+and,O
+Irish,O
+English,O
+backgrounds,O
+.,O
+ , 
+Additional,O
+mutations,O
+were,O
+observed,O
+in,O
+Japanese,O
+,,O
+Utah,O
+Mormon,O
+,,O
+and,O
+African,O
+American,O
+patients,O
+.,O
+ , 
+These,O
+assays,O
+should,O
+facilitate,O
+screening,O
+for,O
+A,O
+-,O
+T,O
+heterozygotes,O
+in,O
+the,O
+populations,O
+studied,O
+.,O
+ , 
+#17273962
+Mitochondrial,O
+haplogroup,O
+N9a,O
+confers,O
+resistance,O
+against,O
+type,O
+2,O
+diabetes,O
+in,O
+Asians,O
+.,O
+ , 
+Because,O
+mitochondria,O
+play,O
+pivotal,O
+roles,O
+in,O
+both,O
+insulin,O
+secretion,O
+from,O
+the,O
+pancreatic,O
+beta,O
+cells,O
+and,O
+insulin,O
+resistance,O
+of,O
+skeletal,O
+muscles,O
+,,O
+we,O
+performed,O
+a,O
+large,O
+-,O
+scale,O
+association,O
+study,O
+to,O
+identify,O
+mitochondrial,O
+haplogroups,O
+that,O
+may,O
+confer,O
+resistance,O
+against,O
+or,O
+susceptibility,O
+to,O
+type,O
+2,O
+diabetes,O
+mellitus,O
+(,O
+T2DM,O
+),O
+.,O
+ , 
+The,O
+study,O
+population,O
+comprised,O
+2,906,O
+unrelated,O
+Japanese,O
+individuals,O
+,,O
+including,O
+1,289,O
+patients,O
+with,O
+T2DM,O
+and,O
+1,617,O
+controls,O
+,,O
+and,O
+1,365,O
+unrelated,O
+Korean,O
+individuals,O
+,,O
+including,O
+732,O
+patients,O
+with,O
+T2DM,O
+and,O
+633,O
+controls,O
+.,O
+ , 
+The,O
+genotypes,O
+for,O
+25,O
+polymorphisms,O
+in,O
+the,O
+coding,O
+region,O
+of,O
+the,O
+mitochondrial,O
+genome,O
+were,O
+determined,O
+,,O
+and,O
+the,O
+haplotypes,O
+were,O
+classified,O
+into,O
+10,O
+major,O
+haplogroups,O
+(,O
+i.e.,O
+,,O
+F,O
+,,O
+B,O
+,,O
+A,O
+,,O
+N9a,O
+,,O
+M7a,O
+,,O
+M7b,O
+,,O
+G,O
+,,O
+D4a,O
+,,O
+D4b,O
+,,O
+and,O
+D5,O
+),O
+.,O
+ , 
+Multivariate,O
+logistic,O
+-,O
+regression,O
+analysis,O
+with,O
+adjustment,O
+for,O
+age,O
+and,O
+sex,O
+revealed,O
+that,O
+the,O
+mitochondrial,O
+haplogroup,O
+N9a,O
+was,O
+significantly,O
+associated,O
+with,O
+resistance,O
+against,O
+T2DM,O
+(,O
+P=.0002,O
+),O
+with,O
+an,O
+odds,O
+ratio,O
+of,O
+0.55,O
+(,O
+95,O
+%,O
+confidence,O
+interval,O
+0.40,O
+-,O
+0.75,O
+),O
+.,O
+ , 
+Even,O
+in,O
+the,O
+modern,O
+environment,O
+,,O
+which,O
+is,O
+often,O
+characterized,O
+by,O
+satiety,O
+and,O
+physical,O
+inactivity,O
+,,O
+this,O
+haplogroup,O
+might,O
+confer,O
+resistance,O
+against,O
+T2DM,O
+.,O
+ , 
+#10874330
+A,O
+novel,O
+mutation,O
+(,B-SNP
+1320InsT,I-SNP
+),I-SNP
+identified,O
+in,O
+two,O
+Argentine,O
+families,O
+with,O
+variegate,O
+porphyria,O
+.,O
+ , 
+#17918732
+An,O
+integrated,O
+genetic,O
+and,O
+functional,O
+analysis,O
+of,O
+the,O
+role,O
+of,O
+type,B-Gene
+II,I-Gene
+transmembrane,I-Gene
+serine,I-Gene
+proteases,I-Gene
+(,B-Gene
+TMPRSSs,I-Gene
+),I-Gene
+in,O
+hearing,O
+loss,O
+.,O
+ , 
+Building,O
+on,O
+our,O
+discovery,O
+that,O
+mutations,O
+in,O
+the,O
+transmembrane,B-Gene
+serine,I-Gene
+protease,I-Gene
+,,I-Gene
+TMPRSS3,B-Gene
+,,I-Gene
+cause,O
+nonsyndromic,O
+deafness,O
+,,O
+we,O
+have,O
+investigated,O
+the,O
+contribution,O
+of,O
+other,O
+TMPRSS,B-Gene
+family,O
+members,O
+to,O
+the,O
+auditory,O
+function,O
+.,O
+ , 
+To,O
+identify,O
+which,O
+of,O
+the,O
+16,O
+known,O
+TMPRSS,B-Gene
+genes,O
+had,O
+a,O
+strong,O
+likelihood,O
+of,O
+involvement,O
+in,O
+hearing,O
+function,O
+,,O
+three,O
+types,O
+of,O
+biological,O
+evidence,O
+were,O
+examined,O
+:,O
+1,O
+),O
+expression,O
+in,O
+inner,O
+ear,O
+tissues,O
+;,O
+2,O
+),O
+location,O
+in,O
+a,O
+genomic,O
+interval,O
+that,O
+contains,O
+a,O
+yet,O
+unidentified,O
+gene,O
+for,O
+deafness,O
+;,O
+and,O
+3,O
+),O
+evaluation,O
+of,O
+hearing,O
+status,O
+of,O
+any,O
+available,O
+Tmprss,O
+knockout,O
+mouse,O
+strains,O
+.,O
+ , 
+This,O
+analysis,O
+demonstrated,O
+that,O
+,,O
+besides,O
+TMPRSS3,B-Gene
+,,I-Gene
+another,O
+TMPRSS,B-Gene
+gene,O
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+essential,O
+for,O
+hearing,O
+and,O
+,,O
+indeed,O
+,,O
+mice,O
+deficient,O
+for,O
+Hepsin,B-Gene
+(,B-Gene
+Hpn,I-Gene
+),I-Gene
+also,O
+known,O
+as,O
+Tmprss1,B-Gene
+exhibited,O
+profound,O
+hearing,O
+loss,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+TMPRSS2,B-Gene
+,,I-Gene
+TMPRSS5,B-Gene
+,,I-Gene
+and,O
+CORIN,B-Gene
+,,I-Gene
+also,O
+named,O
+TMPRSS10,B-Gene
+,,I-Gene
+showed,O
+strong,O
+likelihood,O
+of,O
+involvement,O
+based,O
+on,O
+their,O
+inner,O
+ear,O
+expression,O
+and,O
+mapping,O
+position,O
+within,O
+deafness,O
+loci,O
+PKSR7,B-Gene
+,,I-Gene
+DFNB24,O
+,,O
+and,O
+DFNB25,O
+,,O
+respectively,O
+.,O
+ , 
+These,O
+four,O
+TMPRSS,B-Gene
+genes,O
+were,O
+then,O
+screened,O
+for,O
+mutations,O
+in,O
+affected,O
+members,O
+of,O
+the,O
+DFNB24,O
+and,O
+DFNB25,O
+deafness,O
+families,O
+,,O
+and,O
+in,O
+a,O
+cohort,O
+of,O
+362,O
+sporadic,O
+deaf,O
+cases,O
+.,O
+ , 
+This,O
+large,O
+mutation,O
+screen,O
+revealed,O
+numerous,O
+novel,O
+sequence,O
+variations,O
+including,O
+three,O
+potential,O
+pathogenic,O
+mutations,O
+in,O
+the,O
+TMPRSS5,B-Gene
+gene,O
+.,O
+ , 
+The,O
+mutant,O
+forms,O
+of,O
+TMPRSS5,B-Gene
+showed,O
+reduced,O
+or,O
+absent,O
+proteolytic,O
+activity,O
+.,O
+ , 
+Subsequently,O
+,,O
+TMPRSS,B-Gene
+genes,O
+with,O
+evidence,O
+of,O
+involvement,O
+in,O
+deafness,O
+were,O
+further,O
+characterized,O
+,,O
+and,O
+their,O
+sites,O
+of,O
+expression,O
+were,O
+determined,O
+.,O
+ , 
+Tmprss1,B-Gene
+,,I-Gene
+3,I-Gene
+,,I-Gene
+and,I-Gene
+5,I-Gene
+proteins,O
+were,O
+detected,O
+in,O
+spiral,O
+ganglion,O
+neurons,O
+.,O
+ , 
+Tmprss3,B-Gene
+was,O
+also,O
+present,O
+in,O
+the,O
+organ,O
+of,O
+Corti,O
+.,O
+ , 
+TMPRSS1,B-Gene
+and,O
+3,O
+proteins,O
+appeared,O
+stably,O
+anchored,O
+to,O
+the,O
+endoplasmic,O
+reticulum,O
+membranes,O
+,,O
+whereas,O
+TMPRSS5,B-Gene
+was,O
+also,O
+detected,O
+at,O
+the,O
+plasma,O
+membrane,O
+.,O
+ , 
+Collectively,O
+,,O
+these,O
+results,O
+provide,O
+evidence,O
+that,O
+TMPRSS1,B-Gene
+and,O
+TMPRSS3,B-Gene
+play,O
+and,O
+TMPRSS5,B-Gene
+may,O
+play,O
+important,O
+and,O
+specific,O
+roles,O
+in,O
+hearing,O
+.,O
+ , 
+#10677310
+Fine,O
+localization,O
+of,O
+a,O
+major,O
+disease,O
+-,O
+susceptibility,O
+locus,O
+for,O
+diffuse,O
+panbronchiolitis,O
+.,O
+ , 
+Diffuse,O
+panbronchiolitis,O
+affecting,O
+East,O
+Asians,O
+is,O
+strongly,O
+associated,O
+with,O
+the,O
+class,O
+I,O
+human,B-Gene
+leukocyte,I-Gene
+antigen,I-Gene
+(,B-Gene
+HLA,I-Gene
+),I-Gene
+alleles,O
+.,O
+ , 
+Recent,O
+observations,O
+suggest,O
+that,O
+a,O
+major,O
+disease,O
+-,O
+susceptibility,O
+gene,O
+may,O
+be,O
+located,O
+between,O
+the,O
+HLA,B-Gene
+-,I-Gene
+B,I-Gene
+and,O
+HLA,B-Gene
+-,I-Gene
+A,I-Gene
+loci,O
+in,O
+the,O
+class,O
+I,O
+region,O
+of,O
+the,O
+major,O
+histocompatibility,O
+complex,O
+on,O
+chromosome,O
+6,O
+.,O
+ , 
+To,O
+test,O
+this,O
+possibility,O
+,,O
+we,O
+analyzed,O
+14,O
+polymorphic,O
+markers,O
+in,O
+92,O
+Japanese,O
+patients,O
+and,O
+93,O
+healthy,O
+controls,O
+.,O
+ , 
+Of,O
+these,O
+,,O
+seven,O
+marker,O
+alleles,O
+,,O
+including,O
+HLA,B-Gene
+-,I-Gene
+B54,I-Gene
+and,O
+HLA,B-Gene
+-,I-Gene
+A11,I-Gene
+,,I-Gene
+were,O
+significantly,O
+associated,O
+with,O
+the,O
+disease,O
+.,O
+ , 
+Maximum,O
+-,O
+likelihood,O
+haplotype,O
+analysis,O
+and,O
+subsequent,O
+direct,O
+determination,O
+of,O
+individual,O
+haplotypes,O
+identified,O
+a,O
+group,O
+of,O
+disease,O
+-,O
+associated,O
+haplotypes,O
+,,O
+one,O
+of,O
+which,O
+contained,O
+all,O
+seven,O
+disease,O
+-,O
+associated,O
+marker,O
+alleles,O
+.,O
+ , 
+Another,O
+haplotype,O
+,,O
+containing,O
+HLA,B-Gene
+-,I-Gene
+B*5504,I-Gene
+,,I-Gene
+was,O
+also,O
+associated,O
+with,O
+the,O
+disease,O
+.,O
+ , 
+All,O
+these,O
+haplotypes,O
+seem,O
+to,O
+have,O
+diverged,O
+from,O
+a,O
+common,O
+ancestral,O
+haplotype,O
+in,O
+East,O
+Asians,O
+and,O
+share,O
+a,O
+specific,O
+segment,O
+containing,O
+three,O
+consecutive,O
+markers,O
+between,O
+the,O
+S,O
+and,O
+TFIIH,B-Gene
+loci,O
+in,O
+the,O
+class,O
+I,O
+region,O
+.,O
+ , 
+Furthermore,O
+,,O
+one,O
+of,O
+the,O
+markers,O
+within,O
+the,O
+candidate,O
+region,O
+showed,O
+the,O
+highest,O
+delta,O
+value,O
+,,O
+indicating,O
+the,O
+strongest,O
+association,O
+.,O
+ , 
+Of,O
+20,O
+Korean,O
+patients,O
+with,O
+diffuse,O
+panbronchiolitis,O
+,,O
+17,O
+also,O
+shared,O
+the,O
+combination,O
+of,O
+the,O
+disease,O
+-,O
+associated,O
+marker,O
+alleles,O
+within,O
+the,O
+candidate,O
+region,O
+.,O
+ , 
+These,O
+results,O
+indicate,O
+that,O
+an,O
+HLA,O
+-,O
+associated,O
+major,O
+susceptibility,O
+gene,O
+for,O
+diffuse,O
+panbronchiolitis,O
+is,O
+probably,O
+located,O
+within,O
+the,O
+200,O
+kb,O
+in,O
+the,O
+class,O
+I,O
+region,O
+300,O
+kb,O
+telomeric,O
+of,O
+the,O
+HLA,B-Gene
+-,I-Gene
+B,I-Gene
+locus,O
+on,O
+the,O
+chromosome,O
+6p21.3,O
+.,O
+ , 
+#20672374
+Experience,O
+with,O
+carrier,O
+screening,O
+and,O
+prenatal,O
+diagnosis,O
+for,O
+16,O
+Ashkenazi,O
+Jewish,O
+genetic,O
+diseases,O
+.,O
+ , 
+The,O
+success,O
+of,O
+prenatal,O
+carrier,O
+screening,O
+as,O
+a,O
+disease,O
+prevention,O
+strategy,O
+in,O
+the,O
+Ashkenazi,O
+Jewish,O
+(,O
+AJ,O
+),O
+population,O
+has,O
+driven,O
+the,O
+expansion,O
+of,O
+screening,O
+panels,O
+as,O
+disease,O
+-,O
+causing,O
+founder,O
+mutations,O
+have,O
+been,O
+identified,O
+.,O
+ , 
+However,O
+,,O
+the,O
+carrier,O
+frequencies,O
+of,O
+many,O
+of,O
+these,O
+mutations,O
+have,O
+not,O
+been,O
+reported,O
+in,O
+large,O
+AJ,O
+cohorts,O
+.,O
+ , 
+We,O
+determined,O
+the,O
+carrier,O
+frequencies,O
+of,O
+over,O
+100,O
+mutations,O
+for,O
+16,O
+recessive,O
+disorders,O
+in,O
+the,O
+New,O
+York,O
+metropolitan,O
+area,O
+AJ,O
+population,O
+.,O
+ , 
+Among,O
+the,O
+100,O
+%,O
+AJ,O
+-,O
+descended,O
+individuals,O
+,,O
+screening,O
+for,O
+16,O
+disorders,O
+resulted,O
+in,O
+∼1,O
+in,O
+3.3,O
+being,O
+a,O
+carrier,O
+for,O
+one,O
+disease,O
+and,O
+∼1,O
+in,O
+24,O
+for,O
+two,O
+diseases,O
+.,O
+ , 
+The,O
+carrier,O
+frequencies,O
+ranged,O
+from,O
+0.066,O
+(,O
+1,O
+in,O
+15.2,O
+;,O
+Gaucher,O
+disease,O
+),O
+to,O
+0.006,O
+(,O
+1,O
+in,O
+168,O
+;,O
+nemaline,O
+myopathy,O
+),O
+,,O
+which,O
+averaged,O
+∼15,O
+%,O
+higher,O
+than,O
+those,O
+for,O
+all,O
+screenees,O
+.,O
+ , 
+Importantly,O
+,,O
+over,O
+95,O
+%,O
+of,O
+screenees,O
+chose,O
+to,O
+be,O
+screened,O
+for,O
+all,O
+possible,O
+AJ,O
+diseases,O
+,,O
+including,O
+disorders,O
+with,O
+lower,O
+carrier,O
+frequencies,O
+and/or,O
+detectability,O
+.,O
+ , 
+Carrier,O
+screening,O
+also,O
+identified,O
+rare,O
+individuals,O
+homozygous,O
+for,O
+disease,O
+-,O
+causing,O
+mutations,O
+who,O
+had,O
+previously,O
+unrecognized,O
+clinical,O
+manifestations,O
+.,O
+ , 
+Additionally,O
+,,O
+prenatal,O
+testing,O
+results,O
+and,O
+experience,O
+for,O
+all,O
+16,O
+disorders,O
+(,O
+n,O
+=,O
+574,O
+),O
+are,O
+reported,O
+.,O
+ , 
+Together,O
+,,O
+these,O
+data,O
+indicate,O
+the,O
+general,O
+acceptance,O
+,,O
+carrier,O
+frequencies,O
+,,O
+and,O
+prenatal,O
+testing,O
+results,O
+for,O
+an,O
+expanded,O
+panel,O
+of,O
+16,O
+diseases,O
+in,O
+the,O
+AJ,O
+population,O
+.,O
+ , 
+#19804848
+Familial,O
+hemophagocytic,O
+lymphohistiocytosis,O
+type,O
+5,O
+(,O
+FHL-5,O
+),O
+is,O
+caused,O
+by,O
+mutations,O
+in,O
+Munc18,B-Gene
+-,I-Gene
+2,I-Gene
+and,O
+impaired,O
+binding,O
+to,O
+syntaxin,B-Gene
+11,I-Gene
+.,I-Gene
+ , 
+Rapid,O
+intracellular,O
+transport,O
+and,O
+secretion,O
+of,O
+cytotoxic,O
+granules,O
+through,O
+the,O
+immunological,O
+synapse,O
+requires,O
+a,O
+balanced,O
+interaction,O
+of,O
+several,O
+proteins,O
+.,O
+ , 
+Disturbance,O
+of,O
+this,O
+highly,O
+regulated,O
+process,O
+underlies,O
+familial,O
+hemophagocytic,O
+lymphohistiocytosis,O
+(,O
+FHL,O
+),O
+,,O
+a,O
+genetically,O
+heterogeneous,O
+autosomal,O
+-,O
+recessive,O
+disorder,O
+characterized,O
+by,O
+a,O
+severe,O
+hyperinflammatory,O
+phenotype,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+have,O
+assigned,O
+FHL-5,B-Gene
+to,O
+a,O
+1,O
+Mb,O
+region,O
+on,O
+chromosome,O
+19p,O
+by,O
+using,O
+high,O
+-,O
+resolution,O
+SNP,O
+genotyping,O
+in,O
+eight,O
+unrelated,O
+FHL,O
+patients,O
+from,O
+consanguineous,O
+families,O
+.,O
+ , 
+Subsequently,O
+,,O
+we,O
+found,O
+nine,O
+different,O
+mutations,O
+,,O
+either,O
+truncating,O
+or,O
+missense,O
+,,O
+in,O
+STXBP2,B-Gene
+in,O
+twelve,O
+patients,O
+from,O
+Turkey,O
+,,O
+Saudi,O
+Arabia,O
+,,O
+and,O
+Central,O
+Europe,O
+.,O
+ , 
+STXBP2,B-Gene
+encodes,O
+syntaxin,B-Gene
+binding,I-Gene
+protein,I-Gene
+2,I-Gene
+(,B-Gene
+Munc18,I-Gene
+-,I-Gene
+2,I-Gene
+),I-Gene
+,,O
+involved,O
+in,O
+the,O
+regulation,O
+of,O
+vesicle,O
+transport,O
+to,O
+the,O
+plasma,O
+membrane,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+syntaxin,B-Gene
+11,I-Gene
+,,I-Gene
+a,O
+SNARE,O
+protein,O
+mutated,O
+in,O
+FHL-4,B-Gene
+,,I-Gene
+as,O
+an,O
+interaction,O
+partner,O
+of,O
+STXBP2,B-Gene
+.,I-Gene
+ , 
+This,O
+interaction,O
+is,O
+eliminated,O
+by,O
+the,O
+missense,O
+mutations,O
+found,O
+in,O
+our,O
+FHL-5,B-Gene
+patients,O
+,,O
+which,O
+leads,O
+to,O
+a,O
+decreased,O
+stability,O
+of,O
+both,O
+proteins,O
+,,O
+as,O
+shown,O
+in,O
+patient,O
+lymphocytes,O
+.,O
+ , 
+Activity,O
+of,O
+natural,O
+killer,O
+and,O
+cytotoxic,O
+T,O
+cells,O
+was,O
+markedly,O
+reduced,O
+or,O
+absent,O
+,,O
+as,O
+determined,O
+by,O
+CD107,O
+degranulation,O
+.,O
+ , 
+Our,O
+findings,O
+thus,O
+identify,O
+a,O
+key,O
+role,O
+for,O
+STXBP2,B-Gene
+in,O
+lytic,O
+granule,O
+exocytosis,O
+.,O
+ , 
+#7847381
+Molecular,O
+studies,O
+of,O
+chromosomal,O
+mosaicism,O
+:,O
+relative,O
+frequency,O
+of,O
+chromosome,O
+gain,O
+or,O
+loss,O
+and,O
+possible,O
+role,O
+of,O
+cell,O
+selection,O
+.,O
+ , 
+Studies,O
+of,O
+uniparental,O
+disomy,O
+and,O
+origin,O
+of,O
+nonmosaic,O
+trisomies,O
+indicate,O
+that,O
+both,O
+gain,O
+and,O
+loss,O
+of,O
+a,O
+chromosome,O
+can,O
+occur,O
+after,O
+fertilization,O
+.,O
+ , 
+It,O
+is,O
+therefore,O
+of,O
+interest,O
+to,O
+determine,O
+both,O
+the,O
+relative,O
+frequency,O
+with,O
+which,O
+gain,O
+or,O
+loss,O
+can,O
+contribute,O
+to,O
+chromosomal,O
+mosaicism,O
+and,O
+whether,O
+these,O
+frequencies,O
+are,O
+influenced,O
+by,O
+selective,O
+factors,O
+.,O
+ , 
+Thirty,O
+-,O
+two,O
+mosaic,O
+cases,O
+were,O
+examined,O
+with,O
+molecular,O
+markers,O
+,,O
+to,O
+try,O
+to,O
+determine,O
+which,O
+was,O
+the,O
+primary,O
+and,O
+which,O
+was,O
+the,O
+secondary,O
+cell,O
+line,O
+:,O
+16,O
+cases,O
+of,O
+disomy,O
+/,O
+trisomy,O
+mosaicism,O
+(,O
+5,O
+trisomy,O
+8,O
+,,O
+2,O
+trisomy,O
+13,O
+,,O
+1,O
+trisomy,O
+18,O
+,,O
+4,O
+trisomy,O
+21,O
+,,O
+and,O
+4,O
+involving,O
+the,O
+X,O
+chromosome,O
+),O
+,,O
+14,O
+cases,O
+of,O
+45,X/46,XX,O
+,,O
+and,O
+2,O
+cases,O
+of,O
+45,X/47,XXX,O
+.,O
+ , 
+Of,O
+the,O
+14,O
+cases,O
+of,O
+mosaic,O
+45,X/46,XX,O
+,,O
+chromosome,O
+loss,O
+from,O
+a,O
+normal,O
+disomic,O
+fertilization,O
+predominated,O
+,,O
+supporting,O
+the,O
+hypothesis,O
+that,O
+45,X,O
+might,O
+be,O
+compatible,O
+with,O
+survival,O
+only,O
+when,O
+the,O
+45,X,O
+cell,O
+line,O
+arises,O
+relatively,O
+late,O
+in,O
+development,O
+.,O
+ , 
+Most,O
+cases,O
+of,O
+disomy,O
+/,O
+trisomy,O
+mosaicism,O
+involving,O
+chromosomes,O
+13,O
+,,O
+18,O
+,,O
+21,O
+,,O
+and,O
+X,O
+were,O
+also,O
+frequently,O
+associated,O
+with,O
+somatic,O
+loss,O
+of,O
+one,O
+(,O
+or,O
+more,O
+),O
+chromosome,O
+,,O
+in,O
+these,O
+cases,O
+from,O
+a,O
+trisomic,O
+fertilization,O
+.,O
+ , 
+By,O
+contrast,O
+,,O
+four,O
+of,O
+the,O
+five,O
+trisomy,O
+8,O
+cases,O
+were,O
+consistent,O
+with,O
+a,O
+somatic,O
+gain,O
+of,O
+a,O
+chromosome,O
+8,O
+during,O
+development,O
+from,O
+a,O
+normal,O
+zygote,O
+.,O
+ , 
+It,O
+is,O
+possible,O
+that,O
+survival,O
+of,O
+trisomy,O
+8,O
+is,O
+also,O
+much,O
+more,O
+likely,O
+when,O
+the,O
+aneuploid,O
+cell,O
+line,O
+arises,O
+relatively,O
+late,O
+in,O
+development,O
+.,O
+ , 
+#12557124
+Human,O
+population,O
+genetic,O
+structure,O
+and,O
+inference,O
+of,O
+group,O
+membership,O
+.,O
+ , 
+A,O
+major,O
+goal,O
+of,O
+biomedical,O
+research,O
+is,O
+to,O
+develop,O
+the,O
+capability,O
+to,O
+provide,O
+highly,O
+personalized,O
+health,O
+care,O
+.,O
+ , 
+To,O
+do,O
+so,O
+,,O
+it,O
+is,O
+necessary,O
+to,O
+understand,O
+the,O
+distribution,O
+of,O
+interindividual,O
+genetic,O
+variation,O
+at,O
+loci,O
+underlying,O
+physical,O
+characteristics,O
+,,O
+disease,O
+susceptibility,O
+,,O
+and,O
+response,O
+to,O
+treatment,O
+.,O
+ , 
+Variation,O
+at,O
+these,O
+loci,O
+commonly,O
+exhibits,O
+geographic,O
+structuring,O
+and,O
+may,O
+contribute,O
+to,O
+phenotypic,O
+differences,O
+between,O
+groups,O
+.,O
+ , 
+Thus,O
+,,O
+in,O
+some,O
+situations,O
+,,O
+it,O
+may,O
+be,O
+important,O
+to,O
+consider,O
+these,O
+groups,O
+separately,O
+.,O
+ , 
+Membership,O
+in,O
+these,O
+groups,O
+is,O
+commonly,O
+inferred,O
+by,O
+use,O
+of,O
+a,O
+proxy,O
+such,O
+as,O
+place,O
+-,O
+of,O
+-,O
+origin,O
+or,O
+ethnic,O
+affiliation,O
+.,O
+ , 
+These,O
+inferences,O
+are,O
+frequently,O
+weakened,O
+,,O
+however,O
+,,O
+by,O
+use,O
+of,O
+surrogates,O
+,,O
+such,O
+as,O
+skin,O
+color,O
+,,O
+for,O
+these,O
+proxies,O
+,,O
+the,O
+distribution,O
+of,O
+which,O
+bears,O
+little,O
+resemblance,O
+to,O
+the,O
+distribution,O
+of,O
+neutral,O
+genetic,O
+variation,O
+.,O
+ , 
+Consequently,O
+,,O
+it,O
+has,O
+become,O
+increasingly,O
+controversial,O
+whether,O
+proxies,O
+are,O
+sufficient,O
+and,O
+accurate,O
+representations,O
+of,O
+groups,O
+inferred,O
+from,O
+neutral,O
+genetic,O
+variation,O
+.,O
+ , 
+This,O
+raises,O
+three,O
+questions,O
+:,O
+how,O
+many,O
+data,O
+are,O
+required,O
+to,O
+identify,O
+population,O
+structure,O
+at,O
+a,O
+meaningful,O
+level,O
+of,O
+resolution,O
+,,O
+to,O
+what,O
+level,O
+can,O
+population,O
+structure,O
+be,O
+resolved,O
+,,O
+and,O
+do,O
+some,O
+proxies,O
+represent,O
+population,O
+structure,O
+accurately,O
+?,O
+ , 
+We,O
+assayed,O
+100,O
+Alu,O
+insertion,O
+polymorphisms,O
+in,O
+a,O
+heterogeneous,O
+collection,O
+of,O
+approximately,O
+565,O
+individuals,O
+,,O
+approximately,O
+200,O
+of,O
+whom,O
+were,O
+also,O
+typed,O
+for,O
+60,O
+microsatellites,O
+.,O
+ , 
+Stripped,O
+of,O
+identifying,O
+information,O
+,,O
+correct,O
+assignment,O
+to,O
+the,O
+continent,O
+of,O
+origin,O
+(,O
+Africa,O
+,,O
+Asia,O
+,,O
+or,O
+Europe,O
+),O
+with,O
+a,O
+mean,O
+accuracy,O
+of,O
+at,O
+least,O
+90,O
+%,O
+required,O
+a,O
+minimum,O
+of,O
+60,O
+Alu,O
+markers,O
+or,O
+microsatellites,O
+and,O
+reached,O
+99%-100,O
+%,O
+when,O
+>,O
+/=100,O
+loci,O
+were,O
+used,O
+.,O
+ , 
+Less,O
+accurate,O
+assignment,O
+(,O
+87,O
+%,O
+),O
+to,O
+the,O
+appropriate,O
+genetic,O
+cluster,O
+was,O
+possible,O
+for,O
+a,O
+historically,O
+admixed,O
+sample,O
+from,O
+southern,O
+India,O
+.,O
+ , 
+These,O
+results,O
+set,O
+a,O
+minimum,O
+for,O
+the,O
+number,O
+of,O
+markers,O
+that,O
+must,O
+be,O
+tested,O
+to,O
+make,O
+strong,O
+inferences,O
+about,O
+detecting,O
+population,O
+structure,O
+among,O
+Old,O
+World,O
+populations,O
+under,O
+ideal,O
+experimental,O
+conditions,O
+.,O
+ , 
+We,O
+note,O
+that,O
+,,O
+whereas,O
+some,O
+proxies,O
+correspond,O
+crudely,O
+,,O
+if,O
+at,O
+all,O
+,,O
+to,O
+population,O
+structure,O
+,,O
+the,O
+heuristic,O
+value,O
+of,O
+others,O
+is,O
+much,O
+higher,O
+.,O
+ , 
+This,O
+suggests,O
+that,O
+a,O
+more,O
+flexible,O
+framework,O
+is,O
+needed,O
+for,O
+making,O
+inferences,O
+about,O
+population,O
+structure,O
+and,O
+the,O
+utility,O
+of,O
+proxies,O
+.,O
+ , 
+#8434605
+Identification,O
+of,O
+individuals,O
+by,O
+analysis,O
+of,O
+biallelic,O
+DNA,O
+markers,O
+,,O
+using,O
+PCR,O
+and,O
+solid,O
+-,O
+phase,O
+minisequencing,O
+.,O
+ , 
+We,O
+have,O
+developed,O
+a,O
+new,O
+method,O
+for,O
+forensic,O
+identification,O
+of,O
+individuals,O
+,,O
+in,O
+which,O
+a,O
+panel,O
+of,O
+biallelic,O
+DNA,O
+markers,O
+are,O
+amplified,O
+by,O
+the,O
+PCR,O
+,,O
+and,O
+the,O
+variable,O
+nucleotides,O
+are,O
+detected,O
+in,O
+the,O
+amplified,O
+DNA,O
+fragments,O
+by,O
+the,O
+solid,O
+-,O
+phase,O
+minisequencing,O
+method,O
+.,O
+ , 
+A,O
+panel,O
+of,O
+12,O
+common,O
+polymorphic,O
+nucleotides,O
+located,O
+on,O
+different,O
+chromosomes,O
+with,O
+reported,O
+allele,O
+frequencies,O
+close,O
+to,O
+.5,O
+were,O
+chosen,O
+for,O
+the,O
+test,O
+.,O
+ , 
+The,O
+allele,O
+frequencies,O
+for,O
+most,O
+of,O
+the,O
+markers,O
+were,O
+found,O
+to,O
+be,O
+similar,O
+in,O
+the,O
+Finnish,O
+and,O
+other,O
+Caucasian,O
+populations,O
+.,O
+ , 
+We,O
+also,O
+introduce,O
+a,O
+novel,O
+approach,O
+for,O
+rapid,O
+determination,O
+of,O
+the,O
+population,O
+frequencies,O
+of,O
+biallelic,O
+markers,O
+.,O
+ , 
+By,O
+this,O
+approach,O
+we,O
+were,O
+able,O
+to,O
+determine,O
+the,O
+allele,O
+frequencies,O
+of,O
+the,O
+markers,O
+in,O
+the,O
+Finnish,O
+population,O
+,,O
+by,O
+quantitative,O
+analysis,O
+of,O
+three,O
+pooled,O
+DNA,O
+samples,O
+representing,O
+3,000,O
+individuals,O
+.,O
+ , 
+The,O
+power,O
+of,O
+discrimination,O
+and,O
+exclusion,O
+of,O
+the,O
+solid,O
+-,O
+phase,O
+minisequencing,O
+typing,O
+test,O
+with,O
+12,O
+markers,O
+was,O
+similar,O
+to,O
+that,O
+of,O
+three,O
+VNTR,O
+markers,O
+that,O
+are,O
+routinely,O
+used,O
+in,O
+forensic,O
+analyses,O
+at,O
+our,O
+institute,O
+.,O
+ , 
+The,O
+solid,O
+-,O
+phase,O
+minisequencing,O
+method,O
+was,O
+successfully,O
+applied,O
+to,O
+type,O
+paternity,O
+and,O
+forensic,O
+case,O
+samples,O
+.,O
+ , 
+We,O
+also,O
+show,O
+that,O
+the,O
+quantitative,O
+nature,O
+of,O
+our,O
+method,O
+allows,O
+typing,O
+of,O
+mixed,O
+samples,O
+.,O
+ , 
+#7762555
+The,O
+molecular,O
+basis,O
+of,O
+homocystinuria,O
+due,O
+to,O
+cystathionine,B-Gene
+beta,I-Gene
+-,I-Gene
+synthase,I-Gene
+deficiency,O
+in,O
+Italian,O
+families,O
+,,O
+and,O
+report,O
+of,O
+four,O
+novel,O
+mutations,O
+.,O
+ , 
+Four,O
+new,O
+mutations,O
+in,O
+the,O
+cystathionine,B-Gene
+beta,I-Gene
+-,I-Gene
+synthase,I-Gene
+(,B-Gene
+CBS,I-Gene
+),I-Gene
+gene,O
+have,O
+been,O
+identified,O
+in,O
+Italian,O
+patients,O
+with,O
+homocystinuria,O
+.,O
+ , 
+The,O
+first,O
+mutation,O
+is,O
+a,O
+G,B-SNP
+-,I-SNP
+to,I-SNP
+-,I-SNP
+A,I-SNP
+transition,I-SNP
+at,I-SNP
+base,I-SNP
+374,I-SNP
+in,I-SNP
+exon,I-SNP
+3,I-SNP
+,,I-SNP
+causing,O
+an,O
+arginine,B-SNP
+-,I-SNP
+to,I-SNP
+-,I-SNP
+glutamic,I-SNP
+acid,I-SNP
+substitution,I-SNP
+at,I-SNP
+position,I-SNP
+125,I-SNP
+of,O
+the,O
+protein,O
+(,B-SNP
+R125Q,I-SNP
+),I-SNP
+.,O
+ , 
+This,O
+mutation,O
+has,O
+been,O
+found,O
+in,O
+homozygosity,O
+in,O
+a,O
+patient,O
+partially,O
+responsive,O
+to,O
+pyridoxine,O
+treatment,O
+.,O
+ , 
+The,O
+second,O
+mutation,O
+is,O
+a,O
+C,B-SNP
+-,I-SNP
+to,I-SNP
+-,I-SNP
+T,I-SNP
+transition,I-SNP
+at,I-SNP
+base,I-SNP
+770,I-SNP
+in,I-SNP
+exon,I-SNP
+7,I-SNP
+,,I-SNP
+causing,O
+a,O
+threonine,B-SNP
+-,I-SNP
+to,I-SNP
+-,I-SNP
+methionine,I-SNP
+substitution,I-SNP
+at,I-SNP
+amino,I-SNP
+acid,I-SNP
+257,I-SNP
+of,O
+the,O
+protein,O
+(,B-SNP
+T257,I-SNP
+M,I-SNP
+),I-SNP
+.,O
+ , 
+This,O
+mutation,O
+has,O
+been,O
+observed,O
+in,O
+homozygosity,O
+in,O
+a,O
+patient,O
+nonresponsive,O
+to,O
+the,O
+cofactor,O
+treatment,O
+.,O
+ , 
+The,O
+third,O
+mutation,O
+,,O
+found,O
+in,O
+heterozygosity,O
+in,O
+a,O
+patient,O
+responsive,O
+to,O
+pyridoxine,O
+treatment,O
+,,O
+is,O
+an,O
+insertion,O
+of,O
+68,O
+bp,O
+in,O
+exon,O
+8,O
+at,O
+base,O
+844,O
+,,O
+which,O
+introduces,O
+a,O
+premature,O
+termination,O
+codon,O
+.,O
+ , 
+The,O
+fourth,O
+mutation,O
+is,O
+C,O
+-,O
+to,O
+-,O
+T,O
+transition,O
+in,O
+exon,O
+2,O
+at,O
+base,O
+262,O
+,,O
+causing,O
+a,O
+proline,B-SNP
+-,I-SNP
+to,I-SNP
+-,I-SNP
+serine,I-SNP
+substitution,I-SNP
+at,I-SNP
+position,I-SNP
+88,I-SNP
+of,O
+the,O
+protein,O
+(,B-SNP
+P88S,I-SNP
+),I-SNP
+.,O
+ , 
+This,O
+mutation,O
+is,O
+carried,O
+on,O
+a,O
+single,O
+allele,O
+in,O
+three,O
+affected,O
+sisters,O
+responsive,O
+to,O
+the,O
+cofactor,O
+treatment,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+six,O
+previously,O
+reported,O
+mutations,O
+(,B-SNP
+A114V,I-SNP
+,,I-SNP
+E131D,B-SNP
+,,I-SNP
+P145L,B-SNP
+,,I-SNP
+I278,B-SNP
+T,I-SNP
+,,I-SNP
+G307S,B-SNP
+,,I-SNP
+and,O
+A1224,B-SNP
+-,I-SNP
+2C,I-SNP
+),I-SNP
+have,O
+been,O
+tested,O
+in,O
+14,O
+independent,O
+Italian,O
+families,O
+.,O
+ , 
+Mutations,O
+A114V,B-SNP
+and,O
+I278,B-SNP
+T,I-SNP
+are,O
+carried,O
+by,O
+three,O
+and,O
+by,O
+seven,O
+independent,O
+alleles,O
+,,O
+respectively,O
+.,O
+ , 
+The,O
+other,O
+four,O
+mutations,O
+--,O
+including,O
+G307S,B-SNP
+and,O
+A1224,B-SNP
+-,I-SNP
+2C,I-SNP
+,,I-SNP
+common,O
+among,O
+northern,O
+European,O
+patients,O
+--,O
+have,O
+not,O
+been,O
+detected,O
+.,O
+ , 
+#16329098
+HEY2,B-Gene
+mutations,O
+in,O
+malformed,O
+hearts,O
+.,O
+ , 
+The,O
+basic,O
+helix,O
+-,O
+loop,O
+-,O
+helix,O
+(,O
+bHLH,O
+),O
+transcription,O
+factor,O
+Hey2,B-Gene
+(,B-Gene
+gridlock,I-Gene
+),I-Gene
+is,O
+an,O
+important,O
+determinant,O
+of,O
+mammalian,O
+heart,O
+development,O
+,,O
+but,O
+its,O
+role,O
+in,O
+human,O
+ventricular,O
+septal,O
+defects,O
+is,O
+unknown,O
+.,O
+ , 
+Hey2,B-Gene
+functions,O
+as,O
+a,O
+repressor,O
+through,O
+the,O
+bHLH,O
+domain,O
+.,O
+ , 
+By,O
+direct,O
+sequencing,O
+,,O
+we,O
+analyzed,O
+the,O
+sequences,O
+encoding,O
+the,O
+bHLH,O
+domain,O
+of,O
+the,O
+human,O
+HEY2,B-Gene
+in,O
+52,O
+explanted,O
+hearts,O
+of,O
+unrelated,O
+patients,O
+with,O
+complex,O
+cardiac,O
+malformations,O
+,,O
+notably,O
+ventricular,O
+(,O
+VSD,O
+),O
+and,O
+atrioventricular,O
+septal,O
+defects,O
+(,O
+AVSD,O
+),O
+.,O
+ , 
+We,O
+found,O
+three,O
+nonsynonymous,O
+mutations,O
+,,O
+namely,O
+,,O
+c.286A,B-SNP
+>,I-SNP
+G,I-SNP
+(,B-SNP
+p.,I-SNP
+Thr96Ala,I-SNP
+),I-SNP
+,,O
+c.293A,B-SNP
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+C,I-SNP
+(,B-SNP
+p.,I-SNP
+Asp98Ala,I-SNP
+),I-SNP
+,,O
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+c.299T,B-SNP
+>,I-SNP
+C,I-SNP
+(,B-SNP
+p.,I-SNP
+Leu100Ser,I-SNP
+),I-SNP
+affecting,O
+the,O
+second,O
+helix,O
+of,O
+HEY2,B-Gene
+in,O
+the,O
+diseased,O
+cardiac,O
+tissues,O
+of,O
+two,O
+patients,O
+with,O
+AVSD,O
+.,O
+ , 
+This,O
+result,O
+suggests,O
+a,O
+possible,O
+role,O
+of,O
+HEY2,B-Gene
+in,O
+the,O
+regulation,O
+of,O
+ventricular,O
+septation,O
+in,O
+humans,O
+.,O
+ , 
+Since,O
+the,O
+two,O
+AVSD,O
+patients,O
+carried,O
+also,O
+binding,O
+domain,O
+mutations,O
+in,O
+other,O
+cardiac,O
+-,O
+specific,O
+transcription,O
+factors,O
+,,O
+e.g.,O
+NKX2,B-Gene
+-,I-Gene
+5,I-Gene
+,,I-Gene
+TBX5,B-Gene
+,,I-Gene
+and,O
+GATA4,B-Gene
+,,I-Gene
+breakdown,O
+of,O
+combinatorial,O
+interactions,O
+of,O
+transcription,O
+factors,O
+may,O
+have,O
+contributed,O
+to,O
+the,O
+complexity,O
+of,O
+their,O
+cardiac,O
+malformations,O
+.,O
+ , 
+#19842213
+Shadow,O
+autozygosity,O
+mapping,O
+by,O
+linkage,O
+exclusion,O
+(,O
+SAMPLE,O
+):,O
+a,O
+simple,O
+strategy,O
+to,O
+identify,O
+the,O
+genetic,O
+basis,O
+of,O
+lethal,O
+autosomal,O
+recessive,O
+disorders,O
+.,O
+ , 
+Autozygosity,O
+mapping,O
+has,O
+been,O
+invaluable,O
+for,O
+determining,O
+the,O
+genetic,O
+basis,O
+of,O
+lethal,O
+autosomal,O
+recessive,O
+disorders,O
+,,O
+but,O
+this,O
+approach,O
+remains,O
+challenging,O
+because,O
+DNA,O
+from,O
+affected,O
+individuals,O
+may,O
+often,O
+be,O
+unavailable,O
+or,O
+of,O
+insufficient,O
+quality,O
+for,O
+extensive,O
+molecular,O
+genetic,O
+studies,O
+.,O
+ , 
+To,O
+circumvent,O
+these,O
+difficulties,O
+,,O
+we,O
+developed,O
+a,O
+computer,O
+program,O
+called,O
+",O
+SAMPLE,O
+",O
+(,O
+for,O
+shadow,O
+autozygosity,O
+mapping,O
+by,O
+linkage,O
+exclusion,O
+),O
+to,O
+enhance,O
+autozygosity,O
+mapping,O
+through,O
+the,O
+empirical,O
+analysis,O
+of,O
+haplotypes,O
+of,O
+unaffected,O
+individuals,O
+in,O
+consanguineous,O
+families,O
+.,O
+ , 
+Single,O
+nucleotide,O
+polymorphism,O
+(,O
+SNP,O
+),O
+genotyping,O
+of,O
+unaffected,O
+individuals,O
+in,O
+complex,O
+consanguineous,O
+pedigrees,O
+is,O
+used,O
+to,O
+infer,O
+limited,O
+chromosomal,O
+regions,O
+compatible,O
+with,O
+linkage,O
+to,O
+a,O
+potential,O
+disease,O
+locus,O
+,,O
+and,O
+to,O
+allow,O
+the,O
+immediate,O
+prioritization,O
+of,O
+potential,O
+regions,O
+of,O
+interest,O
+.,O
+ , 
+Further,O
+limited,O
+genotyping,O
+then,O
+enables,O
+the,O
+rapid,O
+confirmation,O
+and,O
+fine,O
+mapping,O
+of,O
+a,O
+disease,O
+locus,O
+.,O
+ , 
+We,O
+demonstrate,O
+the,O
+utility,O
+of,O
+this,O
+strategy,O
+by,O
+using,O
+genotyping,O
+data,O
+from,O
+only,O
+parents,O
+and,O
+unaffected,O
+siblings,O
+,,O
+in,O
+three,O
+consanguineous,O
+families,O
+affected,O
+with,O
+Meckel,O
+-,O
+Gruber,O
+syndrome,O
+,,O
+to,O
+correctly,O
+infer,O
+the,O
+location,O
+of,O
+the,O
+MKS3,B-Gene
+/,B-Gene
+TMEM67,I-Gene
+locus,O
+on,O
+chromosome,O
+8q22.1,O
+.,O
+ , 
+This,O
+strategy,O
+is,O
+practicable,O
+only,O
+with,O
+the,O
+recent,O
+advances,O
+in,O
+whole,O
+genome,O
+genotyping,O
+by,O
+high,O
+-,O
+density,O
+SNP,O
+microarrays,O
+,,O
+and,O
+could,O
+not,O
+be,O
+easily,O
+implemented,O
+in,O
+approaches,O
+that,O
+rely,O
+on,O
+microsatellite,O
+markers,O
+.,O
+ , 
+SAMPLE,O
+is,O
+available,O
+at,O
+http://dna.leeds.ac.uk/sample/.,O
+ , 
+#16909392
+Navajo,O
+neurohepatopathy,O
+is,O
+caused,O
+by,O
+a,O
+mutation,O
+in,O
+the,O
+MPV17,B-Gene
+gene,O
+.,O
+ , 
+Navajo,O
+neurohepatopathy,O
+(,O
+NNH,O
+),O
+is,O
+an,O
+autosomal,O
+recessive,O
+disease,O
+that,O
+is,O
+prevalent,O
+among,O
+Navajo,O
+children,O
+in,O
+the,O
+southwestern,O
+United,O
+States,O
+.,O
+ , 
+The,O
+major,O
+clinical,O
+features,O
+are,O
+hepatopathy,O
+,,O
+peripheral,O
+neuropathy,O
+,,O
+corneal,O
+anesthesia,O
+and,O
+scarring,O
+,,O
+acral,O
+mutilation,O
+,,O
+cerebral,O
+leukoencephalopathy,O
+,,O
+failure,O
+to,O
+thrive,O
+,,O
+and,O
+recurrent,O
+metabolic,O
+acidosis,O
+with,O
+intercurrent,O
+infections,O
+.,O
+ , 
+Infantile,O
+,,O
+childhood,O
+,,O
+and,O
+classic,O
+forms,O
+of,O
+NNH,O
+have,O
+been,O
+described,O
+.,O
+ , 
+Mitochondrial,O
+DNA,O
+(,O
+mtDNA,O
+),O
+depletion,O
+was,O
+detected,O
+in,O
+the,O
+livers,O
+of,O
+two,O
+patients,O
+,,O
+suggesting,O
+a,O
+primary,O
+defect,O
+in,O
+mtDNA,O
+maintenance,O
+.,O
+ , 
+Homozygosity,O
+mapping,O
+of,O
+two,O
+families,O
+with,O
+NNH,O
+suggested,O
+linkage,O
+to,O
+chromosome,O
+2p24,O
+.,O
+ , 
+This,O
+locus,O
+includes,O
+the,O
+MPV17,B-Gene
+gene,O
+,,O
+which,O
+,,O
+when,O
+mutated,O
+,,O
+causes,O
+a,O
+hepatocerebral,O
+form,O
+of,O
+mtDNA,O
+depletion,O
+.,O
+ , 
+Sequencing,O
+of,O
+the,O
+MPV17,B-Gene
+gene,O
+in,O
+six,O
+patients,O
+with,O
+NNH,O
+from,O
+five,O
+families,O
+revealed,O
+the,O
+homozygous,O
+R50Q,B-SNP
+mutation,O
+described,O
+elsewhere,O
+.,O
+ , 
+Identification,O
+of,O
+a,O
+single,O
+missense,O
+mutation,O
+in,O
+patients,O
+with,O
+NNH,O
+confirms,O
+that,O
+the,O
+disease,O
+is,O
+probably,O
+due,O
+to,O
+a,O
+founder,O
+effect,O
+and,O
+extends,O
+the,O
+phenotypic,O
+spectrum,O
+associated,O
+with,O
+MPV17,B-Gene
+mutations,O
+.,O
+ , 
+#8198126
+Notes,O
+on,O
+individual,O
+sequence,O
+variation,O
+in,O
+humans,O
+:,O
+immunoglobulin,O
+kappa,O
+light,O
+chain,O
+.,O
+ , 
+Little,O
+is,O
+known,O
+concerning,O
+the,O
+magnitude,O
+of,O
+variability,O
+in,O
+the,O
+nucleic,O
+acid,O
+sequence,O
+of,O
+DNA,O
+at,O
+the,O
+individual,O
+level,O
+.,O
+ , 
+We,O
+have,O
+collected,O
+a,O
+large,O
+set,O
+of,O
+sequence,O
+data,O
+from,O
+the,O
+human,O
+immunoglobulin,O
+kappa,O
+light,O
+-,O
+chain,O
+-,O
+locus,O
+constant,O
+region,O
+(,O
+10,444,O
+bp,O
+),O
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+subgroup,O
+IV,O
+variable,O
+region,O
+(,O
+18,580,O
+bp,O
+),O
+.,O
+ , 
+For,O
+the,O
+constant,O
+region,O
+,,O
+absolute,O
+conservation,O
+of,O
+sequence,O
+was,O
+observed,O
+,,O
+even,O
+in,O
+intron,O
+and,O
+coding,O
+-,O
+region,O
+silent,O
+sites,O
+,,O
+with,O
+the,O
+exception,O
+of,O
+one,O
+previously,O
+defined,O
+polymorphic,O
+site,O
+.,O
+ , 
+For,O
+the,O
+variable,O
+region,O
+,,O
+12,O
+heterozygous,O
+positions,O
+were,O
+identified,O
+,,O
+giving,O
+a,O
+heterozygosity,O
+of,O
+6,O
+x,O
+10(-4,O
+),O
+per,O
+nucleotide,O
+site,O
+.,O
+ , 
+The,O
+amount,O
+of,O
+nucleic,O
+acid,O
+sequence,O
+variation,O
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+significantly,O
+(,O
+chi,O
+2,O
+=,O
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+),O
+between,O
+these,O
+two,O
+regions,O
+,,O
+and,O
+the,O
+observed,O
+variation,O
+is,O
+two,O
+orders,O
+of,O
+magnitude,O
+lower,O
+than,O
+that,O
+reported,O
+for,O
+two,O
+Drosophila,O
+melanogaster,O
+loci,O
+.,O
+ , 
+These,O
+data,O
+suggest,O
+that,O
+,,O
+for,O
+at,O
+least,O
+some,O
+regions,O
+of,O
+the,O
+human,O
+genome,O
+,,O
+nucleic,O
+acid,O
+sequence,O
+may,O
+be,O
+less,O
+variable,O
+than,O
+previously,O
+estimated,O
+.,O
+ , 
+#21412948
+SNP,O
+uniqueness,O
+problem,O
+:,O
+a,O
+proof,O
+-,O
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+-,O
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+in,O
+HapMap,O
+SNPs,O
+.,O
+ , 
+SNP,O
+-,O
+based,O
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+strongly,O
+affects,O
+our,O
+biomedical,O
+and,O
+clinically,O
+associated,O
+knowledge,O
+.,O
+ , 
+Nonunique,O
+and,O
+false,O
+-,O
+positive,O
+SNP,O
+existence,O
+in,O
+commonly,O
+used,O
+datasets,O
+may,O
+thus,O
+lead,O
+to,O
+biased,O
+,,O
+inaccurate,O
+clinically,O
+associated,O
+conclusions,O
+.,O
+ , 
+We,O
+designed,O
+a,O
+computational,O
+study,O
+to,O
+reveal,O
+the,O
+degree,O
+of,O
+nonunique,O
+/,O
+false,O
+-,O
+positive,O
+SNPs,O
+in,O
+the,O
+HapMap,O
+dataset,O
+.,O
+ , 
+Two,O
+sets,O
+of,O
+SNP,O
+flanking,O
+sequences,O
+were,O
+used,O
+as,O
+queries,O
+for,O
+BLAT,O
+analysis,O
+against,O
+the,O
+human,O
+genome,O
+.,O
+ , 
+4.2,O
+%,O
+and,O
+11.9,O
+%,O
+of,O
+HapMap,O
+SNPs,O
+align,O
+to,O
+the,O
+genome,O
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+(,O
+long,O
+and,O
+short,O
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+),O
+.,O
+ , 
+Furthermore,O
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+an,O
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+of,O
+7.9,O
+%,O
+nonunique,O
+SNPs,O
+are,O
+included,O
+in,O
+common,O
+commercial,O
+genotyping,O
+arrays,O
+(,O
+according,O
+to,O
+our,O
+designed,O
+probes,O
+),O
+.,O
+ , 
+Nonunique,O
+SNPs,O
+identified,O
+in,O
+this,O
+study,O
+are,O
+represented,O
+to,O
+various,O
+degrees,O
+in,O
+clinically,O
+associated,O
+databases,O
+,,O
+stressing,O
+the,O
+consequence,O
+of,O
+inaccurate,O
+SNP,O
+annotation,O
+and,O
+hence,O
+SNP,O
+utilization,O
+.,O
+ , 
+Unfortunately,O
+,,O
+our,O
+results,O
+question,O
+some,O
+disease,O
+-,O
+related,O
+genotyping,O
+analyses,O
+,,O
+raising,O
+a,O
+worrisome,O
+concern,O
+on,O
+their,O
+validity,O
+.,O
+ , 
+#10738004
+A,O
+novel,O
+mutation,O
+(,B-SNP
+Q239R,I-SNP
+),I-SNP
+identified,O
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+a,O
+Taiwan,O
+Chinese,O
+patient,O
+with,O
+type,O
+VI,O
+mucopolysaccharidosis,O
+(,O
+Maroteaux,O
+-,O
+Lamy,O
+syndrome,O
+),O
+.,O
+ , 
+#20506408
+Functionality,O
+of,O
+sequence,O
+variants,O
+in,O
+the,O
+genes,O
+coding,O
+for,O
+the,O
+low,O
+-,O
+density,O
+lipoprotein,O
+receptor,O
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+apolipoprotein,O
+B,O
+in,O
+individuals,O
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+inherited,O
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+.,O
+ , 
+Patients,O
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+familial,O
+hypercholesterolemia,O
+(,O
+FH,O
+),O
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+elevated,O
+LDL,O
+-,O
+C,O
+levels,O
+,,O
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+above,O
+the,O
+90th,O
+percentile,O
+(,O
+P90,O
+),O
+for,O
+age,O
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+gender,O
+.,O
+ , 
+However,O
+,,O
+large,O
+-,O
+scale,O
+genetic,O
+cascade,O
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+15,O
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+LDL,B-Gene
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+LDLR,I-Gene
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+or,O
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+LDL,O
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+P75,O
+.,O
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+Nonpathogenicity,O
+of,O
+sequence,O
+changes,O
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+explain,O
+this,O
+phenomenon,O
+.,O
+ , 
+To,O
+assess,O
+pathogenicity,O
+of,O
+a,O
+mutation,O
+we,O
+proposed,O
+three,O
+criteria,O
+:,O
+(,O
+1,O
+),O
+mean,O
+LDL,O
+-,O
+C,O
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+untreated,O
+mutation,O
+carriers,O
+;,O
+(,O
+2,O
+),O
+higher,O
+mean,O
+LDL,O
+-,O
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+untreated,O
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+;,O
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+in,O
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+at,O
+screening,O
+.,O
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+We,O
+considered,O
+a,O
+mutation,O
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+when,O
+none,O
+of,O
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+three,O
+criteria,O
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+met,O
+.,O
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+We,O
+applied,O
+these,O
+criteria,O
+to,O
+mutations,O
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+determined,O
+in,O
+more,O
+than,O
+50,O
+untreated,O
+adults,O
+.,O
+ , 
+Segregation,O
+analysis,O
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+to,O
+confirm,O
+nonpathogenicity,O
+.,O
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+Forty,O
+-,O
+six,O
+mutations,O
+had,O
+been,O
+tested,O
+in,O
+more,O
+than,O
+50,O
+untreated,O
+subjects,O
+,,O
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+three,O
+were,O
+nonpathogenic,O
+according,O
+to,O
+our,O
+criteria,O
+:,O
+ , 
+one,O
+in,O
+LDLR,B-Gene
+(,B-SNP
+c.108C4A,I-SNP
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+exon,O
+2,O
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+APOB,B-Gene
+(,B-SNP
+c.13154T4C,I-SNP
+and,O
+c.13181T4C,B-SNP
+,,I-SNP
+both,O
+in,O
+exon,O
+29,O
+),O
+.,O
+ , 
+Segregation,O
+analysis,O
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+indicated,O
+nonpathogenicity,O
+.,O
+ , 
+According,O
+to,O
+our,O
+criteria,O
+,,O
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+sequence,O
+variants,O
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+.,O
+ , 
+The,O
+criteria,O
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+help,O
+to,O
+identify,O
+nonpathogenic,O
+sequence,O
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+genetic,O
+cascade,O
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+programs,O
+.,O
+ , 
+#16252239
+Severely,O
+incapacitating,O
+mutations,O
+in,O
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+extreme,O
+short,O
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+RNA,B-Gene
+-,I-Gene
+processing,I-Gene
+endoribonuclease,I-Gene
+RMRP,B-Gene
+as,O
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+essential,O
+cell,O
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+The,O
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+of,O
+an,O
+individual,O
+is,O
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+by,O
+the,O
+regulation,O
+of,O
+cell,O
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+division,O
+,,O
+both,O
+of,O
+which,O
+also,O
+contribute,O
+to,O
+a,O
+wide,O
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+,,O
+diabetes,O
+,,O
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+.,O
+ , 
+To,O
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+a,O
+major,O
+regulator,O
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+,,O
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+performed,O
+positional,O
+cloning,O
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+,,O
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+Homozygosity,O
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+RMRP,B-Gene
+gene,O
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+susceptibility,O
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+cancer,O
+,,O
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+,,O
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+.,O
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+We,O
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+that,O
+different,O
+RMRP,B-Gene
+gene,O
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+decreased,O
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+cycle,O
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+Clinical,O
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+a,O
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+between,O
+the,O
+level,O
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+type,O
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+functional,O
+impairment,O
+in,O
+vitro,O
+and,O
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+severity,O
+of,O
+short,O
+stature,O
+or,O
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+cancer,O
+.,O
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+Whereas,O
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+cartilage,O
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+founder,O
+mutation,O
+affects,O
+both,O
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+,,O
+anauxetic,O
+dysplasia,O
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+B,O
+-,O
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+RNA,O
+(,O
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+Anauxetic,O
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+allowing,O
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+mRNA,O
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+,,O
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+separate,O
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+of,O
+RNase,B-Gene
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+ , 
+#1357966
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+RFLPs,O
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+insulin,O
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+intervening,O
+Alu,O
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+sequences,O
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+ , 
+Multiple,O
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+These,O
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+included,O
+recombination,O
+events,O
+between,O
+Alu,O
+repeat,O
+units,O
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+tyrosine,O
+kinase,O
+-,O
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+-,O
+chain,O
+region,O
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+To,O
+evaluate,O
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+gene,O
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+I,O
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+228,O
+independent,O
+haplotypes,O
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+PstI,B-Gene
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+and,O
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+RFLP,O
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+BglII,B-Gene
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+These,O
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+Observed,O
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+RFLP,O
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+high,O
+levels,O
+of,O
+linkage,O
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+among,O
+RFLP,O
+in,O
+the,O
+beta,O
+-,O
+chain,O
+region,O
+of,O
+the,O
+insulin,O
+receptor,O
+,,O
+but,O
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+between,O
+alpha,O
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+of,O
+the,O
+beta,O
+-,O
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+Disequilibrium,O
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+among,O
+beta,O
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+,,O
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+separation,O
+by,O
+one,O
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+more,O
+Alu,O
+repeat,O
+sequences,O
+.,O
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+The,O
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+strong,O
+linkage,O
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+in,O
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+INSR,B-Gene
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+the,O
+presence,O
+of,O
+both,O
+Alu,O
+and,O
+microsatellite,O
+repeats,O
+suggested,O
+that,O
+these,O
+regions,O
+do,O
+not,O
+have,O
+a,O
+major,O
+impact,O
+on,O
+recombinations,O
+at,O
+this,O
+locus,O
+.,O
+ , 
+#9463309
+The,O
+haptoglobin,O
+-,O
+gene,O
+deletion,O
+responsible,O
+for,O
+anhaptoglobinemia,O
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+We,O
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+found,O
+an,O
+allelic,O
+deletion,O
+of,O
+the,O
+haptoglobin,B-Gene
+(,B-Gene
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+),I-Gene
+gene,O
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+an,O
+individual,O
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+anhaptoglobinemia,O
+.,O
+ , 
+The,O
+Hp,O
+gene,O
+cluster,O
+consists,O
+of,O
+coding,O
+regions,O
+of,O
+the,O
+alpha,O
+chain,O
+and,O
+beta,O
+chain,O
+of,O
+the,O
+haptoglobin,B-Gene
+gene,O
+(,B-Gene
+Hp,I-Gene
+),I-Gene
+and,O
+of,O
+the,O
+alpha,O
+chain,O
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+beta,O
+chain,O
+of,O
+the,O
+haptoglobin,B-Gene
+-,I-Gene
+related,I-Gene
+gene,I-Gene
+(,B-Gene
+Hpr,I-Gene
+),I-Gene
+,,I-Gene
+in,O
+tandem,O
+from,O
+the,O
+5,O
+',O
+side,O
+.,O
+ , 
+Southern,O
+blot,O
+and,O
+PCR,O
+analyses,O
+have,O
+indicated,O
+that,O
+the,O
+individual,O
+with,O
+anhaptoglobinemia,O
+was,O
+homozygous,O
+for,O
+the,O
+gene,O
+deletion,O
+and,O
+that,O
+the,O
+gene,O
+deletion,O
+was,O
+included,O
+at,O
+least,O
+from,O
+the,O
+promoter,O
+region,O
+of,O
+Hp,O
+to,O
+Hpr,B-Gene
+alpha,I-Gene
+but,O
+not,O
+to,O
+Hpr,B-Gene
+beta,I-Gene
+(,O
+Hpdel,O
+),O
+.,O
+ , 
+In,O
+addition,O
+,,O
+we,O
+found,O
+seven,O
+individuals,O
+with,O
+hypohaptoglobinemia,O
+in,O
+three,O
+families,O
+,,O
+and,O
+the,O
+genotypes,O
+of,O
+six,O
+of,O
+the,O
+seven,O
+individuals,O
+were,O
+found,O
+to,O
+be,O
+Hp2,O
+/,O
+Hpdel,O
+.,O
+ , 
+The,O
+phenotypes,O
+and,O
+genotypes,O
+in,O
+one,O
+of,O
+these,O
+three,O
+families,O
+showed,O
+the,O
+father,O
+to,O
+be,O
+hypohaptoglobinemic,O
+(,B-Gene
+Hp2,I-Gene
+),I-Gene
+and,O
+Hp2,O
+/,O
+Hpdel,O
+,,O
+the,O
+mother,O
+to,O
+be,O
+Hp2,B-Gene
+-,I-Gene
+1,I-Gene
+and,O
+Hp1,O
+/,O
+Hp2,O
+,,O
+one,O
+of,O
+the,O
+two,O
+children,O
+to,O
+be,O
+hypohaptoglobinemic,O
+(,B-Gene
+Hp2,I-Gene
+),I-Gene
+and,O
+Hp2,O
+/,O
+Hpdel,O
+,,O
+and,O
+the,O
+other,O
+child,O
+to,O
+be,O
+Hp1,B-Gene
+and,O
+Hp1,O
+/,O
+Hpdel,O
+,,O
+showing,O
+an,O
+anomalous,O
+inheritance,O
+of,O
+Hp,O
+phenotypes,O
+in,O
+the,O
+child,O
+with,O
+Hp1,B-Gene
+.,I-Gene
+ , 
+The,O
+Hp2,O
+/,O
+Hpdel,O
+individuals,O
+had,O
+an,O
+extremely,O
+low,O
+level,O
+of,O
+Hp,O
+(,O
+mean+/-SD,O
+=,O
+0.049+/-0,O
+.,O
+ , 
+043,O
+mg,O
+/,O
+ml,O
+;,O
+n=6,O
+),O
+,,O
+compared,O
+with,O
+the,O
+level,O
+(,O
+1.64+/-1.07,O
+mg,O
+/,O
+ml,O
+),O
+obtained,O
+from,O
+52,O
+healthy,O
+volunteers,O
+having,O
+phenotype,O
+Hp2,B-Gene
+,,I-Gene
+whereas,O
+the,O
+serum,O
+ , 
+Hp,O
+level,O
+of,O
+an,O
+individual,O
+with,O
+Hp1,O
+/,O
+Hpdel,O
+was,O
+0.50,O
+mg,O
+/,O
+ml,O
+,,O
+which,O
+was,O
+approximately,O
+half,O
+the,O
+level,O
+of,O
+Hp,O
+in,O
+control,O
+sera,O
+from,O
+the,O
+Hp1,B-Gene
+phenotype,O
+(,O
+1.26+/-0.33,O
+mg,O
+/,O
+ml,O
+;,O
+n=9,O
+),O
+,,O
+showing,O
+a,O
+gene,O
+-,O
+dosage,O
+effect,O
+.,O
+ , 
+The,O
+other,O
+allele,O
+(,B-Gene
+Hp2,I-Gene
+),I-Gene
+of,O
+individuals,O
+with,O
+Hp2,O
+/,O
+Hpdel,O
+was,O
+found,O
+to,O
+have,O
+,,O
+in,O
+all,O
+exons,O
+,,O
+no,O
+mutation,O
+,,O
+by,O
+DNA,O
+sequencing,O
+.,O
+ , 
+On,O
+the,O
+basis,O
+of,O
+the,O
+present,O
+study,O
+,,O
+the,O
+mechanism,O
+of,O
+anhaptoglobinemia,O
+and,O
+the,O
+mechanism,O
+of,O
+anomalous,O
+inheritance,O
+of,O
+Hp,O
+phenotypes,O
+were,O
+well,O
+explained,O
+.,O
+ , 
+However,O
+,,O
+the,O
+mechanism,O
+of,O
+hypohaptoglobinemia,O
+remains,O
+unknown,O
+.,O
+ , 
+#15570555
+Systematic,O
+evaluation,O
+of,O
+genetic,O
+variation,O
+at,O
+the,O
+androgen,O
+receptor,O
+locus,O
+and,O
+risk,O
+of,O
+prostate,O
+cancer,O
+in,O
+a,O
+multiethnic,O
+cohort,O
+study,O
+.,O
+ , 
+Repeat,O
+length,O
+of,O
+the,O
+CAG,O
+microsatellite,O
+polymorphism,O
+in,O
+exon,O
+1,O
+of,O
+the,O
+androgen,B-Gene
+receptor,I-Gene
+(,B-Gene
+AR,I-Gene
+),I-Gene
+gene,O
+has,O
+been,O
+associated,O
+with,O
+risk,O
+of,O
+prostate,O
+cancer,O
+in,O
+humans,O
+.,O
+ , 
+This,O
+association,O
+has,O
+been,O
+the,O
+focus,O
+of,O
+>,O
+20,O
+primary,O
+epidemiological,O
+publications,O
+and,O
+multiple,O
+review,O
+articles,O
+,,O
+but,O
+a,O
+consistent,O
+and,O
+reproducible,O
+association,O
+has,O
+yet,O
+to,O
+be,O
+confirmed,O
+.,O
+ , 
+We,O
+systematically,O
+addressed,O
+possible,O
+causes,O
+of,O
+false,O
+-,O
+negative,O
+and,O
+false,O
+-,O
+positive,O
+association,O
+in,O
+>,O
+4,000,O
+individuals,O
+from,O
+a,O
+multiethnic,O
+,,O
+prospective,O
+cohort,O
+study,O
+of,O
+prostate,O
+cancer,O
+,,O
+comprehensively,O
+studying,O
+genetic,O
+variation,O
+by,O
+microsatellite,O
+genotyping,O
+,,O
+direct,O
+resequencing,O
+of,O
+exons,O
+in,O
+advanced,O
+cancer,O
+cases,O
+,,O
+and,O
+haplotype,O
+analysis,O
+across,O
+the,O
+180,O
+-,O
+kb,O
+AR,B-Gene
+genomic,O
+locus,O
+.,O
+ , 
+These,O
+data,O
+failed,O
+to,O
+confirm,O
+that,O
+common,O
+genetic,O
+variation,O
+in,O
+the,O
+AR,B-Gene
+gene,O
+locus,O
+influences,O
+risk,O
+of,O
+prostate,O
+cancer,O
+.,O
+ , 
+A,O
+systematic,O
+approach,O
+that,O
+assesses,O
+both,O
+coding,O
+and,O
+noncoding,O
+genetic,O
+variation,O
+in,O
+large,O
+and,O
+diverse,O
+patient,O
+samples,O
+can,O
+help,O
+clarify,O
+hypotheses,O
+about,O
+association,O
+between,O
+genetic,O
+variants,O
+and,O
+disease,O
+.,O
+ , 
+#11992269
+The,O
+power,O
+of,O
+multivariate,O
+quantitative,O
+-,O
+trait,O
+loci,O
+linkage,O
+analysis,O
+is,O
+influenced,O
+by,O
+the,O
+correlation,O
+between,O
+variables,O
+.,O
+ , 
+#8100466
+Detection,O
+of,O
+polymorphisms,O
+using,O
+thermal,O
+cycling,O
+with,O
+a,O
+single,O
+oligonucleotide,O
+on,O
+a,O
+DNA,O
+sequencing,O
+gel,O
+.,O
+ , 
+A,O
+method,O
+is,O
+described,O
+for,O
+the,O
+detection,O
+of,O
+restriction,O
+fragment,O
+length,O
+polymorphisms,O
+(,O
+RFLPs,O
+),O
+in,O
+single,O
+copy,O
+genes,O
+in,O
+mammalian,O
+cells,O
+using,O
+one,O
+5'-labelled,O
+oligonucleotide,O
+.,O
+ , 
+This,O
+linear,O
+amplification,O
+(,O
+LA,O
+),O
+method,O
+employs,O
+a,O
+single,O
+oligonucleotide,O
+as,O
+primer,O
+,,O
+which,O
+is,O
+extended,O
+by,O
+Taq,O
+DNA,O
+polymerase,O
+up,O
+to,O
+a,O
+restriction,O
+enzyme,O
+cleavage,O
+site,O
+.,O
+ , 
+The,O
+products,O
+are,O
+arithmetically,O
+amplified,O
+by,O
+thermal,O
+cycling,O
+.,O
+ , 
+The,O
+size,O
+of,O
+the,O
+products,O
+are,O
+determined,O
+by,O
+the,O
+sequence,O
+of,O
+the,O
+oligonucleotide,O
+and,O
+the,O
+position,O
+of,O
+the,O
+restriction,O
+enzyme,O
+cleavage,O
+site,O
+.,O
+ , 
+Hence,O
+,,O
+an,O
+RFLP,O
+can,O
+be,O
+observed,O
+by,O
+measuring,O
+the,O
+size,O
+of,O
+the,O
+products,O
+.,O
+ , 
+Polymorphisms,O
+which,O
+differ,O
+in,O
+size,O
+by,O
+a,O
+small,O
+number,O
+of,O
+base,O
+pairs,O
+,,O
+as,O
+are,O
+found,O
+in,O
+(,O
+CA)n,O
+repeats,O
+,,O
+are,O
+especially,O
+suitable,O
+for,O
+analysis,O
+by,O
+the,O
+LA,O
+procedure,O
+since,O
+the,O
+products,O
+are,O
+run,O
+on,O
+DNA,O
+sequencing,O
+gels,O
+.,O
+ , 
+A,O
+number,O
+of,O
+genes,O
+were,O
+examined,O
+by,O
+the,O
+procedure,O
+and,O
+all,O
+produced,O
+a,O
+satisfactory,O
+signal,O
+including,O
+GC,O
+-,O
+rich,O
+template,O
+.,O
+ , 
+It,O
+is,O
+proposed,O
+that,O
+the,O
+LA,O
+method,O
+would,O
+be,O
+suitable,O
+for,O
+large,O
+-,O
+scale,O
+genetic,O
+linkage,O
+analysis,O
+.,O
+ , 
+The,O
+LA,O
+procedure,O
+has,O
+many,O
+advantages,O
+including,O
+the,O
+ability,O
+to,O
+multiplex,O
+signals,O
+under,O
+the,O
+same,O
+conditions,O
+,,O
+and,O
+lower,O
+cost,O
+since,O
+only,O
+one,O
+primer,O
+is,O
+needed,O
+.,O
+ , 
+#21397065
+Autosomal,O
+-,O
+recessive,O
+posterior,O
+microphthalmos,O
+is,O
+caused,O
+by,O
+mutations,O
+in,O
+PRSS56,B-Gene
+,,I-Gene
+a,O
+gene,O
+encoding,O
+a,O
+trypsin,O
+-,O
+like,O
+serine,O
+protease,O
+.,O
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+Posterior,O
+microphthalmos,O
+(,O
+MCOP,O
+),O
+is,O
+a,O
+rare,O
+isolated,O
+developmental,O
+anomaly,O
+of,O
+the,O
+eye,O
+characterized,O
+by,O
+extreme,O
+hyperopia,O
+due,O
+to,O
+short,O
+axial,O
+length,O
+.,O
+ , 
+The,O
+population,O
+of,O
+the,O
+Faroe,O
+Islands,O
+shows,O
+a,O
+high,O
+prevalence,O
+of,O
+an,O
+autosomal,O
+-,O
+recessive,O
+form,O
+(,O
+arMCOP,O
+),O
+of,O
+the,O
+disease,O
+.,O
+ , 
+Based,O
+on,O
+published,O
+linkage,O
+data,O
+,,O
+we,O
+refined,O
+the,O
+position,O
+of,O
+the,O
+disease,O
+locus,O
+(,B-Gene
+MCOP6,I-Gene
+),I-Gene
+in,O
+an,O
+interval,O
+of,O
+250,O
+kb,O
+in,O
+chromosome,O
+2q37.1,O
+in,O
+two,O
+large,O
+Faroese,O
+families,O
+.,O
+ , 
+We,O
+detected,O
+three,O
+different,O
+mutations,O
+in,O
+PRSS56,B-Gene
+.,I-Gene
+ , 
+Patients,O
+of,O
+the,O
+Faroese,O
+families,O
+were,O
+either,O
+homozygous,O
+for,O
+c.926G,B-SNP
+>,I-SNP
+C,I-SNP
+(,B-SNP
+p.,I-SNP
+Trp309Ser,I-SNP
+),I-SNP
+or,O
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+for,O
+c.926G,B-SNP
+>,I-SNP
+C,I-SNP
+and,O
+c.526C,B-SNP
+>,I-SNP
+G,I-SNP
+(,B-SNP
+p.,I-SNP
+Arg176Gly,I-SNP
+),I-SNP
+,,O
+whereas,O
+a,O
+homozygous,O
+1,O
+ ,O
+bp,O
+duplication,O
+(,B-SNP
+c.1066dupC,I-SNP
+),I-SNP
+was,O
+identified,O
+in,O
+five,O
+patients,O
+with,O
+arMCOP,O
+from,O
+a,O
+consanguineous,O
+Tunisian,O
+family,O
+.,O
+ , 
+In,O
+one,O
+patient,O
+with,O
+MCOP,O
+from,O
+the,O
+Faroe,O
+Islands,O
+and,O
+in,O
+another,O
+one,O
+from,O
+Turkey,O
+,,O
+no,O
+PRSS56,B-Gene
+mutation,O
+was,O
+detected,O
+,,O
+suggesting,O
+nonallelic,O
+heterogeneity,O
+of,O
+the,O
+trait,O
+.,O
+ , 
+Using,O
+RT,O
+-,O
+PCR,O
+,,O
+PRSS56,B-Gene
+transcripts,O
+were,O
+detected,O
+in,O
+samples,O
+derived,O
+from,O
+the,O
+human,O
+adult,O
+retina,O
+,,O
+cornea,O
+,,O
+sclera,O
+,,O
+and,O
+optic,O
+nerve,O
+.,O
+ , 
+The,O
+expression,O
+of,O
+the,O
+mouse,O
+ortholog,O
+could,O
+be,O
+first,O
+detected,O
+in,O
+the,O
+eye,O
+at,O
+E17,O
+and,O
+was,O
+maintained,O
+into,O
+adulthood,O
+.,O
+ , 
+The,O
+predicted,O
+PRSS56,B-Gene
+protein,O
+is,O
+a,O
+603,O
+amino,O
+acid,O
+long,O
+secreted,O
+trypsin,O
+-,O
+like,O
+serine,O
+peptidase,O
+.,O
+ , 
+The,O
+c.1066dupC,B-SNP
+is,O
+likely,O
+to,O
+result,O
+in,O
+a,O
+functional,O
+null,O
+allele,O
+,,O
+whereas,O
+the,O
+two,O
+point,O
+mutations,O
+predict,O
+the,O
+replacement,O
+of,O
+evolutionary,O
+conserved,O
+and,O
+functionally,O
+important,O
+residues,O
+.,O
+ , 
+Molecular,O
+modeling,O
+of,O
+the,O
+p.,B-SNP
+Trp309Ser,I-SNP
+mutant,O
+suggests,O
+that,O
+both,O
+the,O
+affinity,O
+and,O
+reactivity,O
+of,O
+the,O
+enzyme,O
+toward,O
+in,O
+ ,O
+vivo,O
+protein,O
+substrates,O
+are,O
+likely,O
+to,O
+be,O
+substantially,O
+reduced,O
+.,O
+ , 
+#9259194
+Rapid,O
+characterization,O
+of,O
+the,O
+variable,O
+length,O
+polythymidine,O
+tract,O
+in,O
+the,O
+cystic,B-Gene
+fibrosis,I-Gene
+(,B-Gene
+CFTR,I-Gene
+),I-Gene
+gene,O
+:,O
+association,O
+of,O
+the,O
+5,O
+T,O
+allele,O
+with,O
+selected,O
+CFTR,B-Gene
+mutations,O
+and,O
+its,O
+incidence,O
+in,O
+atypical,O
+sinopulmonary,O
+disease,O
+.,O
+ , 
+The,O
+CFTR,B-Gene
+intron,O
+8,O
+variable,O
+length,O
+polythymidine,O
+tract,O
+modulates,O
+the,O
+cystic,O
+fibrosis,O
+(,O
+CF,O
+),O
+phenotype,O
+associated,O
+with,O
+the,O
+mutation,O
+R117H.,B-SNP
+ , 
+To,O
+explore,O
+whether,O
+other,O
+mutations,O
+reside,O
+on,O
+multiple,O
+intron,O
+8,O
+backgrounds,O
+with,O
+discernible,O
+impacts,O
+on,O
+phenotype,O
+,,O
+we,O
+developed,O
+an,O
+allele,O
+-,O
+specific,O
+PCR,O
+assay,O
+to,O
+characterize,O
+this,O
+locus,O
+.,O
+ , 
+Our,O
+approach,O
+types,O
+samples,O
+rapidly,O
+without,O
+the,O
+use,O
+or,O
+radioisotopes,O
+.,O
+ , 
+Polythymidine,O
+alleles,O
+were,O
+identified,O
+for,O
+mutations,O
+either,O
+associated,O
+with,O
+a,O
+wide,O
+range,O
+of,O
+clinical,O
+phenotypes,O
+(,B-SNP
+R117H,I-SNP
+,,I-SNP
+R347P,B-SNP
+,,I-SNP
+G85E,B-SNP
+,,I-SNP
+D1152H,B-SNP
+,,I-SNP
+R334W,B-SNP
+,,I-SNP
+2789,B-SNP
++,I-SNP
+5,I-SNP
+G,I-SNP
+>,I-SNP
+A,I-SNP
+,,I-SNP
+3849,B-SNP
++,I-SNP
+10,I-SNP
+kb,I-SNP
+C,I-SNP
+>,I-SNP
+T,I-SNP
+),I-SNP
+,,O
+and/or,O
+located,O
+at,O
+hypermutable,O
+CpG,O
+loci,O
+(,B-SNP
+R117H,I-SNP
+,,I-SNP
+3845,B-SNP
++,I-SNP
+10,I-SNP
+kb,I-SNP
+C,I-SNP
+>,I-SNP
+T,I-SNP
+,,I-SNP
+R553X,B-SNP
+,,I-SNP
+R334W,B-SNP
+,,I-SNP
+S945L,B-SNP
+and,O
+R75Q,B-SNP
+),I-SNP
+.,O
+ , 
+R117H,B-SNP
+was,O
+detected,O
+in,O
+cis,O
+with,O
+each,O
+of,O
+three,O
+alleles,O
+(,O
+5,O
+T,O
+,,O
+7,O
+T,O
+,,O
+9,O
+T,O
+),O
+at,O
+the,O
+intron,O
+8,O
+locus,O
+.,O
+ , 
+The,O
+novel,O
+R117H-9,B-SNP
+T,O
+association,O
+was,O
+detected,O
+in,O
+a,O
+10,O
+-,O
+month,O
+African,O
+-,O
+American,O
+male,O
+with,O
+borderline,O
+-,O
+to,O
+-,O
+mildly,O
+elevated,O
+sweat,O
+chloride,O
+values,O
+(,O
+approximately,O
+50,O
+-,O
+66,O
+mEq,O
+/,O
+L,O
+),O
+.,O
+ , 
+All,O
+other,O
+mutations,O
+studied,O
+were,O
+associated,O
+with,O
+7,O
+T,O
+except,O
+3849,B-SNP
++,I-SNP
+10,I-SNP
+kb,I-SNP
+C,I-SNP
+>,I-SNP
+T,I-SNP
+,,I-SNP
+which,O
+was,O
+detected,O
+on,O
+both,O
+7,O
+T,O
+and,O
+9,O
+T,O
+backgrounds,O
+,,O
+but,O
+not,O
+5T.,O
+Three,O
+individuals,O
+with,O
+a,O
+delta,B-SNP
+F508/3849,B-SNP
++,I-SNP
+10,I-SNP
+kb,I-SNP
+C,I-SNP
+>,I-SNP
+T,I-SNP
+genotype,O
+were,O
+9T,9,O
+T,O
+and,O
+had,O
+pancreatic,O
+sufficiency,O
+and,O
+normal,O
+sweat,O
+chloride,O
+values,O
+,,O
+whereas,O
+15,O
+others,O
+who,O
+carried,O
+3849,B-SNP
++,I-SNP
+10,I-SNP
+kb,I-SNP
+C,I-SNP
+>,I-SNP
+T,I-SNP
+on,O
+a,O
+7,O
+T,O
+background,O
+had,O
+variable,O
+pancreatic,O
+function,O
+(,O
+sufficient,O
+,,O
+n,O
+=,O
+12,O
+,,O
+insufficient,O
+,,O
+n,O
+=,O
+3,O
+),O
+,,O
+and,O
+variable,O
+sweat,O
+chloride,O
+values,O
+(,O
+normal,O
+,,O
+n,O
+=,O
+12,O
+,,O
+elevated,O
+,,O
+n,O
+=,O
+3,O
+),O
+.,O
+ , 
+Surprisingly,O
+,,O
+when,O
+not,O
+associated,O
+with,O
+known,O
+CFTR,B-Gene
+mutations,O
+,,O
+5,O
+T,O
+was,O
+detected,O
+with,O
+elevated,O
+frequency,O
+among,O
+individuals,O
+with,O
+sinopulmonary,O
+disease,O
+of,O
+ill,O
+-,O
+defined,O
+etiology,O
+,,O
+but,O
+with,O
+some,O
+characteristics,O
+of,O
+variant,O
+CF,O
+.,O
+ , 
+In,O
+summary,O
+,,O
+the,O
+5,O
+T,O
+allele,O
+was,O
+not,O
+found,O
+in,O
+cis,O
+with,O
+CF,O
+-,O
+causing,O
+mutations,O
+besides,O
+R117H,B-SNP
+,,I-SNP
+but,O
+an,O
+elevated,O
+5,O
+T,O
+allele,O
+frequency,O
+in,O
+variant,O
+CF,O
+patients,O
+suggests,O
+5,O
+T,O
+may,O
+be,O
+associated,O
+with,O
+disease,O
+in,O
+some,O
+situations,O
+.,O
+ , 
+#21835305
+Microcephaly,O
+with,O
+simplified,O
+gyration,O
+,,O
+epilepsy,O
+,,O
+and,O
+infantile,O
+diabetes,O
+linked,O
+to,O
+inappropriate,O
+apoptosis,O
+of,O
+neural,O
+progenitors,O
+.,O
+ , 
+We,O
+describe,O
+a,O
+syndrome,O
+of,O
+primary,O
+microcephaly,O
+with,O
+simplified,O
+gyral,O
+pattern,O
+in,O
+combination,O
+with,O
+severe,O
+infantile,O
+epileptic,O
+encephalopathy,O
+and,O
+early,O
+-,O
+onset,O
+permanent,O
+diabetes,O
+in,O
+two,O
+unrelated,O
+consanguineous,O
+families,O
+with,O
+at,O
+least,O
+three,O
+affected,O
+children,O
+.,O
+ , 
+Linkage,O
+analysis,O
+revealed,O
+a,O
+region,O
+on,O
+chromosome,O
+18,O
+with,O
+a,O
+significant,O
+LOD,O
+score,O
+of,O
+4.3,O
+.,O
+ , 
+In,O
+this,O
+area,O
+,,O
+two,O
+homozygous,O
+nonconserved,O
+missense,O
+mutations,O
+in,O
+immediate,B-Gene
+early,I-Gene
+response,I-Gene
+3,I-Gene
+interacting,I-Gene
+protein,I-Gene
+1,I-Gene
+(,B-Gene
+IER3IP1,I-Gene
+),I-Gene
+were,O
+found,O
+in,O
+patients,O
+from,O
+both,O
+families,O
+.,O
+ , 
+IER3IP1,B-Gene
+is,O
+highly,O
+expressed,O
+in,O
+the,O
+fetal,O
+brain,O
+cortex,O
+and,O
+fetal,O
+pancreas,O
+and,O
+is,O
+thought,O
+to,O
+be,O
+involved,O
+in,O
+endoplasmic,O
+reticulum,O
+stress,O
+response,O
+.,O
+ , 
+We,O
+reported,O
+one,O
+of,O
+these,O
+families,O
+previously,O
+in,O
+a,O
+paper,O
+on,O
+Wolcott,O
+-,O
+Rallison,O
+syndrome,O
+(,O
+WRS,O
+),O
+.,O
+ , 
+WRS,O
+is,O
+characterized,O
+by,O
+increased,O
+apoptotic,O
+cell,O
+death,O
+as,O
+part,O
+of,O
+an,O
+uncontrolled,O
+unfolded,O
+protein,O
+response,O
+.,O
+ , 
+Increased,O
+apoptosis,O
+has,O
+been,O
+shown,O
+to,O
+be,O
+a,O
+cause,O
+of,O
+microcephaly,O
+in,O
+ ,O
+animal,O
+models,O
+.,O
+ , 
+An,O
+autopsy,O
+specimen,O
+from,O
+one,O
+patient,O
+showed,O
+increased,O
+apoptosis,O
+in,O
+the,O
+cerebral,O
+cortex,O
+and,O
+pancreas,O
+beta,O
+cells,O
+,,O
+implicating,O
+premature,O
+cell,O
+death,O
+as,O
+the,O
+pathogenetic,O
+mechanism,O
+.,O
+ , 
+Both,O
+patient,O
+fibroblasts,O
+and,O
+control,O
+fibroblasts,O
+treated,O
+with,O
+siRNA,O
+specific,O
+for,O
+IER3IP1,B-Gene
+showed,O
+an,O
+increased,O
+susceptibility,O
+to,O
+apoptotic,O
+cell,O
+death,O
+under,O
+stress,O
+conditions,O
+in,O
+comparison,O
+to,O
+controls,O
+.,O
+ , 
+This,O
+directly,O
+implicates,O
+IER3IP1,B-Gene
+in,O
+the,O
+regulation,O
+of,O
+cell,O
+survival,O
+.,O
+ , 
+Identification,O
+of,O
+IER3IP1,B-Gene
+mutations,O
+sheds,O
+light,O
+on,O
+the,O
+mechanisms,O
+of,O
+brain,O
+development,O
+and,O
+on,O
+the,O
+pathogenesis,O
+of,O
+infantile,O
+epilepsy,O
+and,O
+early,O
+-,O
+onset,O
+permanent,O
+diabetes,O
+.,O
+ , 
+#9718346
+A,O
+gene,O
+involved,O
+in,O
+XY,O
+sex,O
+reversal,O
+is,O
+located,O
+on,O
+chromosome,O
+9,O
+,,O
+distal,O
+to,O
+marker,O
+D9S1779,O
+.,O
+ , 
+The,O
+genetic,O
+mechanisms,O
+involved,O
+in,O
+sex,O
+differentiation,O
+are,O
+poorly,O
+understood,O
+,,O
+and,O
+progress,O
+in,O
+identification,O
+of,O
+the,O
+genes,O
+involved,O
+has,O
+been,O
+slow,O
+.,O
+ , 
+The,O
+fortuitous,O
+finding,O
+of,O
+chromosomal,O
+rearrangements,O
+in,O
+association,O
+with,O
+a,O
+sex,O
+-,O
+reversed,O
+phenotype,O
+has,O
+led,O
+to,O
+the,O
+isolation,O
+of,O
+SRY,B-Gene
+and,O
+SOX9,B-Gene
+,,I-Gene
+both,O
+shown,O
+to,O
+be,O
+involved,O
+in,O
+the,O
+sex,O
+-,O
+determining,O
+pathway,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+duplications,O
+of,O
+the,O
+X,O
+chromosome,O
+,,O
+deletions,O
+of,O
+chromosomes,O
+9,O
+and,O
+10,O
+,,O
+and,O
+translocations,O
+involving,O
+chromosome,O
+17,O
+have,O
+been,O
+reported,O
+to,O
+be,O
+associated,O
+with,O
+abnormal,O
+testicular,O
+differentiation,O
+,,O
+leading,O
+to,O
+male,O
+-,O
+to,O
+-,O
+female,O
+sex,O
+reversal,O
+in,O
+46,XY,O
+individuals,O
+.,O
+ , 
+We,O
+present,O
+the,O
+cytogenetic,O
+and,O
+molecular,O
+analyses,O
+of,O
+four,O
+sex,O
+-,O
+reversed,O
+XY,O
+females,O
+,,O
+each,O
+with,O
+gonadal,O
+dysgenesis,O
+and,O
+other,O
+variable,O
+malformations,O
+,,O
+and,O
+with,O
+terminal,O
+deletions,O
+of,O
+distal,O
+chromosome,O
+9p,O
+,,O
+resulting,O
+from,O
+unbalanced,O
+autosomal,O
+translocations,O
+.,O
+ , 
+PCR,O
+amplification,O
+and,O
+DNA,O
+sequence,O
+analysis,O
+of,O
+SRY,B-Gene
+revealed,O
+no,O
+mutations,O
+in,O
+the,O
+high,O
+-,O
+mobility,O
+-,O
+group,O
+domain,O
+(,O
+i.e.,O
+,,O
+HMG,O
+box,O
+),O
+in,O
+any,O
+of,O
+the,O
+four,O
+patients,O
+.,O
+ , 
+Conventional,O
+and,O
+molecular,O
+cytogenetic,O
+analyses,O
+of,O
+metaphase,O
+chromosomes,O
+from,O
+each,O
+patient,O
+suggest,O
+that,O
+the,O
+smallest,O
+region,O
+of,O
+overlap,O
+(,O
+SRO,O
+),O
+of,O
+deletions,O
+involves,O
+a,O
+very,O
+small,O
+region,O
+of,O
+distal,O
+band,O
+9p24,O
+.,O
+ , 
+Loss,O
+-,O
+of,O
+-,O
+heterozygosity,O
+studies,O
+using,O
+17,O
+highly,O
+polymorphic,O
+microsatellite,O
+markers,O
+,,O
+as,O
+well,O
+as,O
+FISH,O
+using,O
+YAC,O
+clones,O
+corresponding,O
+to,O
+the,O
+most,O
+distal,O
+markers,O
+on,O
+9p,O
+,,O
+showed,O
+that,O
+the,O
+SRO,O
+lies,O
+distal,O
+to,O
+marker,O
+D9S1779,O
+.,O
+ , 
+These,O
+results,O
+significantly,O
+narrow,O
+the,O
+putative,O
+sex,O
+-,O
+determining,O
+gene,O
+to,O
+the,O
+very,O
+terminal,O
+region,O
+of,O
+the,O
+short,O
+arm,O
+of,O
+chromosome,O
+9,O
+.,O
+ , 
+#13680528
+A,O
+genomewide,O
+screen,O
+of,O
+345,O
+families,O
+for,O
+autism,O
+-,O
+susceptibility,O
+loci,O
+.,O
+ , 
+We,O
+previously,O
+reported,O
+a,O
+genomewide,O
+scan,O
+to,O
+identify,O
+autism,O
+-,O
+susceptibility,O
+loci,O
+in,O
+110,O
+multiplex,O
+families,O
+,,O
+showing,O
+suggestive,O
+evidence,O
+(,O
+P,O
+<,O
+.01,O
+),O
+for,O
+linkage,O
+to,O
+autism,O
+-,O
+spectrum,O
+disorders,O
+(,O
+ASD,O
+),O
+on,O
+chromosomes,O
+5,O
+,,O
+8,O
+,,O
+16,O
+,,O
+19,O
+,,O
+and,O
+X,O
+and,O
+showing,O
+nominal,O
+evidence,O
+(,O
+P,O
+<,O
+.05,O
+),O
+on,O
+several,O
+additional,O
+chromosomes,O
+(,O
+2,O
+,,O
+3,O
+,,O
+4,O
+,,O
+10,O
+,,O
+11,O
+,,O
+12,O
+,,O
+15,O
+,,O
+18,O
+,,O
+and,O
+20,O
+),O
+.,O
+ , 
+In,O
+this,O
+follow,O
+-,O
+up,O
+analysis,O
+we,O
+have,O
+increased,O
+the,O
+sample,O
+size,O
+threefold,O
+,,O
+while,O
+holding,O
+the,O
+study,O
+design,O
+constant,O
+,,O
+so,O
+that,O
+we,O
+now,O
+report,O
+345,O
+multiplex,O
+families,O
+,,O
+each,O
+with,O
+at,O
+least,O
+two,O
+siblings,O
+affected,O
+with,O
+autism,O
+or,O
+ASD,O
+phenotype,O
+.,O
+ , 
+Along,O
+with,O
+235,O
+new,O
+multiplex,O
+families,O
+,,O
+73,O
+new,O
+microsatellite,O
+markers,O
+were,O
+also,O
+added,O
+in,O
+10,O
+regions,O
+,,O
+thereby,O
+increasing,O
+the,O
+marker,O
+density,O
+at,O
+these,O
+strategic,O
+locations,O
+from,O
+10,O
+cM,O
+to,O
+approximately,O
+2,O
+cM,O
+and,O
+bringing,O
+the,O
+total,O
+number,O
+of,O
+markers,O
+to,O
+408,O
+over,O
+the,O
+entire,O
+genome,O
+.,O
+ , 
+Multipoint,O
+maximum,O
+LOD,O
+scores,O
+(,O
+MLS,O
+),O
+obtained,O
+from,O
+affected,O
+-,O
+sib,O
+-,O
+pair,O
+analysis,O
+of,O
+all,O
+345,O
+families,O
+yielded,O
+suggestive,O
+evidence,O
+for,O
+linkage,O
+on,O
+chromosomes,O
+17,O
+,,O
+5,O
+,,O
+11,O
+,,O
+4,O
+,,O
+and,O
+8,O
+(,O
+listed,O
+in,O
+order,O
+by,O
+MLS,O
+),O
+(,O
+P,O
+<,O
+.01,O
+),O
+.,O
+ , 
+The,O
+most,O
+significant,O
+findings,O
+were,O
+an,O
+MLS,O
+of,O
+2.83,O
+(,O
+P,O
+=,O
+.00029,O
+),O
+on,O
+chromosome,O
+17q,O
+,,O
+near,O
+the,O
+serotonin,O
+transporter,O
+(,O
+5,O
+-,O
+hydroxytryptamine,O
+transporter,O
+[,O
+5,O
+-,O
+HTT,O
+],O
+),O
+,,O
+and,O
+an,O
+MLS,O
+of,O
+2.54,O
+(,O
+P,O
+=,O
+.00059,O
+),O
+on,O
+5p,O
+.,O
+ , 
+The,O
+present,O
+follow,O
+-,O
+up,O
+genome,O
+scan,O
+,,O
+which,O
+used,O
+a,O
+consistent,O
+research,O
+design,O
+across,O
+studies,O
+and,O
+examined,O
+the,O
+largest,O
+ASD,O
+sample,O
+collection,O
+reported,O
+to,O
+date,O
+,,O
+gave,O
+either,O
+equivalent,O
+or,O
+marginally,O
+increased,O
+evidence,O
+for,O
+linkage,O
+at,O
+several,O
+chromosomal,O
+regions,O
+implicated,O
+in,O
+our,O
+previous,O
+scan,O
+but,O
+eliminated,O
+evidence,O
+for,O
+linkage,O
+at,O
+other,O
+regions,O
+.,O
+ , 
+#10330344
+Congenital,O
+insensitivity,O
+to,O
+pain,O
+with,O
+anhidrosis,O
+:,O
+novel,O
+mutations,O
+in,O
+the,O
+TRKA,B-Gene
+(,B-Gene
+NTRK1,I-Gene
+),I-Gene
+gene,O
+encoding,O
+a,O
+high,O
+-,O
+affinity,O
+receptor,O
+for,O
+nerve,O
+growth,O
+factor,O
+.,O
+ , 
+Congenital,O
+insensitivity,O
+to,O
+pain,O
+with,O
+anhidrosis,O
+(,O
+CIPA,O
+),O
+is,O
+characterized,O
+by,O
+recurrent,O
+episodes,O
+of,O
+unexplained,O
+fever,O
+,,O
+anhidrosis,O
+(,O
+inability,O
+to,O
+sweat,O
+),O
+,,O
+absence,O
+of,O
+reaction,O
+to,O
+noxious,O
+stimuli,O
+,,O
+self,O
+-,O
+mutilating,O
+behavior,O
+,,O
+and,O
+mental,O
+retardation,O
+.,O
+ , 
+Human,O
+TRKA,B-Gene
+encodes,O
+a,O
+high,O
+-,O
+affinity,O
+tyrosine,O
+kinase,O
+receptor,O
+for,O
+nerve,O
+growth,O
+factor,O
+(,O
+NGF,O
+),O
+,,O
+a,O
+member,O
+of,O
+the,O
+neurotrophin,O
+family,O
+that,O
+induces,O
+neurite,O
+outgrowth,O
+and,O
+promotes,O
+survival,O
+of,O
+embryonic,O
+sensory,O
+and,O
+sympathetic,O
+neurons,O
+.,O
+ , 
+We,O
+have,O
+recently,O
+demonstrated,O
+that,O
+TRKA,B-Gene
+is,O
+responsible,O
+for,O
+CIPA,O
+by,O
+identifying,O
+three,O
+mutations,O
+in,O
+a,O
+region,O
+encoding,O
+the,O
+intracellular,O
+tyrosine,O
+kinase,O
+domain,O
+of,O
+TRKA,B-Gene
+in,O
+one,O
+Ecuadorian,O
+and,O
+three,O
+Japanese,O
+families,O
+.,O
+ , 
+We,O
+have,O
+developed,O
+a,O
+comprehensive,O
+strategy,O
+to,O
+screen,O
+for,O
+TRKA,B-Gene
+mutations,O
+,,O
+on,O
+the,O
+basis,O
+of,O
+the,O
+gene,O
+'s,O
+structure,O
+and,O
+organization,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+11,O
+novel,O
+mutations,O
+,,O
+in,O
+seven,O
+affected,O
+families,O
+.,O
+ , 
+These,O
+are,O
+six,O
+missense,O
+mutations,O
+,,O
+two,O
+frameshift,O
+mutations,O
+,,O
+one,O
+nonsense,O
+mutation,O
+,,O
+and,O
+two,O
+splice,O
+-,O
+site,O
+mutations,O
+.,O
+ , 
+Mendelian,O
+inheritance,O
+of,O
+the,O
+mutations,O
+is,O
+confirmed,O
+in,O
+six,O
+families,O
+for,O
+which,O
+parent,O
+samples,O
+are,O
+available,O
+.,O
+ , 
+Two,O
+mutations,O
+are,O
+linked,O
+,,O
+on,O
+the,O
+same,O
+chromosome,O
+,,O
+to,O
+Arg85Ser,B-SNP
+and,O
+to,O
+His598Tyr;Gly607Val,B-SNP
+,,I-SNP
+hence,O
+,,O
+they,O
+probably,O
+represent,O
+double,O
+and,O
+triple,O
+mutations,O
+.,O
+ , 
+The,O
+mutations,O
+are,O
+distributed,O
+in,O
+an,O
+extracellular,O
+domain,O
+,,O
+involved,O
+in,O
+NGF,O
+binding,O
+,,O
+as,O
+well,O
+as,O
+the,O
+intracellular,O
+signal,O
+-,O
+transduction,O
+domain,O
+.,O
+ , 
+These,O
+data,O
+suggest,O
+that,O
+TRKA,B-Gene
+defects,O
+cause,O
+CIPA,O
+in,O
+various,O
+ethnic,O
+groups,O
+.,O
+ , 
+#12717633
+A,O
+whole,O
+-,O
+genome,O
+screen,O
+of,O
+a,O
+quantitative,O
+trait,O
+of,O
+age,O
+-,O
+related,O
+maculopathy,O
+in,O
+sibships,O
+from,O
+the,O
+Beaver,O
+Dam,O
+Eye,O
+Study,O
+.,O
+ , 
+Age,O
+-,O
+related,O
+maculopathy,O
+(,O
+ARM,O
+),O
+is,O
+a,O
+leading,O
+cause,O
+of,O
+visual,O
+impairment,O
+among,O
+the,O
+elderly,O
+in,O
+Western,O
+populations,O
+.,O
+ , 
+To,O
+identify,O
+ARM,O
+-,O
+susceptibility,O
+loci,O
+,,O
+we,O
+genotyped,O
+a,O
+subset,O
+of,O
+subjects,O
+from,O
+the,O
+Beaver,O
+Dam,O
+(,O
+WI,O
+),O
+Eye,O
+Study,O
+and,O
+performed,O
+a,O
+model,O
+-,O
+free,O
+genomewide,O
+linkage,O
+analysis,O
+for,O
+markers,O
+linked,O
+to,O
+a,O
+quantitative,O
+measure,O
+of,O
+ARM,O
+.,O
+ , 
+We,O
+initially,O
+genotyped,O
+345,O
+autosomal,O
+markers,O
+in,O
+325,O
+individuals,O
+(,O
+N=263,O
+sib,O
+pairs,O
+),O
+from,O
+102,O
+pedigrees,O
+.,O
+ , 
+Ten,O
+regions,O
+suggestive,O
+of,O
+linkage,O
+with,O
+ARM,O
+were,O
+observed,O
+on,O
+chromosomes,O
+3,O
+,,O
+5,O
+,,O
+6,O
+,,O
+12,O
+,,O
+15,O
+,,O
+and,O
+16,O
+.,O
+ , 
+Prior,O
+to,O
+fine,O
+mapping,O
+,,O
+the,O
+most,O
+significant,O
+regions,O
+were,O
+an,O
+18,O
+-,O
+cM,O
+region,O
+on,O
+chromosome,O
+12,O
+,,O
+near,O
+D12S1300,O
+(,O
+P=.0159,O
+),O
+;,O
+a,O
+region,O
+on,O
+chromosome,O
+3,O
+,,O
+near,O
+D3S1763,O
+,,O
+with,O
+a,O
+P,O
+value,O
+of.0062,O
+;,O
+and,O
+a,O
+6,O
+-,O
+cM,O
+region,O
+on,O
+chromosome,O
+16,O
+,,O
+near,O
+D16S769,O
+,,O
+with,O
+a,O
+P,O
+value,O
+of.0086,O
+.,O
+ , 
+After,O
+expanding,O
+our,O
+analysis,O
+to,O
+include,O
+25,O
+additional,O
+fine,O
+-,O
+mapping,O
+markers,O
+,,O
+we,O
+found,O
+that,O
+a,O
+14,O
+-,O
+cM,O
+region,O
+on,O
+chromosome,O
+12,O
+,,O
+near,O
+D12S346,O
+(,O
+located,O
+at,O
+106.89,O
+cM,O
+),O
+,,O
+showed,O
+the,O
+strongest,O
+indication,O
+of,O
+linkage,O
+,,O
+with,O
+a,O
+P,O
+value,O
+of.004,O
+.,O
+ , 
+Three,O
+other,O
+regions,O
+,,O
+on,O
+chromosomes,O
+5,O
+,,O
+6,O
+,,O
+and,O
+15,O
+,,O
+that,O
+were,O
+nominally,O
+significant,O
+at,O
+P,O
+<,O
+or,O
+=,O
+.01,O
+are,O
+also,O
+appropriate,O
+for,O
+fine,O
+mapping,O
+.,O
+ , 
+#10737991
+Identification,O
+of,O
+fifteen,O
+novel,O
+PHEX,B-Gene
+gene,O
+mutations,O
+in,O
+Finnish,O
+patients,O
+with,O
+hypophosphatemic,O
+rickets,O
+.,O
+ , 
+We,O
+have,O
+carried,O
+out,O
+a,O
+mutation,O
+screening,O
+of,O
+the,O
+PHEX,B-Gene
+gene,O
+in,O
+Finnish,O
+patients,O
+with,O
+hypophosphatemia,O
+.,O
+ , 
+A,O
+total,O
+of,O
+100,O
+%,O
+(,O
+5/5,O
+),O
+of,O
+the,O
+familial,O
+HYP,O
+patients,O
+(,O
+X,O
+-,O
+linked,O
+hypophosphatemia,O
+),O
+and,O
+93,O
+%,O
+(,O
+14/15,O
+),O
+of,O
+the,O
+sporadic,O
+cases,O
+were,O
+found,O
+to,O
+carry,O
+a,O
+mutation,O
+in,O
+the,O
+PHEX,O
+gene,O
+.,O
+ , 
+We,O
+identified,O
+18,O
+mutations,O
+,,O
+of,O
+which,O
+15,O
+were,O
+novel,O
+.,O
+ , 
+We,O
+report,O
+also,O
+a,O
+new,O
+polymorphism,O
+46bp,O
+upstream,O
+of,O
+exon,O
+16,O
+.,O
+ , 
+Two,O
+families,O
+were,O
+segregating,O
+the,O
+same,O
+nonsense,O
+mutation,O
+in,O
+exon,O
+1,O
+(,B-SNP
+R20X,I-SNP
+),I-SNP
+,,O
+but,O
+since,O
+this,O
+mutation,O
+has,O
+been,O
+previously,O
+reported,O
+in,O
+three,O
+independent,O
+studies,O
+,,O
+we,O
+consider,O
+it,O
+to,O
+be,O
+a,O
+mutational,O
+hotspot,O
+rather,O
+than,O
+a,O
+Finnish,O
+founder,O
+mutation,O
+.,O
+ , 
+We,O
+did,O
+not,O
+find,O
+PHEX,B-Gene
+gene,O
+mutations,O
+in,O
+two,O
+additional,O
+hypophosphatemia,O
+families,O
+in,O
+which,O
+the,O
+mode,O
+of,O
+inheritance,O
+was,O
+other,O
+than,O
+X,O
+-,O
+linked,O
+dominant,O
+.,O
+ , 
+Also,O
+,,O
+no,O
+mutation,O
+could,O
+be,O
+detected,O
+in,O
+a,O
+patient,O
+with,O
+suspected,O
+oncogenic,O
+osteomalacia,O
+(,O
+OHO,O
+),O
+.,O
+ , 
+#9915936
+1998,O
+ASHG,O
+presidential,O
+address,O
+.,O
+ , 
+Making,O
+genomic,O
+medicine,O
+a,O
+reality,O
+.,O
+ , 
+#11317353
+Variable,O
+expressivity,O
+and,O
+mutation,O
+databases,O
+:,O
+The,O
+androgen,O
+receptor,O
+gene,O
+mutations,O
+database,O
+.,O
+ , 
+For,O
+over,O
+50,O
+years,O
+genetics,O
+has,O
+presumed,O
+that,O
+variations,O
+in,O
+phenotypic,O
+expression,O
+have,O
+,,O
+for,O
+the,O
+most,O
+part,O
+,,O
+been,O
+the,O
+result,O
+of,O
+alterations,O
+in,O
+genotype,O
+.,O
+ , 
+The,O
+importance,O
+and,O
+value,O
+of,O
+mutation,O
+databases,O
+has,O
+been,O
+based,O
+on,O
+the,O
+premise,O
+that,O
+the,O
+same,O
+gene,O
+or,O
+allelic,O
+variation,O
+in,O
+a,O
+specific,O
+gene,O
+that,O
+has,O
+been,O
+proven,O
+to,O
+determine,O
+a,O
+specific,O
+phenotype,O
+,,O
+will,O
+always,O
+produce,O
+the,O
+same,O
+phenotype,O
+.,O
+ , 
+However,O
+,,O
+recent,O
+evidence,O
+has,O
+shown,O
+that,O
+so,O
+called,O
+",O
+simple,O
+",O
+Mendelian,O
+disorders,O
+or,O
+monogenic,O
+traits,O
+are,O
+often,O
+far,O
+from,O
+simple,O
+,,O
+exhibiting,O
+phenotypic,O
+variation,O
+(,O
+variable,O
+expressivity,O
+),O
+that,O
+can,O
+not,O
+be,O
+explained,O
+solely,O
+by,O
+a,O
+gene,O
+or,O
+allelic,O
+alteration,O
+.,O
+ , 
+The,O
+AR,B-Gene
+gene,O
+mutations,O
+database,O
+now,O
+lists,O
+25,O
+cases,O
+where,O
+different,O
+degrees,O
+of,O
+androgen,O
+insensitivity,O
+are,O
+caused,O
+by,O
+identical,O
+mutations,O
+in,O
+the,O
+androgen,B-Gene
+receptor,I-Gene
+gene,I-Gene
+.,I-Gene
+ , 
+In,O
+five,O
+of,O
+these,O
+cases,O
+the,O
+phenotypic,O
+variability,O
+is,O
+due,O
+to,O
+somatic,O
+mosaicism,O
+,,O
+that,O
+is,O
+,,O
+somatic,O
+mutations,O
+that,O
+occur,O
+in,O
+only,O
+certain,O
+cells,O
+of,O
+androgen,O
+-,O
+sensitive,O
+tissue,O
+.,O
+ , 
+Recently,O
+,,O
+a,O
+number,O
+of,O
+other,O
+cases,O
+of,O
+variable,O
+expressivity,O
+have,O
+also,O
+been,O
+linked,O
+to,O
+somatic,O
+mosaicism,O
+.,O
+ , 
+The,O
+impact,O
+of,O
+variable,O
+expressivity,O
+due,O
+to,O
+somatic,O
+mutations,O
+and,O
+mosaicism,O
+on,O
+mutation,O
+databases,O
+is,O
+discussed,O
+.,O
+ , 
+In,O
+particular,O
+,,O
+the,O
+effect,O
+of,O
+an,O
+organism,O
+exhibiting,O
+genetic,O
+heterogeneity,O
+within,O
+its,O
+tissues,O
+,,O
+and,O
+the,O
+possibility,O
+of,O
+an,O
+organism,O
+'s,O
+genotype,O
+changing,O
+over,O
+its,O
+lifetime,O
+,,O
+are,O
+considered,O
+to,O
+have,O
+important,O
+implications,O
+for,O
+mutation,O
+databases,O
+in,O
+the,O
+future,O
+.,O
+ , 
+#10521316
+Primary,O
+autosomal,O
+recessive,O
+microcephaly,O
+:,O
+homozygosity,O
+mapping,O
+of,O
+MCPH4,B-Gene
+to,O
+chromosome,O
+15,O
+.,O
+ , 
+#8304350
+Apolipoprotein,B-Gene
+E,I-Gene
+polymorphism,O
+influences,O
+postprandial,O
+retinyl,O
+palmitate,O
+but,O
+not,O
+triglyceride,O
+concentrations,O
+.,O
+ , 
+To,O
+quantify,O
+the,O
+effect,O
+of,O
+the,O
+apolipoprotein,B-Gene
+(,I-Gene
+apo,I-Gene
+),I-Gene
+E,I-Gene
+polymorphism,O
+on,O
+the,O
+magnitude,O
+of,O
+postprandial,O
+lipemia,O
+,,O
+we,O
+have,O
+defined,O
+its,O
+role,O
+in,O
+determining,O
+the,O
+response,O
+to,O
+a,O
+single,O
+high,O
+-,O
+fat,O
+meal,O
+in,O
+a,O
+large,O
+sample,O
+of,O
+(,O
+N,O
+=,O
+474,O
+),O
+individuals,O
+taking,O
+part,O
+in,O
+the,O
+biethnic,O
+Atherosclerosis,O
+Risk,O
+in,O
+Communities,O
+Study,O
+.,O
+ , 
+The,O
+profile,O
+of,O
+postprandial,O
+response,O
+in,O
+plasma,O
+was,O
+monitored,O
+over,O
+8,O
+h,O
+by,O
+triglyceride,O
+,,O
+triglyceride,B-Gene
+-,I-Gene
+rich,I-Gene
+lipoprotein,I-Gene
+(,I-Gene
+TGRL)-triglyceride,I-Gene
+,,I-Gene
+apo,O
+B-48,O
+/,O
+apo,O
+B-100,O
+ratio,O
+,,O
+and,O
+retinyl,O
+palmitate,O
+concentrations,O
+,,O
+and,O
+the,O
+apo,B-Gene
+E,I-Gene
+polymorphism,O
+was,O
+determined,O
+by,O
+DNA,O
+amplification,O
+and,O
+digestion,O
+.,O
+ , 
+The,O
+frequency,O
+of,O
+the,O
+apo,B-Gene
+E,I-Gene
+alleles,O
+and,O
+their,O
+effects,O
+on,O
+fasting,O
+lipid,O
+levels,O
+in,O
+this,O
+sample,O
+were,O
+similar,O
+to,O
+those,O
+reported,O
+elsewhere,O
+.,O
+ , 
+Postprandial,O
+plasma,O
+retinyl,O
+palmitate,O
+response,O
+to,O
+a,O
+high,O
+-,O
+fat,O
+meal,O
+with,O
+vitamin,O
+A,O
+was,O
+significantly,O
+different,O
+among,O
+apo,B-Gene
+E,I-Gene
+genotypes,O
+,,O
+with,O
+delayed,O
+clearance,O
+in,O
+individuals,O
+with,O
+an,O
+epsilon,O
+2,O
+allele,O
+,,O
+compared,O
+with,O
+epsilon,O
+3/3,O
+and,O
+epsilon,O
+3/4,O
+individuals,O
+.,O
+ , 
+In,O
+the,O
+sample,O
+of,O
+397,O
+Caucasians,O
+,,O
+average,O
+retinyl,O
+palmitate,O
+response,O
+was,O
+1,489,O
+micrograms,O
+/,O
+dl,O
+in,O
+epsilon,O
+2/3,O
+individuals,O
+,,O
+compared,O
+with,O
+1,037,O
+micrograms,O
+/,O
+dl,O
+in,O
+epsilon,O
+3/3,O
+individuals,O
+and,O
+1,108,O
+micrograms,O
+/,O
+dl,O
+in,O
+epsilon,O
+3/4,O
+individuals,O
+.,O
+ , 
+The,O
+apo,B-Gene
+E,I-Gene
+polymorphism,O
+accounted,O
+for,O
+7.1,O
+%,O
+of,O
+the,O
+interindividual,O
+variation,O
+in,O
+postprandial,O
+retinyl,O
+palmitate,O
+response,O
+,,O
+a,O
+contribution,O
+proportionally,O
+greater,O
+than,O
+its,O
+well,O
+-,O
+known,O
+effect,O
+on,O
+fasting,O
+LDL,O
+-,O
+cholesterol,O
+.,O
+ , 
+However,O
+,,O
+despite,O
+this,O
+effect,O
+on,O
+postprandial,O
+retinyl,O
+palmitate,O
+,,O
+the,O
+profile,O
+of,O
+postprandial,O
+triglyceride,O
+response,O
+was,O
+not,O
+significantly,O
+different,O
+among,O
+apo,B-Gene
+E,I-Gene
+genotypes,O
+.,O
+ , 
+The,O
+profile,O
+of,O
+postprandial,O
+response,O
+was,O
+consistent,O
+between,O
+the,O
+sample,O
+of,O
+Caucasians,O
+and,O
+a,O
+smaller,O
+sample,O
+of,O
+black,O
+subjects,O
+.,O
+ , 
+While,O
+these,O
+data,O
+indicate,O
+that,O
+the,O
+removal,O
+of,O
+remnant,O
+particles,O
+from,O
+circulation,O
+is,O
+delayed,O
+in,O
+subjects,O
+with,O
+the,O
+epsilon,O
+2/3,O
+genotype,O
+,,O
+there,O
+is,O
+no,O
+reported,O
+evidence,O
+that,O
+the,O
+epsilon,O
+2,O
+allele,O
+predisposes,O
+to,O
+coronary,O
+artery,O
+disease,O
+(,O
+CAD,O
+),O
+.,O
+ , 
+The,O
+results,O
+of,O
+this,O
+study,O
+provide,O
+not,O
+only,O
+a,O
+reliable,O
+estimate,O
+of,O
+the,O
+magnitude,O
+of,O
+the,O
+effect,O
+of,O
+the,O
+apo,B-Gene
+E,I-Gene
+polymorphism,O
+on,O
+various,O
+measurements,O
+commonly,O
+used,O
+to,O
+characterize,O
+postprandial,O
+lipemia,O
+,,O
+but,O
+also,O
+provide,O
+mechanistic,O
+insight,O
+into,O
+the,O
+effects,O
+of,O
+the,O
+apo,B-Gene
+E,I-Gene
+gene,O
+polymorphism,O
+on,O
+postprandial,O
+lipemia,O
+and,O
+CAD,O
+.,O
+ , 
+#12145744
+The,O
+Xq22,O
+inversion,O
+breakpoint,O
+interrupted,O
+a,O
+novel,O
+Ras,B-Gene
+-,I-Gene
+like,O
+GTPase,O
+gene,O
+in,O
+a,O
+patient,O
+with,O
+Duchenne,O
+muscular,O
+dystrophy,O
+and,O
+profound,O
+mental,O
+retardation,O
+.,O
+ , 
+A,O
+male,O
+patient,O
+with,O
+profound,O
+mental,O
+retardation,O
+,,O
+athetosis,O
+,,O
+nystagmus,O
+,,O
+and,O
+severe,O
+congenital,O
+hypotonia,O
+(,O
+Duchenne,O
+muscular,O
+dystrophy,O
+[,O
+DMD,O
+],O
+),O
+was,O
+previously,O
+shown,O
+to,O
+carry,O
+a,O
+pericentric,O
+inversion,O
+of,O
+the,O
+X,O
+chromosome,O
+,,O
+46,Y,O
+,,O
+inv(X)(p21.2q22.2,O
+),O
+.,O
+ , 
+His,O
+mother,O
+carried,O
+this,O
+inversion,O
+on,O
+one,O
+X,O
+allele,O
+.,O
+ , 
+The,O
+patient,O
+'s,O
+condition,O
+was,O
+originally,O
+misdiagnosed,O
+as,O
+cerebral,O
+palsy,O
+,,O
+and,O
+only,O
+later,O
+was,O
+it,O
+diagnosed,O
+as,O
+DMD,O
+.,O
+ , 
+Because,O
+the,O
+DMD,B-Gene
+gene,O
+is,O
+located,O
+at,O
+Xp21.2,O
+,,O
+which,O
+is,O
+one,O
+breakpoint,O
+of,O
+the,O
+inv(X,O
+),O
+,,O
+and,O
+because,O
+its,O
+defects,O
+are,O
+rarely,O
+associated,O
+with,O
+severe,O
+mental,O
+retardation,O
+,,O
+the,O
+other,O
+clinical,O
+features,O
+of,O
+this,O
+patient,O
+were,O
+deemed,O
+likely,O
+to,O
+be,O
+associated,O
+with,O
+the,O
+opposite,O
+breakpoint,O
+at,O
+Xq22,O
+.,O
+ , 
+Our,O
+precise,O
+molecular,O
+-,O
+cytogenetic,O
+characterization,O
+of,O
+both,O
+breakpoints,O
+revealed,O
+three,O
+catastrophic,O
+genetic,O
+events,O
+that,O
+had,O
+probably,O
+influenced,O
+neuromuscular,O
+and,O
+cognitive,O
+development,O
+:,O
+deletion,O
+of,O
+part,O
+of,O
+the,O
+DMD,B-Gene
+gene,O
+at,O
+Xp21.2,O
+,,O
+duplication,O
+of,O
+the,O
+human,B-Gene
+proteolipid,I-Gene
+protein,I-Gene
+gene,O
+(,B-Gene
+PLP,I-Gene
+),I-Gene
+at,O
+Xq22.2,O
+,,O
+and,O
+disruption,O
+of,O
+a,O
+novel,O
+gene,O
+.,O
+ , 
+The,O
+latter,O
+sequence,O
+,,O
+showing,O
+a,O
+high,O
+degree,O
+of,O
+homology,O
+to,O
+the,O
+Sec4,B-Gene
+gene,O
+of,O
+yeast,O
+,,O
+encoded,O
+a,O
+putative,O
+small,O
+guanine,O
+-,O
+protein,O
+,,O
+Ras,B-Gene
+-,I-Gene
+like,O
+GTPase,O
+that,O
+we,O
+have,O
+termed,O
+",B-Gene
+RLGP,I-Gene
+.,I-Gene
+",O
+ , 
+Immunocytochemistry,O
+located,O
+RLGP,B-Gene
+at,O
+mitochondria,O
+.,O
+ , 
+We,O
+speculate,O
+that,O
+disruption,O
+of,O
+RLGP,B-Gene
+was,O
+responsible,O
+for,O
+the,O
+patient,O
+'s,O
+profound,O
+mental,O
+retardation,O
+.,O
+ , 
+#22213154
+Update,O
+of,O
+PAX2,B-Gene
+mutations,O
+in,O
+renal,O
+coloboma,O
+syndrome,O
+and,O
+establishment,O
+of,O
+a,O
+locus,O
+-,O
+specific,O
+database,O
+.,O
+ , 
+Renal,O
+coloboma,O
+syndrome,O
+,,O
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+known,O
+as,O
+papillorenal,O
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+an,O
+autosomal,O
+-,O
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+by,O
+ocular,O
+and,O
+renal,O
+malformations,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+paired,O
+-,O
+box,O
+gene,O
+,,O
+PAX2,B-Gene
+,,I-Gene
+have,O
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+identified,O
+in,O
+approximately,O
+half,O
+of,O
+individuals,O
+with,O
+classic,O
+findings,O
+of,O
+renal,O
+hypoplasia,O
+/,O
+dysplasia,O
+and,O
+abnormalities,O
+of,O
+the,O
+optic,O
+nerve,O
+.,O
+ , 
+Prior,O
+to,O
+2011,O
+,,O
+there,O
+was,O
+no,O
+actively,O
+maintained,O
+locus,O
+-,O
+specific,O
+database,O
+(,O
+LSDB,O
+),O
+cataloguing,O
+the,O
+extent,O
+of,O
+genetic,O
+variation,O
+in,O
+the,O
+PAX2,B-Gene
+gene,O
+and,O
+phenotypic,O
+variation,O
+in,O
+individuals,O
+with,O
+renal,O
+coloboma,O
+syndrome,O
+.,O
+ , 
+Review,O
+of,O
+published,O
+cases,O
+and,O
+the,O
+collective,O
+diagnostic,O
+experience,O
+of,O
+three,O
+laboratories,O
+in,O
+the,O
+United,O
+States,O
+,,O
+France,O
+,,O
+and,O
+New,O
+Zealand,O
+identified,O
+55,O
+unique,O
+mutations,O
+in,O
+173,O
+individuals,O
+from,O
+86,O
+families,O
+.,O
+ , 
+The,O
+three,O
+clinical,O
+laboratories,O
+participating,O
+in,O
+this,O
+collaboration,O
+contributed,O
+28,O
+novel,O
+variations,O
+in,O
+68,O
+individuals,O
+in,O
+33,O
+families,O
+,,O
+which,O
+represent,O
+a,O
+50,O
+%,O
+increase,O
+in,O
+the,O
+number,O
+of,O
+variations,O
+,,O
+patients,O
+,,O
+and,O
+families,O
+published,O
+in,O
+the,O
+medical,O
+literature,O
+.,O
+ , 
+An,O
+LSDB,O
+was,O
+created,O
+using,O
+the,O
+Leiden,O
+Open,O
+Variation,O
+Database,O
+platform,O
+:,O
+www.lovd.nl/PAX2,O
+.,O
+ , 
+The,O
+most,O
+common,O
+findings,O
+reported,O
+in,O
+this,O
+series,O
+were,O
+abnormal,O
+renal,O
+structure,O
+or,O
+function,O
+(,O
+92,O
+%,O
+of,O
+individuals,O
+),O
+,,O
+ophthalmological,O
+abnormalities,O
+(,O
+77,O
+%,O
+of,O
+individuals,O
+),O
+,,O
+and,O
+hearing,O
+loss,O
+(,O
+7,O
+%,O
+of,O
+individuals,O
+),O
+.,O
+ , 
+Additional,O
+clinical,O
+findings,O
+and,O
+genetic,O
+counseling,O
+implications,O
+are,O
+discussed,O
+.,O
+ , 
+#10884361
+Statistical,O
+approaches,O
+to,O
+gene,O
+mapping,O
+.,O
+ , 
+#9326327
+Molecular,O
+definition,O
+of,O
+22q11,O
+deletions,O
+in,O
+151,O
+velo,O
+-,O
+cardio,O
+-,O
+facial,O
+syndrome,O
+patients,O
+.,O
+ , 
+Velo,O
+-,O
+cardio,O
+-,O
+facial,O
+syndrome,O
+(,O
+VCFS,O
+),O
+is,O
+a,O
+relatively,O
+common,O
+developmental,O
+disorder,O
+characterized,O
+by,O
+craniofacial,O
+anomalies,O
+and,O
+conotruncal,O
+heart,O
+defects,O
+.,O
+ , 
+Many,O
+VCFS,O
+patients,O
+have,O
+hemizygous,O
+deletions,O
+for,O
+a,O
+part,O
+of,O
+22q11,O
+,,O
+suggesting,O
+that,O
+haploinsufficiency,O
+in,O
+this,O
+region,O
+is,O
+responsible,O
+for,O
+its,O
+etiology,O
+.,O
+ , 
+Because,O
+most,O
+cases,O
+of,O
+VCFS,O
+are,O
+sporadic,O
+,,O
+portions,O
+of,O
+22q11,O
+may,O
+be,O
+prone,O
+to,O
+rearrangement,O
+.,O
+ , 
+To,O
+understand,O
+the,O
+molecular,O
+basis,O
+for,O
+chromosomal,O
+deletions,O
+,,O
+we,O
+defined,O
+the,O
+extent,O
+of,O
+the,O
+deletion,O
+,,O
+by,O
+genotyping,O
+151,O
+VCFS,O
+patients,O
+and,O
+performing,O
+haplotype,O
+analysis,O
+on,O
+105,O
+,,O
+using,O
+15,O
+consecutive,O
+polymorphic,O
+markers,O
+in,O
+22q11,O
+.,O
+ , 
+We,O
+found,O
+that,O
+83,O
+%,O
+had,O
+a,O
+deletion,O
+and,O
+>,O
+90,O
+%,O
+of,O
+these,O
+had,O
+a,O
+similar,O
+approximately,O
+3,O
+Mb,O
+deletion,O
+,,O
+suggesting,O
+that,O
+sequences,O
+flanking,O
+the,O
+common,O
+breakpoints,O
+are,O
+susceptible,O
+to,O
+rearrangement,O
+.,O
+ , 
+We,O
+found,O
+no,O
+correlation,O
+between,O
+the,O
+presence,O
+or,O
+size,O
+of,O
+the,O
+deletion,O
+and,O
+the,O
+phenotype,O
+.,O
+ , 
+To,O
+further,O
+define,O
+the,O
+chromosomal,O
+breakpoints,O
+among,O
+the,O
+VCFS,O
+patients,O
+,,O
+we,O
+developed,O
+somatic,O
+hybrid,O
+cell,O
+lines,O
+from,O
+a,O
+set,O
+of,O
+VCFS,O
+patients,O
+.,O
+ , 
+An,O
+11,O
+-,O
+kb,O
+resolution,O
+physical,O
+map,O
+of,O
+a,O
+1,080,O
+-,O
+kb,O
+region,O
+that,O
+includes,O
+deletion,O
+breakpoints,O
+was,O
+constructed,O
+,,O
+incorporating,O
+genes,O
+and,O
+expressed,O
+sequence,O
+tags,O
+(,O
+ESTs,O
+),O
+isolated,O
+by,O
+the,O
+hybridization,O
+selection,O
+method,O
+.,O
+ , 
+The,O
+ordered,O
+markers,O
+were,O
+used,O
+to,O
+examine,O
+the,O
+two,O
+separated,O
+copies,O
+of,O
+chromosome,O
+22,O
+in,O
+the,O
+somatic,O
+hybrid,O
+cell,O
+lines,O
+.,O
+ , 
+In,O
+some,O
+cases,O
+,,O
+we,O
+were,O
+able,O
+to,O
+map,O
+the,O
+chromosome,O
+breakpoints,O
+within,O
+a,O
+single,O
+cosmid,O
+.,O
+ , 
+A,O
+480,O
+-,O
+kb,O
+critical,O
+region,O
+for,O
+VCFS,O
+has,O
+been,O
+delineated,O
+,,O
+including,O
+the,O
+genes,O
+for,O
+GSCL,B-Gene
+,,I-Gene
+CTP,B-Gene
+,,I-Gene
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+HIRA,B-Gene
+,,I-Gene
+and,O
+TMVCF,B-Gene
+,,I-Gene
+as,O
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+as,O
+a,O
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+of,O
+novel,O
+ordered,O
+ESTs,O
+.,O
+ , 
+#20529654
+ASHG,O
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+Addresses,O
+.,O
+ , 
+2009,O
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+Allan,O
+Award,O
+address,O
+:,O
+Life,O
+in,O
+the,O
+sandbox,O
+:,O
+unfinished,O
+business,O
+.,O
+ , 
+#16960802
+Mutations,O
+in,O
+CABP4,B-Gene
+,,I-Gene
+the,O
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+Ca2,B-Gene
++,I-Gene
+-binding,I-Gene
+protein,I-Gene
+4,I-Gene
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+recessive,O
+night,O
+blindness,O
+.,O
+ , 
+Mutations,O
+in,O
+genes,O
+encoding,O
+either,O
+components,O
+of,O
+the,O
+phototransduction,O
+cascade,O
+or,O
+proteins,O
+presumably,O
+involved,O
+in,O
+signaling,O
+from,O
+photoreceptors,O
+to,O
+adjacent,O
+second,O
+-,O
+order,O
+neurons,O
+have,O
+been,O
+shown,O
+to,O
+cause,O
+congenital,O
+stationary,O
+night,O
+blindness,O
+(,O
+CSNB,O
+),O
+.,O
+ , 
+Sequence,O
+alterations,O
+in,O
+CACNA1F,B-Gene
+lead,O
+to,O
+the,O
+incomplete,O
+type,O
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+CSNB,O
+(,O
+CSNB2,O
+),O
+,,O
+which,O
+can,O
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+by,O
+standard,O
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+(,O
+ERG,O
+),O
+.,O
+ , 
+CSNB2,O
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+with,O
+a,O
+reduced,O
+rod,O
+b,O
+-,O
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+,,O
+a,O
+substantially,O
+reduced,O
+cone,O
+a,O
+-,O
+wave,O
+,,O
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+a,O
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+30,O
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+ERG,O
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+.,O
+ , 
+CACNA1F,B-Gene
+ , 
+encodes,O
+the,O
+alpha,O
+1,O
+-,O
+subunit,O
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+L,O
+-,O
+type,O
+Ca2,O
++,O
+channel,O
+(,B-Gene
+Cav1.4,I-Gene
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+),O
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+specific,O
+to,O
+photoreceptors,O
+and,O
+is,O
+present,O
+at,O
+high,O
+density,O
+in,O
+the,O
+synaptic,O
+terminals,O
+.,O
+ , 
+Ten,O
+of,O
+our,O
+patients,O
+with,O
+CSNB2,O
+showed,O
+no,O
+mutation,O
+in,O
+CACNA1F.,B-Gene
+To,O
+identify,O
+the,O
+disease,O
+-,O
+causing,O
+mutations,O
+,,O
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+a,O
+candidate,O
+-,O
+gene,O
+approach,O
+.,O
+ , 
+CABP4,B-Gene
+,,I-Gene
+a,O
+member,O
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+calcium,O
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+protein,O
+(,O
+CABP,O
+),O
+family,O
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+located,O
+in,O
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+is,O
+directly,O
+associated,O
+with,O
+the,O
+C,O
+-,O
+terminal,O
+domain,O
+of,O
+the,O
+Cav1.4,B-Gene
+alpha,I-Gene
+.,O
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+Mice,O
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+either,O
+Cabp4,B-Gene
+or,O
+Cav1.4,B-Gene
+alpha,I-Gene
+display,O
+a,O
+CSNB2,O
+-,O
+like,O
+phenotype,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+for,O
+the,O
+first,O
+time,O
+that,O
+mutations,O
+in,O
+CABP4,B-Gene
+lead,O
+to,O
+autosomal,O
+recessive,O
+CSNB,O
+.,O
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+Our,O
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+compound,O
+heterozygous,O
+mutations,O
+in,O
+two,O
+families,O
+.,O
+ , 
+We,O
+also,O
+show,O
+that,O
+these,O
+mutations,O
+reduce,O
+the,O
+transcript,O
+levels,O
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+30%-40,O
+%,O
+of,O
+those,O
+in,O
+controls,O
+.,O
+ , 
+This,O
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+that,O
+the,O
+reduced,O
+amount,O
+of,O
+CABP4,B-Gene
+is,O
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+reason,O
+for,O
+the,O
+signaling,O
+defect,O
+in,O
+these,O
+patients,O
+.,O
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+#10862097
+Identification,O
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+(,B-SNP
+Y4236X,I-SNP
+,,I-SNP
+Q3820X,B-SNP
+,,I-SNP
+11745,B-SNP
++,I-SNP
+2,I-SNP
+ins3,I-SNP
+),I-SNP
+in,O
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+dominant,O
+polycystic,B-Gene
+kidney,I-Gene
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+gene,O
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+PKD1,I-Gene
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+#20607857
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+database,O
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+CF,O
+and,O
+CFTR,O
+-,O
+related,O
+disorders,O
+.,O
+ , 
+With,O
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+(,O
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+CFTR,O
+-,O
+related,O
+diseases,O
+(,O
+CFTR,O
+-,O
+RD,O
+),O
+,,O
+the,O
+number,O
+of,O
+sequence,O
+variations,O
+in,O
+the,O
+CFTR,B-Gene
+gene,O
+is,O
+constantly,O
+raising,O
+.,O
+ , 
+CF,O
+and,O
+particularly,O
+CFTR,O
+-,O
+RD,O
+provide,O
+a,O
+particular,O
+challenge,O
+because,O
+of,O
+many,O
+unclassified,O
+variants,O
+and,O
+identical,O
+genotypes,O
+associated,O
+with,O
+different,O
+phenotypes,O
+.,O
+ , 
+Using,O
+the,O
+Universal,O
+Mutation,O
+Database,O
+(,O
+UMD,O
+),O
+software,O
+we,O
+have,O
+constructed,O
+UMD,O
+-,O
+CFTR,O
+(,O
+freely,O
+available,O
+at,O
+the,O
+URL,O
+:,O
+http://www.umd.be/CFTR/,O
+),O
+,,O
+the,O
+first,O
+comprehensive,O
+relational,O
+CFTR,O
+database,O
+that,O
+allows,O
+an,O
+in,O
+-,O
+depth,O
+analysis,O
+and,O
+annotation,O
+of,O
+all,O
+variations,O
+identified,O
+in,O
+individuals,O
+whose,O
+CFTR,B-Gene
+genes,O
+have,O
+been,O
+analyzed,O
+extensively,O
+.,O
+ , 
+The,O
+system,O
+has,O
+been,O
+tested,O
+on,O
+the,O
+molecular,O
+data,O
+from,O
+757,O
+patients,O
+(,O
+540,O
+CF,O
+and,O
+217,O
+CBAVD,O
+),O
+including,O
+disease,O
+-,O
+causing,O
+,,O
+unclassified,O
+,,O
+and,O
+nonpathogenic,O
+alterations,O
+(,O
+301,O
+different,O
+sequence,O
+variations,O
+),O
+representing,O
+3,973,O
+entries,O
+.,O
+ , 
+Tools,O
+are,O
+provided,O
+to,O
+assess,O
+the,O
+pathogenicity,O
+of,O
+mutations,O
+.,O
+ , 
+UMD,O
+-,O
+CFTR,O
+also,O
+offers,O
+a,O
+number,O
+of,O
+query,O
+tools,O
+and,O
+graphical,O
+views,O
+providing,O
+instant,O
+access,O
+to,O
+the,O
+list,O
+of,O
+mutations,O
+,,O
+their,O
+frequencies,O
+,,O
+positions,O
+and,O
+predicted,O
+consequences,O
+,,O
+or,O
+correlations,O
+between,O
+genotypes,O
+,,O
+haplotypes,O
+,,O
+and,O
+phenotypes,O
+.,O
+ , 
+UMD,O
+-,O
+CFTR,O
+offers,O
+a,O
+way,O
+to,O
+compile,O
+not,O
+only,O
+disease,O
+-,O
+causing,O
+genotypes,O
+but,O
+also,O
+haplotypes,O
+.,O
+ , 
+It,O
+will,O
+help,O
+the,O
+CFTR,O
+scientific,O
+and,O
+medical,O
+communities,O
+to,O
+improve,O
+sequence,O
+variation,O
+interpretation,O
+,,O
+evaluate,O
+the,O
+putative,O
+influence,O
+of,O
+haplotypes,O
+on,O
+mutations,O
+,,O
+and,O
+correlate,O
+molecular,O
+data,O
+with,O
+phenotypes,O
+.,O
+ , 
+#22444671
+Mutations,O
+in,O
+the,O
+glycosylphosphatidylinositol,B-Gene
+gene,O
+PIGL,B-Gene
+cause,O
+CHIME,O
+syndrome,O
+.,O
+ , 
+CHIME,O
+syndrome,O
+is,O
+characterized,O
+by,O
+colobomas,O
+,,O
+heart,O
+defects,O
+,,O
+ichthyosiform,O
+dermatosis,O
+,,O
+mental,O
+retardation,O
+(,O
+intellectual,O
+disability,O
+),O
+,,O
+and,O
+ear,O
+anomalies,O
+,,O
+including,O
+conductive,O
+hearing,O
+loss,O
+.,O
+ , 
+Whole,O
+-,O
+exome,O
+sequencing,O
+on,O
+five,O
+previously,O
+reported,O
+cases,O
+identified,O
+PIGL,B-Gene
+,,I-Gene
+the,O
+de,O
+-,O
+N,O
+-,O
+acetylase,O
+required,O
+for,O
+glycosylphosphatidylinositol,O
+(,O
+GPI,O
+),O
+anchor,O
+formation,O
+,,O
+as,O
+a,O
+strong,O
+candidate,O
+.,O
+ , 
+Furthermore,O
+,,O
+cell,O
+lines,O
+derived,O
+from,O
+these,O
+cases,O
+had,O
+significantly,O
+reduced,O
+levels,O
+of,O
+the,O
+two,O
+GPI,O
+anchor,O
+markers,O
+,,O
+CD59,B-Gene
+and,O
+a,O
+GPI,O
+-,O
+binding,O
+toxin,O
+,,O
+aerolysin,O
+(,O
+FLAER,O
+),O
+,,O
+confirming,O
+the,O
+pathogenicity,O
+of,O
+the,O
+mutations,O
+.,O
+ , 
+#18355774
+SNP,O
+arrays,O
+in,O
+heterogeneous,O
+tissue,O
+:,O
+highly,O
+accurate,O
+collection,O
+of,O
+both,O
+germline,O
+and,O
+somatic,O
+genetic,O
+information,O
+from,O
+unpaired,O
+single,O
+tumor,O
+samples,O
+.,O
+ , 
+SNP,O
+arrays,O
+provide,O
+reliable,O
+genotypes,O
+and,O
+can,O
+detect,O
+chromosomal,O
+aberrations,O
+at,O
+a,O
+high,O
+resolution,O
+.,O
+ , 
+However,O
+,,O
+tissue,O
+heterogeneity,O
+is,O
+currently,O
+a,O
+major,O
+limitation,O
+for,O
+somatic,O
+tissue,O
+analysis,O
+.,O
+ , 
+We,O
+have,O
+developed,O
+SOMATICs,O
+,,O
+an,O
+original,O
+program,O
+for,O
+accurate,O
+analysis,O
+of,O
+heterogeneous,O
+tissue,O
+samples,O
+.,O
+ , 
+Fifty,O
+-,O
+four,O
+samples,O
+(,O
+42,O
+tumors,O
+and,O
+12,O
+normal,O
+tissues,O
+),O
+were,O
+processed,O
+through,O
+Illumina,O
+Beadarrays,O
+and,O
+then,O
+analyzed,O
+with,O
+SOMATICs,O
+.,O
+ , 
+We,O
+demonstrate,O
+that,O
+tissue,O
+heterogeneity,O
+-,O
+related,O
+limitations,O
+not,O
+only,O
+can,O
+be,O
+overcome,O
+but,O
+can,O
+also,O
+be,O
+turned,O
+into,O
+an,O
+advantage,O
+.,O
+ , 
+First,O
+,,O
+admixture,O
+of,O
+normal,O
+cells,O
+with,O
+tumor,O
+can,O
+be,O
+used,O
+as,O
+an,O
+internal,O
+reference,O
+,,O
+thereby,O
+enabling,O
+highly,O
+sensitive,O
+detection,O
+of,O
+somatic,O
+deletions,O
+without,O
+having,O
+corresponding,O
+normal,O
+tissue,O
+.,O
+ , 
+Second,O
+,,O
+the,O
+presence,O
+of,O
+normal,O
+cells,O
+allows,O
+for,O
+discrimination,O
+of,O
+somatic,O
+from,O
+germline,O
+aberrations,O
+,,O
+and,O
+the,O
+proportion,O
+of,O
+cells,O
+in,O
+the,O
+tissue,O
+sample,O
+that,O
+are,O
+harboring,O
+the,O
+somatic,O
+events,O
+can,O
+be,O
+assessed,O
+.,O
+ , 
+Third,O
+,,O
+relatively,O
+early,O
+versus,O
+late,O
+somatic,O
+events,O
+can,O
+also,O
+be,O
+distinguished,O
+,,O
+assuming,O
+that,O
+late,O
+events,O
+occur,O
+only,O
+in,O
+subsets,O
+of,O
+cancer,O
+cells,O
+.,O
+ , 
+Finally,O
+,,O
+admixture,O
+by,O
+normal,O
+cells,O
+allows,O
+inference,O
+of,O
+germline,O
+genotypes,O
+from,O
+a,O
+cancer,O
+sample,O
+.,O
+ , 
+All,O
+this,O
+information,O
+can,O
+be,O
+obtained,O
+from,O
+any,O
+cancer,O
+sample,O
+containing,O
+a,O
+proportion,O
+of,O
+40,O
+-,O
+75,O
+%,O
+of,O
+cancer,O
+cells,O
+.,O
+ , 
+SOMATICs,O
+is,O
+a,O
+ready,O
+-,O
+to,O
+-,O
+use,O
+open,O
+-,O
+source,O
+program,O
+that,O
+integrates,O
+all,O
+of,O
+these,O
+features,O
+into,O
+a,O
+simple,O
+format,O
+,,O
+comprehensively,O
+describing,O
+each,O
+chromosomal,O
+event,O
+.,O
+ , 
+#20887961
+Mutations,O
+in,O
+SCARF2,B-Gene
+are,O
+responsible,O
+for,O
+Van,O
+Den,O
+Ende,O
+-,O
+Gupta,O
+syndrome,O
+.,O
+ , 
+Van,O
+Den,O
+Ende,O
+-,O
+Gupta,O
+syndrome,O
+(,O
+VDEGS,O
+),O
+is,O
+an,O
+extremely,O
+rare,O
+autosomal,O
+-,O
+recessive,O
+disorder,O
+characterized,O
+by,O
+distinctive,O
+craniofacial,O
+features,O
+,,O
+which,O
+include,O
+blepharophimosis,O
+,,O
+malar,O
+and/or,O
+maxillary,O
+hypoplasia,O
+,,O
+a,O
+narrow,O
+and,O
+beaked,O
+nose,O
+,,O
+and,O
+an,O
+everted,O
+lower,O
+lip,O
+.,O
+ , 
+Other,O
+features,O
+are,O
+arachnodactyly,O
+,,O
+camptodactyly,O
+,,O
+peculiar,O
+skeletal,O
+abnormalities,O
+,,O
+and,O
+normal,O
+development,O
+and,O
+intelligence,O
+.,O
+ , 
+We,O
+present,O
+molecular,O
+data,O
+on,O
+four,O
+VDEGS,O
+patients,O
+from,O
+three,O
+consanguineous,O
+Qatari,O
+families,O
+belonging,O
+to,O
+the,O
+same,O
+highly,O
+inbred,O
+Bedouin,O
+tribe,O
+.,O
+ , 
+The,O
+patients,O
+were,O
+genotyped,O
+with,O
+SNP,O
+microarrays,O
+,,O
+and,O
+a,O
+2.4,O
+Mb,O
+homozygous,O
+region,O
+was,O
+found,O
+on,O
+chromosome,O
+22q11,O
+in,O
+an,O
+area,O
+overlapping,O
+the,O
+DiGeorge,O
+critical,O
+region,O
+.,O
+ , 
+This,O
+region,O
+contained,O
+44,O
+genes,O
+,,O
+including,O
+SCARF2,B-Gene
+,,I-Gene
+a,O
+gene,O
+that,O
+is,O
+expressed,O
+during,O
+development,O
+in,O
+a,O
+number,O
+of,O
+mouse,O
+tissues,O
+relevant,O
+to,O
+the,O
+symptoms,O
+described,O
+above,O
+.,O
+ , 
+Sanger,O
+sequencing,O
+identified,O
+a,O
+missense,O
+change,O
+,,O
+c.773G,B-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+C258Y,I-SNP
+),I-SNP
+,,O
+in,O
+exon,O
+4,O
+in,O
+the,O
+two,O
+closely,O
+related,O
+patients,O
+and,O
+a,O
+2,O
+bp,O
+deletion,O
+in,O
+exon,O
+8,O
+,,O
+c.1328_1329delTG,B-SNP
+(,B-SNP
+p.,I-SNP
+V443DfsX83,I-SNP
+),I-SNP
+,,O
+in,O
+two,O
+unrelated,O
+individuals,O
+.,O
+ , 
+In,O
+parallel,O
+with,O
+the,O
+candidate,O
+gene,O
+approach,O
+,,O
+complete,O
+exome,O
+sequencing,O
+was,O
+used,O
+to,O
+confirm,O
+that,O
+SCARF2,B-Gene
+was,O
+the,O
+gene,O
+responsible,O
+for,O
+VDEGS,O
+.,O
+ , 
+SCARF2,B-Gene
+contains,O
+putative,O
+epidermal,O
+growth,O
+factor,O
+-,O
+like,O
+domains,O
+in,O
+its,O
+extracellular,O
+domain,O
+,,O
+along,O
+with,O
+a,O
+number,O
+of,O
+positively,O
+charged,O
+residues,O
+in,O
+its,O
+intracellular,O
+domain,O
+,,O
+indicating,O
+that,O
+it,O
+may,O
+be,O
+involved,O
+in,O
+intracellular,O
+signaling,O
+.,O
+ , 
+However,O
+,,O
+the,O
+function,O
+of,O
+SCARF2,B-Gene
+has,O
+not,O
+been,O
+characterized,O
+,,O
+and,O
+this,O
+study,O
+reports,O
+that,O
+phenotypic,O
+effects,O
+can,O
+be,O
+associated,O
+with,O
+defects,O
+in,O
+the,O
+scavenger,O
+receptor,O
+F,O
+family,O
+of,O
+genes,O
+.,O
+ , 
+#8434594
+Educating,O
+the,O
+medical,O
+community,O
+through,O
+a,O
+teratology,O
+newsletter,O
+.,O
+ , 
+To,O
+educate,O
+a,O
+geographically,O
+and,O
+professionally,O
+diverse,O
+group,O
+of,O
+health,O
+care,O
+providers,O
+about,O
+teratology,O
+in,O
+an,O
+economic,O
+and,O
+efficient,O
+manner,O
+,,O
+we,O
+developed,O
+a,O
+locally,O
+written,O
+and,O
+distributed,O
+teratology,O
+newsletter,O
+.,O
+ , 
+Response,O
+to,O
+the,O
+newsletter,O
+,,O
+from,O
+readers,O
+as,O
+well,O
+as,O
+from,O
+our,O
+staff,O
+and,O
+funding,O
+agencies,O
+,,O
+suggests,O
+that,O
+such,O
+a,O
+newsletter,O
+can,O
+be,O
+a,O
+valuable,O
+tool,O
+in,O
+educating,O
+medical,O
+communities,O
+about,O
+teratology,O
+.,O
+ , 
+#15712269
+Identification,O
+and,O
+characterization,O
+of,O
+five,O
+novel,O
+MAN2B1,B-Gene
+mutations,O
+in,O
+Italian,O
+patients,O
+with,O
+alpha,O
+-,O
+mannosidosis,O
+.,O
+ , 
+Mutation,O
+analysis,O
+performed,O
+on,O
+six,O
+Italian,O
+families,O
+with,O
+alpha,O
+-,O
+mannosidosis,O
+type,O
+II,O
+allowed,O
+the,O
+identification,O
+of,O
+five,O
+new,O
+mutations,O
+in,O
+the,O
+MAN2B1,B-Gene
+gene,O
+:,O
+c.157G,B-SNP
+>,I-SNP
+T,I-SNP
+,,I-SNP
+c.562C,B-SNP
+>,I-SNP
+T,I-SNP
+,,I-SNP
+c.599A,B-SNP
+>,I-SNP
+T,I-SNP
+,,I-SNP
+c.293dupA,B-SNP
+,,I-SNP
+c.2402G,B-SNP
+>,I-SNP
+ , 
+A,B-SNP
+(,B-SNP
+p.,I-SNP
+E53X,I-SNP
+,,I-SNP
+p.,B-SNP
+R188X,I-SNP
+,,I-SNP
+p.,B-SNP
+H200L,I-SNP
+,,I-SNP
+p.,B-SNP
+Y99VfsX61,I-SNP
+,,I-SNP
+p.,B-SNP
+G801D,I-SNP
+),I-SNP
+.,O
+ , 
+Protein,O
+residues,O
+G801,O
+and,O
+H200,O
+are,O
+conserved,O
+among,O
+the,O
+four,O
+mammalian,O
+alpha,O
+-,O
+mannosidases,O
+cloned,O
+to,O
+date,O
+:,O
+human,O
+,,O
+cattle,O
+,,O
+cat,O
+and,O
+mouse,O
+.,O
+ , 
+In,O
+vitro,O
+expression,O
+studies,O
+demonstrated,O
+that,O
+both,O
+missense,O
+mutations,O
+expressed,O
+no,O
+residual,O
+alpha,O
+-,O
+mannosidase,O
+activity,O
+indicating,O
+that,O
+they,O
+are,O
+disease,O
+-,O
+causing,O
+mutations,O
+.,O
+ , 
+Modelling,O
+into,O
+the,O
+three,O
+-,O
+dimensional,O
+structure,O
+revealed,O
+that,O
+the,O
+p.,B-SNP
+H200L,I-SNP
+could,O
+involve,O
+the,O
+catalytic,O
+mechanism,O
+,,O
+whereas,O
+p.,B-SNP
+G801D,I-SNP
+would,O
+affect,O
+the,O
+correct,O
+folding,O
+of,O
+the,O
+enzyme,O
+.,O
+ , 
+#21412943
+Novel,O
+C2orf71,B-Gene
+mutations,O
+account,O
+for,O
+∼1,O
+%,O
+of,O
+cases,O
+in,O
+a,O
+large,O
+French,O
+arRP,O
+cohort,O
+.,O
+ , 
+Autosomal,O
+-,O
+recessive,O
+retinitis,O
+pigmentosa,O
+(,O
+arRP,O
+),O
+is,O
+a,O
+genetically,O
+heterogeneous,O
+group,O
+of,O
+disorders,O
+to,O
+which,O
+a,O
+novel,O
+gene,O
+,,O
+C2orf71,B-Gene
+,,I-Gene
+was,O
+recently,O
+associated,O
+.,O
+ , 
+The,O
+purpose,O
+of,O
+our,O
+study,O
+was,O
+to,O
+establish,O
+the,O
+prevalence,O
+and,O
+nature,O
+of,O
+C2orf71,B-Gene
+mutations,O
+in,O
+a,O
+clinically,O
+well,O
+-,O
+characterized,O
+cohort,O
+of,O
+345,O
+sporadic,O
+and,O
+arRP,O
+French,O
+cases,O
+.,O
+ , 
+Direct,O
+sequencing,O
+of,O
+C2orf71,B-Gene
+was,O
+performed,O
+in,O
+209,O
+subjects,O
+for,O
+whom,O
+mutations,O
+had,O
+previously,O
+been,O
+excluded,O
+by,O
+microarray,O
+technology,O
+and,O
+direct,O
+sequencing,O
+of,O
+EYS,B-Gene
+.,I-Gene
+ , 
+Putative,O
+pathogenicity,O
+of,O
+the,O
+identified,O
+variants,O
+was,O
+evaluated,O
+through,O
+co,O
+-,O
+segregation,O
+analysis,O
+,,O
+screening,O
+of,O
+more,O
+than,O
+188,O
+control,O
+chromosomes,O
+and,O
+prediction,O
+programs,O
+.,O
+ , 
+We,O
+identified,O
+two,O
+patients,O
+compound,O
+heterozygous,O
+for,O
+mutations,O
+predicted,O
+to,O
+lead,O
+to,O
+a,O
+premature,O
+stop,O
+codon,O
+,,O
+3,O
+of,O
+which,O
+are,O
+novel,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+3,O
+patients,O
+carried,O
+a,O
+single,O
+variant,O
+of,O
+likely,O
+pathogenicity,O
+.,O
+ , 
+Furthermore,O
+a,O
+large,O
+number,O
+of,O
+novel,O
+putative,O
+non,O
+-,O
+disease,O
+causing,O
+variants,O
+were,O
+identified,O
+,,O
+highlighting,O
+the,O
+extremely,O
+polymorphic,O
+nature,O
+of,O
+C2orf71,B-Gene
+.,I-Gene
+ , 
+To,O
+our,O
+knowledge,O
+,,O
+our,O
+study,O
+provides,O
+the,O
+first,O
+large,O
+scale,O
+screening,O
+of,O
+C2orf71,B-Gene
+in,O
+a,O
+French,O
+arRP,O
+cohort,O
+through,O
+direct,O
+sequencing,O
+and,O
+suggests,O
+that,O
+it,O
+would,O
+account,O
+for,O
+approximately,O
+1,O
+%,O
+of,O
+arRP,O
+cases,O
+.,O
+ , 
+#8751879
+The,O
+genetics,O
+of,O
+traditional,O
+living,O
+:,O
+Y,O
+-,O
+chromosomal,O
+and,O
+mitochondrial,O
+lineages,O
+in,O
+the,O
+Sinai,O
+Peninsula,O
+.,O
+ , 
+#1415265
+Molecular,O
+genetic,O
+study,O
+of,O
+the,O
+frequency,O
+of,O
+monosomy,O
+22q11,O
+in,O
+DiGeorge,O
+syndrome,O
+.,O
+ , 
+It,O
+is,O
+well,O
+established,O
+that,O
+DiGeorge,O
+syndrome,O
+(,O
+DGS,O
+),O
+may,O
+be,O
+associated,O
+with,O
+monosomy,O
+of,O
+22q11,O
+-,O
+pter,O
+.,O
+ , 
+More,O
+recently,O
+,,O
+DNA,O
+probes,O
+have,O
+been,O
+used,O
+to,O
+detect,O
+hemizygosity,O
+for,O
+this,O
+region,O
+in,O
+patients,O
+with,O
+no,O
+visible,O
+karyotypic,O
+abnormality,O
+.,O
+ , 
+However,O
+,,O
+DGS,O
+has,O
+also,O
+been,O
+described,O
+in,O
+cases,O
+where,O
+the,O
+cytogenetic,O
+abnormality,O
+does,O
+not,O
+involve,O
+22q11,O
+;,O
+for,O
+instance,O
+,,O
+four,O
+cases,O
+of,O
+10p-,O
+have,O
+been,O
+reported,O
+.,O
+ , 
+In,O
+this,O
+study,O
+we,O
+have,O
+prospectively,O
+analyzed,O
+patients,O
+,,O
+by,O
+using,O
+DNA,O
+markers,O
+from,O
+22q11,O
+,,O
+to,O
+assess,O
+the,O
+frequency,O
+of,O
+22q11,O
+rearrangements,O
+in,O
+DGS,O
+.,O
+ , 
+Twenty,O
+-,O
+one,O
+of,O
+22,O
+cases,O
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+demonstrable,O
+hemizygosity,O
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+22q11,O
+.,O
+ , 
+Cytogenetic,O
+analysis,O
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+identified,O
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+6,O
+of,O
+16,O
+cases,O
+tested,O
+;,O
+in,O
+6,O
+other,O
+cases,O
+no,O
+karyotype,O
+was,O
+available,O
+.,O
+ , 
+When,O
+these,O
+results,O
+are,O
+combined,O
+with,O
+those,O
+from,O
+our,O
+previous,O
+studies,O
+,,O
+33,O
+of,O
+35,O
+DGS,O
+patients,O
+had,O
+chromosome,O
+22q11,O
+deletions,O
+detectable,O
+by,O
+DNA,O
+probes,O
+.,O
+ , 
+#11078480
+The,O
+extent,O
+of,O
+linkage,O
+disequilibrium,O
+in,O
+four,O
+populations,O
+with,O
+distinct,O
+demographic,O
+histories,O
+.,O
+ , 
+The,O
+design,O
+and,O
+feasibility,O
+of,O
+whole,O
+-,O
+genome,O
+-,O
+association,O
+studies,O
+are,O
+critically,O
+dependent,O
+on,O
+the,O
+extent,O
+of,O
+linkage,O
+disequilibrium,O
+(,O
+LD,O
+),O
+between,O
+markers,O
+.,O
+ , 
+Although,O
+there,O
+has,O
+been,O
+extensive,O
+theoretical,O
+discussion,O
+of,O
+this,O
+,,O
+few,O
+empirical,O
+data,O
+exist,O
+.,O
+ , 
+The,O
+authors,O
+have,O
+determined,O
+the,O
+extent,O
+of,O
+LD,O
+among,O
+38,O
+biallelic,O
+markers,O
+with,O
+minor,O
+allele,O
+frequencies,O
+>,O
+.1,O
+,,O
+since,O
+these,O
+are,O
+most,O
+comparable,O
+to,O
+the,O
+common,O
+disease,O
+-,O
+susceptibility,O
+polymorphisms,O
+that,O
+association,O
+studies,O
+aim,O
+to,O
+detect,O
+.,O
+ , 
+The,O
+markers,O
+come,O
+from,O
+three,O
+chromosomal,O
+regions-1,335,O
+kb,O
+on,O
+chromosome,O
+13q12,O
+-,O
+13,O
+,,O
+380,O
+kb,O
+on,O
+chromosome,O
+19q13.2,O
+,,O
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+120,O
+kb,O
+on,O
+chromosome,O
+22q13.3,O
+-,O
+which,O
+have,O
+been,O
+extensively,O
+mapped,O
+.,O
+ , 
+These,O
+markers,O
+were,O
+examined,O
+in,O
+approximately,O
+1,600,O
+individuals,O
+from,O
+four,O
+populations,O
+,,O
+all,O
+of,O
+European,O
+origin,O
+but,O
+with,O
+different,O
+demographic,O
+histories,O
+;,O
+Afrikaners,O
+,,O
+Ashkenazim,O
+,,O
+Finns,O
+,,O
+and,O
+East,O
+Anglian,O
+British,O
+.,O
+ , 
+There,O
+are,O
+few,O
+differences,O
+,,O
+either,O
+in,O
+allele,O
+frequencies,O
+or,O
+in,O
+LD,O
+,,O
+among,O
+the,O
+populations,O
+studied,O
+.,O
+ , 
+A,O
+similar,O
+inverse,O
+relationship,O
+was,O
+found,O
+between,O
+LD,O
+and,O
+distance,O
+in,O
+each,O
+genomic,O
+region,O
+and,O
+in,O
+each,O
+population,O
+.,O
+ , 
+Mean,O
+D,O
+',O
+is.68,O
+for,O
+marker,O
+pairs,O
+<,O
+5,O
+kb,O
+apart,O
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+is.24,O
+for,O
+pairs,O
+separated,O
+by,O
+10,O
+-,O
+20,O
+kb,O
+,,O
+and,O
+the,O
+level,O
+of,O
+LD,O
+is,O
+not,O
+different,O
+from,O
+that,O
+seen,O
+in,O
+unlinked,O
+marker,O
+pairs,O
+separated,O
+by,O
+>,O
+500,O
+kb,O
+.,O
+ , 
+However,O
+,,O
+only,O
+50,O
+%,O
+of,O
+marker,O
+pairs,O
+at,O
+distances,O
+<,O
+5,O
+kb,O
+display,O
+sufficient,O
+LD,O
+(,O
+delta>.3,O
+),O
+to,O
+be,O
+useful,O
+in,O
+association,O
+studies,O
+.,O
+ , 
+Results,O
+of,O
+the,O
+present,O
+study,O
+,,O
+if,O
+representative,O
+of,O
+the,O
+whole,O
+genome,O
+,,O
+suggest,O
+that,O
+a,O
+whole,O
+-,O
+genome,O
+scan,O
+searching,O
+for,O
+common,O
+disease,O
+-,O
+susceptibility,O
+alleles,O
+would,O
+require,O
+markers,O
+spaced,O
+<,O
+or,O
+=,O
+5,O
+kb,O
+apart,O
+.,O
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+#20537301
+A,O
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+haplotype,O
+map,O
+as,O
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+genotyping,O
+duplicated,O
+haploid,O
+genomes,O
+finds,O
+a,O
+predominant,O
+haplotype,O
+preference,O
+at,O
+copy,O
+-,O
+number,O
+variation,O
+events,O
+.,O
+ , 
+The,O
+majority,O
+of,O
+complete,O
+hydatidiform,O
+moles,O
+(,O
+CHMs,O
+),O
+harbor,O
+duplicated,O
+haploid,O
+genomes,O
+that,O
+originate,O
+from,O
+sperm,O
+.,O
+ , 
+This,O
+makes,O
+CHMs,O
+more,O
+advantageous,O
+than,O
+conventional,O
+diploid,O
+cells,O
+for,O
+determining,O
+haplotypes,O
+of,O
+SNPs,O
+and,O
+copy,O
+-,O
+number,O
+variations,O
+(,O
+CNVs,O
+),O
+,,O
+because,O
+all,O
+of,O
+the,O
+genetic,O
+variants,O
+in,O
+a,O
+CHM,O
+genome,O
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+.,O
+ , 
+Here,O
+we,O
+report,O
+SNP,O
+and,O
+CNV,O
+haplotype,O
+structures,O
+determined,O
+by,O
+analysis,O
+of,O
+100,O
+CHMs,O
+from,O
+Japanese,O
+subjects,O
+via,O
+high,O
+-,O
+density,O
+DNA,O
+arrays,O
+.,O
+ , 
+The,O
+obtained,O
+haplotype,O
+map,O
+should,O
+be,O
+useful,O
+as,O
+a,O
+reference,O
+for,O
+the,O
+haplotype,O
+structure,O
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+Asian,O
+populations,O
+.,O
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+We,O
+resolved,O
+common,O
+CNV,O
+regions,O
+(,O
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+CNV,O
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+the,O
+examined,O
+samples,O
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+CNV,O
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+(,O
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+),O
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+found,O
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+the,O
+haplotype,O
+backgrounds,O
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+CNV,O
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+#8328463
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+Medical,O
+Genetics,O
+.,O
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+Prenatal,O
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+situ,O
+hybridization,O
+(,O
+FISH,O
+),O
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+#9497253
+Splice,O
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+-,O
+Najjar,O
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+1,O
+.,O
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+Crigler,O
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+type,O
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+(,O
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+),O
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+a,O
+recessively,O
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+,,O
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+lethal,O
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+by,O
+severe,O
+unconjugated,O
+hyperbilirubinemia,O
+resulting,O
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+deficiency,O
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+the,O
+hepatic,O
+enzyme,O
+bilirubin,O
+-,O
+UDP,O
+-,O
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+.,O
+ , 
+In,O
+all,O
+CN-1,O
+patients,O
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+,,O
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+in,O
+one,O
+of,O
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+five,O
+exons,O
+of,O
+the,O
+gene,O
+(,B-Gene
+UGT1A1,I-Gene
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+encoding,O
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+UGT,I-Gene
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+enzyme,O
+.,O
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+We,O
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+,,O
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+,,O
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+gene,O
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+One,O
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+,,O
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+1,O
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+2,O
+.,O
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+The,O
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+shift,O
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+site,O
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+3,O
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+in,O
+the,O
+second,O
+allele,O
+a,O
+premature,O
+translation,O
+-,O
+termination,O
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+in,O
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+1,O
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+Bilirubin,B-Gene
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+UGT1,I-Gene
+mRNA,O
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+is,O
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+in,O
+the,O
+liver,O
+only,O
+.,O
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+To,O
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+the,O
+effects,O
+of,O
+these,O
+splice,O
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+DNA,O
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+relevant,O
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+The,O
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+expressed,O
+mRNAs,O
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+.,O
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+In,O
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+cases,O
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+use,O
+of,O
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+splice,O
+sites,O
+,,O
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+consequent,O
+deletions,O
+in,O
+the,O
+processed,O
+mRNA,O
+.,O
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+This,O
+is,O
+the,O
+first,O
+report,O
+of,O
+intronic,O
+mutations,O
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+CN-1,O
+and,O
+of,O
+the,O
+determination,O
+of,O
+the,O
+consequences,O
+of,O
+these,O
+mutations,O
+on,O
+mRNA,O
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+,,O
+by,O
+ex,O
+vivo,O
+expression,O
+.,O
+ , 
+#11112662
+A,O
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+maternal,O
+uniparental,O
+disomy,O
+of,O
+chromosome,O
+7q31,O
+-,O
+qter,O
+in,O
+Silver,O
+-,O
+Russell,O
+syndrome,O
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+a,O
+candidate,O
+gene,O
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+.,O
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+Maternal,O
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+(,O
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+),O
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+inheritance,O
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+chromosomes,O
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+mother,O
+,,O
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+in,O
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+10,O
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+Silver,O
+-,O
+Russell,O
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+SRS,O
+),O
+.,O
+ , 
+It,O
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+been,O
+suggested,O
+that,O
+at,O
+least,O
+one,O
+imprinted,O
+gene,O
+that,O
+regulates,O
+growth,O
+and,O
+development,O
+resides,O
+on,O
+human,O
+chromosome,O
+7,O
+.,O
+ , 
+To,O
+date,O
+,,O
+three,O
+imprinted,O
+genes,O
+-,B-Gene
+PEG1,I-Gene
+/,B-Gene
+MEST,I-Gene
+,,I-Gene
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+-,I-Gene
+COP,I-Gene
+,,I-Gene
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+GRB10,B-Gene
+-,I-Gene
+have,O
+been,O
+identified,O
+on,O
+chromosome,O
+7,O
+,,O
+but,O
+their,O
+role,O
+in,O
+the,O
+etiology,O
+of,O
+SRS,O
+remains,O
+uncertain,O
+.,O
+ , 
+In,O
+a,O
+systematic,O
+screening,O
+with,O
+microsatellite,O
+markers,O
+,,O
+for,O
+matUPD7,O
+cases,O
+among,O
+patients,O
+with,O
+SRS,O
+,,O
+we,O
+identified,O
+a,O
+patient,O
+who,O
+had,O
+a,O
+small,O
+segment,O
+of,O
+matUPD7,O
+and,O
+biparental,O
+inheritance,O
+of,O
+the,O
+remainder,O
+of,O
+chromosome,O
+7,O
+.,O
+ , 
+Such,O
+a,O
+pattern,O
+may,O
+be,O
+explained,O
+by,O
+somatic,O
+recombination,O
+in,O
+the,O
+zygote,O
+.,O
+ , 
+The,O
+matUPD7,O
+segment,O
+at,O
+7q31,O
+-,O
+qter,O
+extends,O
+for,O
+35,O
+Mb,O
+and,O
+includes,O
+the,O
+imprinted,O
+gene,O
+cluster,O
+of,O
+PEG1,B-Gene
+/,B-Gene
+MEST,I-Gene
+and,O
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+-,I-Gene
+COP,I-Gene
+at,O
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+.,O
+ , 
+GRB10,B-Gene
+at,O
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+-,O
+p12,O
+is,O
+located,O
+within,O
+a,O
+region,O
+of,O
+biparental,O
+inheritance,O
+.,O
+ , 
+Although,O
+partial,O
+UPD,O
+has,O
+previously,O
+been,O
+reported,O
+for,O
+chromosomes,O
+6,O
+,,O
+11,O
+,,O
+14,O
+,,O
+and,O
+15,O
+,,O
+this,O
+is,O
+the,O
+first,O
+report,O
+of,O
+a,O
+patient,O
+with,O
+SRS,O
+who,O
+has,O
+segmental,O
+matUPD7,O
+.,O
+ , 
+Our,O
+findings,O
+delimit,O
+a,O
+candidate,O
+imprinted,O
+region,O
+sufficient,O
+to,O
+cause,O
+SRS,O
+.,O
+ , 
+#14974085
+Noonan,O
+syndrome,O
+-,O
+associated,O
+SHP2,B-Gene
+/,B-Gene
+PTPN11,I-Gene
+mutants,O
+cause,O
+EGF,B-Gene
+-,I-Gene
+dependent,O
+prolonged,O
+GAB1,B-Gene
+binding,O
+and,O
+sustained,O
+ERK2,B-Gene
+/,B-Gene
+MAPK1,I-Gene
+activation,O
+.,O
+ , 
+Noonan,O
+syndrome,O
+is,O
+a,O
+developmental,O
+disorder,O
+with,O
+dysmorphic,O
+facies,O
+,,O
+short,O
+stature,O
+,,O
+cardiac,O
+defects,O
+,,O
+and,O
+skeletal,O
+anomalies,O
+,,O
+which,O
+can,O
+be,O
+caused,O
+by,O
+missense,O
+PTPN11,B-Gene
+mutations,O
+.,O
+ , 
+PTPN11,B-Gene
+encodes,O
+Src,B-Gene
+homology,I-Gene
+2,I-Gene
+domain,I-Gene
+-,I-Gene
+containing,I-Gene
+tyrosine,I-Gene
+phosphatase,I-Gene
+2,I-Gene
+(,B-Gene
+SHP2,I-Gene
+or,O
+SHP-2,B-Gene
+),I-Gene
+,,O
+a,O
+protein,O
+tyrosine,O
+phosphatase,O
+that,O
+acts,O
+in,O
+signal,O
+transduction,O
+downstream,O
+to,O
+growth,O
+factor,O
+,,O
+hormone,O
+,,O
+and,O
+cytokine,O
+receptors,O
+.,O
+ , 
+We,O
+compared,O
+the,O
+functional,O
+effects,O
+of,O
+three,O
+Noonan,O
+syndrome,O
+-,O
+causative,O
+PTPN11,B-Gene
+mutations,O
+on,O
+SHP2,B-Gene
+'s,I-Gene
+phosphatase,O
+activity,O
+,,O
+interaction,O
+with,O
+a,O
+binding,O
+partner,O
+,,O
+and,O
+signal,O
+transduction,O
+.,O
+ , 
+All,O
+SHP2,B-Gene
+mutants,O
+had,O
+significantly,O
+increased,O
+basal,O
+phosphatase,O
+activity,O
+compared,O
+to,O
+wild,O
+type,O
+,,O
+but,O
+that,O
+activity,O
+varied,O
+significantly,O
+between,O
+mutants,O
+and,O
+was,O
+further,O
+increased,O
+after,O
+epidermal,O
+growth,O
+factor,O
+stimulation,O
+.,O
+ , 
+Cells,O
+expressing,O
+SHP2,B-Gene
+mutants,O
+had,O
+prolonged,O
+extracellular,O
+signal,B-Gene
+-,I-Gene
+regulated,I-Gene
+kinase,I-Gene
+2,I-Gene
+activation,O
+,,O
+which,O
+was,O
+ligand,O
+-,O
+dependent,O
+.,O
+ , 
+Binding,O
+of,O
+SHP2,B-Gene
+mutants,O
+to,O
+Grb2,O
+-,O
+associated,O
+binder-1,O
+was,O
+increased,O
+and,O
+sustained,O
+,,O
+and,O
+tyrosine,O
+phosphorylation,O
+of,O
+both,O
+proteins,O
+was,O
+prolonged,O
+.,O
+ , 
+Coexpression,O
+of,O
+Grb2,O
+-,O
+associated,O
+binder-1,O
+-,O
+FF,O
+,,O
+which,O
+lacks,O
+SHP2,B-Gene
+binding,O
+motifs,O
+,,O
+blocked,O
+the,O
+epidermal,O
+growth,O
+factor,O
+-,O
+mediated,O
+increase,O
+in,O
+SHP2,B-Gene
+'s,I-Gene
+phosphatase,O
+activity,O
+and,O
+resulted,O
+in,O
+a,O
+dramatic,O
+reduction,O
+of,O
+extracellular,O
+signal,O
+-,O
+regulated,O
+kinase,O
+2,O
+activation,O
+.,O
+ , 
+Taken,O
+together,O
+,,O
+these,O
+results,O
+document,O
+that,O
+Noonan,O
+syndrome,O
+-,O
+associated,O
+PTPN11,B-Gene
+mutations,O
+increase,O
+SHP2,B-Gene
+'s,I-Gene
+basal,O
+phosphatase,O
+activity,O
+,,O
+with,O
+greater,O
+activation,O
+when,O
+residues,O
+directly,O
+involved,O
+in,O
+binding,O
+at,O
+the,O
+interface,O
+between,O
+the,O
+N,O
+-,O
+terminal,O
+Src,O
+homology,O
+2,O
+and,O
+protein,O
+tyrosine,O
+phosphatase,O
+domains,O
+are,O
+altered,O
+.,O
+ , 
+The,O
+SHP2,O
+mutants,O
+prolonged,O
+signal,O
+flux,O
+through,O
+the,O
+RAS,B-Gene
+/,B-Gene
+mitogen,I-Gene
+-,I-Gene
+activated,I-Gene
+protein,I-Gene
+kinase,I-Gene
+(,B-Gene
+ERK2,I-Gene
+/,I-Gene
+MAPK1,I-Gene
+),I-Gene
+pathway,O
+in,O
+a,O
+ligand,O
+-,O
+dependent,O
+manner,O
+that,O
+required,O
+docking,O
+through,O
+Grb2,B-Gene
+-,I-Gene
+associated,I-Gene
+binder-1,I-Gene
+(,B-Gene
+GAB1,I-Gene
+),I-Gene
+,,O
+leading,O
+to,O
+increased,O
+cell,O
+proliferation,O
+.,O
+ , 
+#7668247
+Very,O
+-,O
+long,O
+-,O
+chain,O
+acyl,O
+-,O
+CoA,O
+dehydrogenase,O
+deficiency,O
+:,O
+molecular,O
+genetics,O
+of,O
+a,O
+mitochondrial,O
+membrane,O
+enzyme,O
+.,O
+ , 
+#8434583
+Germ,O
+-,O
+line,O
+origins,O
+of,O
+mutation,O
+in,O
+families,O
+with,O
+hemophilia,O
+B,O
+:,O
+the,O
+sex,O
+ratio,O
+varies,O
+with,O
+the,O
+type,O
+of,O
+mutation,O
+.,O
+ , 
+Previous,O
+epidemiological,O
+and,O
+biochemical,O
+studies,O
+have,O
+generated,O
+conflicting,O
+estimates,O
+of,O
+the,O
+sex,O
+ratio,O
+of,O
+mutation,O
+.,O
+ , 
+Direct,O
+genomic,O
+sequencing,O
+in,O
+combination,O
+with,O
+haplotype,O
+analysis,O
+extends,O
+previous,O
+analyses,O
+by,O
+allowing,O
+the,O
+precise,O
+mutation,O
+to,O
+be,O
+determined,O
+in,O
+a,O
+given,O
+family,O
+.,O
+ , 
+From,O
+analysis,O
+of,O
+the,O
+factor,B-Gene
+IX,I-Gene
+gene,O
+of,O
+260,O
+consecutive,O
+families,O
+with,O
+hemophilia,O
+B,O
+,,O
+we,O
+report,O
+the,O
+germ,O
+-,O
+line,O
+origin,O
+of,O
+mutation,O
+in,O
+25,O
+families,O
+.,O
+ , 
+When,O
+combined,O
+with,O
+14,O
+origins,O
+of,O
+mutation,O
+reported,O
+by,O
+others,O
+and,O
+with,O
+4,O
+origins,O
+previously,O
+reported,O
+by,O
+us,O
+,,O
+a,O
+total,O
+of,O
+25,O
+occur,O
+in,O
+the,O
+female,O
+germ,O
+line,O
+,,O
+and,O
+18,O
+occur,O
+in,O
+the,O
+male,O
+germ,O
+line,O
+.,O
+ , 
+The,O
+excess,O
+of,O
+germ,O
+-,O
+line,O
+origins,O
+in,O
+females,O
+does,O
+not,O
+imply,O
+an,O
+overall,O
+excess,O
+mutation,O
+rate,O
+per,O
+base,O
+pair,O
+in,O
+the,O
+female,O
+germ,O
+line,O
+.,O
+ , 
+Bayesian,O
+analysis,O
+of,O
+the,O
+data,O
+indicates,O
+that,O
+the,O
+sex,O
+ratio,O
+varies,O
+with,O
+the,O
+type,O
+of,O
+mutation,O
+.,O
+ , 
+The,O
+aggregate,O
+of,O
+single,O
+-,O
+base,O
+substitutions,O
+shows,O
+a,O
+male,O
+predominance,O
+of,O
+germ,O
+-,O
+line,O
+mutations,O
+(,O
+P,O
+<,O
+.002,O
+),O
+.,O
+ , 
+The,O
+maximum,O
+-,O
+likelihood,O
+estimate,O
+of,O
+the,O
+male,O
+predominance,O
+is,O
+3.5,O
+-,O
+fold,O
+.,O
+ , 
+Of,O
+the,O
+single,O
+-,O
+base,O
+substitutions,O
+,,O
+transitions,O
+at,O
+the,O
+dinucleotide,O
+CpG,O
+show,O
+the,O
+largest,O
+male,O
+predominance,O
+(,O
+11,O
+-,O
+fold,O
+),O
+.,O
+ , 
+In,O
+contrast,O
+to,O
+single,O
+-,O
+base,O
+substitutions,O
+,,O
+deletions,O
+display,O
+a,O
+sex,O
+ratio,O
+of,O
+unity,O
+.,O
+ , 
+Analysis,O
+of,O
+the,O
+parental,O
+age,O
+at,O
+transmission,O
+of,O
+a,O
+new,O
+mutation,O
+suggests,O
+that,O
+germ,O
+-,O
+line,O
+mutations,O
+are,O
+associated,O
+with,O
+a,O
+small,O
+increase,O
+in,O
+parental,O
+age,O
+in,O
+females,O
+but,O
+little,O
+,,O
+if,O
+any,O
+,,O
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+in,O
+males,O
+.,O
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+Although,O
+direct,O
+genomic,O
+sequencing,O
+offers,O
+a,O
+general,O
+method,O
+for,O
+defining,O
+the,O
+origin,O
+of,O
+mutation,O
+in,O
+specific,O
+families,O
+,,O
+accurate,O
+estimates,O
+of,O
+the,O
+sex,O
+ratios,O
+of,O
+different,O
+mutational,O
+classes,O
+require,O
+large,O
+sample,O
+sizes,O
+and,O
+careful,O
+correction,O
+for,O
+multiple,O
+biases,O
+of,O
+ascertainment,O
+.,O
+ , 
+The,O
+biases,O
+in,O
+the,O
+present,O
+data,O
+result,O
+in,O
+an,O
+underestimate,O
+of,O
+the,O
+enhancement,O
+of,O
+mutation,O
+in,O
+males,O
+.,O
+ , 
+#17203459
+ZFHX1B,B-Gene
+mutations,O
+in,O
+patients,O
+with,O
+Mowat,O
+-,O
+Wilson,O
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+.,O
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+Mowat,O
+-,O
+Wilson,O
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+(,O
+MWS,O
+),O
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+a,O
+recently,O
+delineated,O
+mental,O
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+(,O
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+congenital,O
+anomaly,O
+syndrome,O
+,,O
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+by,O
+typical,O
+facies,O
+,,O
+severe,O
+MR,O
+,,O
+epilepsy,O
+,,O
+and,O
+variable,O
+congenital,O
+malformations,O
+,,O
+including,O
+Hirschsprung,O
+disease,O
+(,O
+HSCR,O
+),O
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+,,O
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+(,O
+CHD,O
+),O
+,,O
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+corpus,O
+callosum,O
+(,O
+ACC,O
+),O
+.,O
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+It,O
+is,O
+caused,O
+by,O
+de,O
+novo,O
+heterozygous,O
+mutations,O
+or,O
+deletions,O
+of,O
+the,O
+ZFHX1B,B-Gene
+gene,O
+located,O
+at,O
+2q22,O
+.,O
+ , 
+ZFHX1B,B-Gene
+encodes,O
+Smad,B-Gene
+-,I-Gene
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+(,B-Gene
+SMADIP1,I-Gene
+or,O
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+),I-Gene
+,,O
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+transcriptional,O
+corepressor,O
+involved,O
+in,O
+the,O
+transforming,O
+growth,O
+factor,O
+-,O
+beta,O
+signaling,O
+pathway,O
+.,O
+ , 
+It,O
+is,O
+a,O
+highly,O
+evolutionarily,O
+conserved,O
+gene,O
+,,O
+widely,O
+expressed,O
+in,O
+embryological,O
+development,O
+.,O
+ , 
+Over,O
+100,O
+mutations,O
+have,O
+been,O
+described,O
+in,O
+patients,O
+with,O
+clinically,O
+typical,O
+MWS,O
+,,O
+who,O
+almost,O
+always,O
+have,O
+whole,O
+gene,O
+deletions,O
+or,O
+truncating,O
+mutations,O
+(,O
+nonsense,O
+or,O
+frameshift,O
+),O
+of,O
+ZFHX1B,B-Gene
+,,I-Gene
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+that,O
+haploinsufficiency,O
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+basis,O
+of,O
+MWS,O
+pathology,O
+.,O
+ , 
+No,O
+obvious,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+could,O
+be,O
+identified,O
+so,O
+far,O
+,,O
+but,O
+atypical,O
+phenotypes,O
+have,O
+been,O
+reported,O
+with,O
+missense,O
+or,O
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+mutations,O
+in,O
+the,O
+ZFHX1B,B-Gene
+gene,O
+.,O
+ , 
+In,O
+this,O
+work,O
+we,O
+describe,O
+40,O
+novel,O
+mutations,O
+and,O
+we,O
+summarize,O
+the,O
+various,O
+mutational,O
+reports,O
+published,O
+since,O
+the,O
+identification,O
+of,O
+the,O
+causative,O
+gene,O
+.,O
+ , 
+#18683858
+Ancestry,O
+informative,O
+marker,O
+sets,O
+for,O
+determining,O
+continental,O
+origin,O
+and,O
+admixture,O
+proportions,O
+in,O
+common,O
+populations,O
+in,O
+America,O
+.,O
+ , 
+To,O
+provide,O
+a,O
+resource,O
+for,O
+assessing,O
+continental,O
+ancestry,O
+in,O
+a,O
+wide,O
+variety,O
+of,O
+genetic,O
+studies,O
+,,O
+we,O
+identified,O
+,,O
+validated,O
+,,O
+and,O
+characterized,O
+a,O
+set,O
+of,O
+128,O
+ancestry,O
+informative,O
+markers,O
+(,O
+AIMs,O
+),O
+.,O
+ , 
+The,O
+markers,O
+were,O
+chosen,O
+for,O
+informativeness,O
+,,O
+genome,O
+-,O
+wide,O
+distribution,O
+,,O
+and,O
+genotype,O
+reproducibility,O
+on,O
+two,O
+platforms,O
+(,O
+TaqMan,O
+assays,O
+and,O
+Illumina,O
+arrays,O
+),O
+.,O
+ , 
+We,O
+analyzed,O
+genotyping,O
+data,O
+from,O
+825,O
+subjects,O
+with,O
+diverse,O
+ancestry,O
+,,O
+including,O
+European,O
+,,O
+East,O
+Asian,O
+,,O
+Amerindian,O
+,,O
+African,O
+,,O
+South,O
+Asian,O
+,,O
+Mexican,O
+,,O
+and,O
+Puerto,O
+Rican,O
+.,O
+ , 
+A,O
+comprehensive,O
+set,O
+of,O
+128,O
+AIMs,O
+and,O
+subsets,O
+as,O
+small,O
+as,O
+24,O
+AIMs,O
+are,O
+shown,O
+to,O
+be,O
+useful,O
+tools,O
+for,O
+ascertaining,O
+the,O
+origin,O
+of,O
+subjects,O
+from,O
+particular,O
+continents,O
+,,O
+and,O
+to,O
+correct,O
+for,O
+population,O
+stratification,O
+in,O
+admixed,O
+population,O
+sample,O
+sets,O
+.,O
+ , 
+Our,O
+findings,O
+provide,O
+general,O
+guidelines,O
+for,O
+the,O
+application,O
+of,O
+specific,O
+AIM,O
+subsets,O
+as,O
+a,O
+resource,O
+for,O
+wide,O
+application,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+investigators,O
+can,O
+use,O
+TaqMan,O
+assays,O
+for,O
+the,O
+selected,O
+AIMs,O
+as,O
+a,O
+simple,O
+and,O
+cost,O
+efficient,O
+tool,O
+to,O
+control,O
+for,O
+differences,O
+in,O
+continental,O
+ancestry,O
+when,O
+conducting,O
+association,O
+studies,O
+in,O
+ethnically,O
+diverse,O
+populations,O
+.,O
+ , 
+#10408772
+Insertion,O
+of,O
+Alu,O
+element,O
+responsible,O
+for,O
+acute,O
+intermittent,O
+porphyria,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+report,O
+a,O
+large,O
+Finnish,O
+family,O
+in,O
+which,O
+an,O
+Alu,O
+element,O
+interferes,O
+with,O
+the,O
+coding,O
+region,O
+of,O
+the,O
+porphobilinogen,B-Gene
+deaminase,I-Gene
+(,B-Gene
+PBGD,I-Gene
+),I-Gene
+gene,O
+resulting,O
+in,O
+acute,O
+intermittent,O
+porphyria,O
+(,O
+AIP,O
+),O
+.,O
+ , 
+Polymerase,O
+chain,O
+reaction,O
+(,O
+PCR,O
+),O
+and,O
+single,O
+-,O
+strand,O
+conformation,O
+polymorphism,O
+(,O
+SSCP,O
+),O
+analysis,O
+of,O
+exon,O
+5,O
+among,O
+patients,O
+showed,O
+an,O
+abnormal,O
+band,O
+around,O
+350,O
+bp,O
+apart,O
+from,O
+the,O
+normal,O
+bands,O
+.,O
+ , 
+Subcloning,O
+and,O
+sequencing,O
+of,O
+the,O
+fragment,O
+revealed,O
+a,O
+333,O
+-,O
+bp,O
+Alu,O
+sequence,O
+that,O
+was,O
+directly,O
+inserted,O
+into,O
+exon,O
+5,O
+in,O
+antisense,O
+orientation,O
+.,O
+ , 
+The,O
+junction,O
+sequences,O
+included,O
+a,O
+13,O
+-,O
+bp,O
+target,O
+site,O
+duplication,O
+.,O
+ , 
+This,O
+Alu,O
+cassette,O
+belongs,O
+to,O
+a,O
+Ya5,O
+subfamily,O
+,,O
+one,O
+of,O
+the,O
+youngest,O
+and,O
+currently,O
+most,O
+active,O
+Alu,O
+subfamilies,O
+in,O
+evolution,O
+.,O
+ , 
+The,O
+Alu,O
+insertion,O
+resulted,O
+in,O
+a,O
+dramatically,O
+decreased,O
+steady,O
+-,O
+state,O
+level,O
+of,O
+the,O
+allelic,O
+transcript,O
+,,O
+as,O
+this,O
+Alu,O
+sequence,O
+could,O
+not,O
+be,O
+demonstrated,O
+by,O
+direct,O
+sequencing,O
+of,O
+the,O
+amplified,O
+cDNA,O
+synthesized,O
+from,O
+total,O
+RNA,O
+extracted,O
+from,O
+the,O
+patients,O
+',O
+lymphoblast,O
+cell,O
+lines,O
+.,O
+ , 
+A,O
+stop,O
+codon,O
+present,O
+in,O
+the,O
+reading,O
+frame,O
+causes,O
+premature,O
+termination,O
+of,O
+PBGD,B-Gene
+synthesis,O
+.,O
+ , 
+The,O
+predicted,O
+polypeptide,O
+contains,O
+64,O
+of,O
+the,O
+361,O
+amino,O
+acids,O
+of,O
+PBGD,B-Gene
+,,I-Gene
+followed,O
+by,O
+13,O
+amino,O
+acids,O
+that,O
+are,O
+not,O
+identical,O
+to,O
+the,O
+PBGD,B-Gene
+polypeptide,O
+.,O
+ , 
+To,O
+further,O
+characterize,O
+the,O
+consequences,O
+of,O
+the,O
+insertion,O
+,,O
+the,O
+Alu,O
+sequence,O
+was,O
+inserted,O
+into,O
+exon,O
+5,O
+of,O
+the,O
+PBGD,B-Gene
+cDNA,O
+and,O
+expressed,O
+in,O
+the,O
+eukaryotic,O
+COS-1,O
+cell,O
+line,O
+.,O
+ , 
+The,O
+mutated,O
+construct,O
+expressed,O
+no,O
+enzyme,O
+activity,O
+comparable,O
+to,O
+that,O
+of,O
+the,O
+wild,O
+-,O
+type,O
+PBGD,B-Gene
+;,I-Gene
+furthermore,O
+,,O
+no,O
+mutant,O
+protein,O
+could,O
+be,O
+detected,O
+by,O
+Western,O
+blot,O
+analysis,O
+.,O
+ , 
+#9199562
+Identification,O
+of,O
+proximal,O
+spinal,O
+muscular,O
+atrophy,O
+carriers,O
+and,O
+patients,O
+by,O
+analysis,O
+of,O
+SMNT,B-Gene
+and,O
+SMNC,B-Gene
+gene,O
+copy,O
+number,O
+.,O
+ , 
+The,O
+survival,O
+motor,O
+neuron,O
+(,O
+SMN,O
+),O
+transcript,O
+is,O
+encoded,O
+by,O
+two,O
+genes,O
+,,O
+SMNT,B-Gene
+and,O
+SMNC,B-Gene
+.,I-Gene
+ , 
+The,O
+autosomal,O
+recessive,O
+proximal,O
+spinal,O
+muscular,O
+atrophy,O
+that,O
+maps,O
+to,O
+5q12,O
+is,O
+caused,O
+by,O
+mutations,O
+in,O
+the,O
+SMNT,B-Gene
+gene,O
+.,O
+ , 
+The,O
+SMNT,B-Gene
+gene,O
+can,O
+be,O
+distinguished,O
+from,O
+the,O
+SMNC,B-Gene
+gene,O
+by,O
+base,O
+-,O
+pair,O
+changes,O
+in,O
+exons,O
+7,O
+and,O
+8,O
+.,O
+ , 
+SMNT,B-Gene
+exon,O
+7,O
+is,O
+not,O
+detected,O
+in,O
+approximately,O
+95,O
+%,O
+of,O
+SMA,O
+cases,O
+due,O
+to,O
+either,O
+deletion,O
+or,O
+sequence,O
+-,O
+conversion,O
+events,O
+.,O
+ , 
+Small,O
+mutations,O
+in,O
+SMNT,B-Gene
+now,O
+have,O
+been,O
+identified,O
+in,O
+some,O
+of,O
+the,O
+remaining,O
+nondeletion,O
+patients,O
+.,O
+ , 
+However,O
+,,O
+there,O
+is,O
+no,O
+reliable,O
+quantitative,O
+assay,O
+for,O
+SMNT,B-Gene
+,,I-Gene
+to,O
+distinguish,O
+SMA,O
+compound,O
+heterozygotes,O
+from,O
+non-5q,O
+SMA,O
+-,O
+like,O
+cases,O
+(,O
+phenocopies,O
+),O
+and,O
+to,O
+accurately,O
+determine,O
+carrier,O
+status,O
+.,O
+ , 
+We,O
+have,O
+developed,O
+a,O
+quantitative,O
+PCR,O
+assay,O
+for,O
+the,O
+determination,O
+of,O
+SMNT,B-Gene
+and,O
+SMNC,B-Gene
+gene,O
+-,O
+copy,O
+number,O
+.,O
+ , 
+This,O
+report,O
+demonstrates,O
+how,O
+risk,O
+estimates,O
+for,O
+the,O
+diagnosis,O
+and,O
+detection,O
+of,O
+SMA,O
+carriers,O
+can,O
+be,O
+modified,O
+by,O
+the,O
+accurate,O
+determination,O
+of,O
+SMNT,B-Gene
+copy,O
+number,O
+.,O
+ , 
+#18252226
+Acetylcholine,O
+receptor,O
+pathway,O
+mutations,O
+explain,O
+various,O
+fetal,O
+akinesia,O
+deformation,O
+sequence,O
+disorders,O
+.,O
+ , 
+Impaired,O
+fetal,O
+movement,O
+causes,O
+malformations,O
+,,O
+summarized,O
+as,O
+fetal,O
+akinesia,O
+deformation,O
+sequence,O
+(,O
+FADS,O
+),O
+,,O
+and,O
+is,O
+triggered,O
+by,O
+environmental,O
+and,O
+genetic,O
+factors,O
+.,O
+ , 
+Acetylcholine,B-Gene
+receptor,I-Gene
+(,B-Gene
+AChR,I-Gene
+),I-Gene
+components,O
+are,O
+suspects,O
+because,O
+mutations,O
+in,O
+the,O
+fetally,O
+expressed,O
+gamma,O
+subunit,O
+(,B-Gene
+CHRNG,I-Gene
+),I-Gene
+of,O
+AChR,B-Gene
+were,O
+found,O
+in,O
+two,O
+FADS,O
+disorders,O
+,,O
+lethal,O
+multiple,O
+pterygium,O
+syndrome,O
+(,O
+LMPS,O
+),O
+and,O
+Escobar,O
+syndrome,O
+.,O
+ , 
+Other,O
+AChR,B-Gene
+subunits,O
+alpha1,O
+,,O
+beta1,O
+,,O
+and,O
+delta,O
+(,B-Gene
+CHRNA1,I-Gene
+,,I-Gene
+CHRNB1,B-Gene
+,,I-Gene
+CHRND,B-Gene
+),I-Gene
+as,O
+well,O
+as,O
+receptor,O
+-,O
+associated,O
+protein,O
+of,O
+the,O
+synapse,O
+(,B-Gene
+RAPSN,I-Gene
+),I-Gene
+previously,O
+revealed,O
+missense,O
+or,O
+compound,O
+nonsense,O
+-,O
+missense,O
+mutations,O
+in,O
+viable,O
+congenital,O
+myasthenic,O
+syndrome,O
+;,O
+lethality,O
+of,O
+homozygous,O
+null,O
+mutations,O
+was,O
+predicted,O
+but,O
+never,O
+shown,O
+.,O
+ , 
+We,O
+provide,O
+the,O
+first,O
+report,O
+to,O
+our,O
+knowledge,O
+of,O
+homozygous,O
+nonsense,O
+mutations,O
+in,O
+CHRNA1,B-Gene
+and,O
+CHRND,B-Gene
+and,O
+show,O
+that,O
+they,O
+were,O
+lethal,O
+,,O
+whereas,O
+novel,O
+recessive,O
+missense,O
+mutations,O
+in,O
+RAPSN,B-Gene
+caused,O
+a,O
+severe,O
+but,O
+not,O
+necessarily,O
+lethal,O
+phenotype,O
+.,O
+ , 
+To,O
+elucidate,O
+disease,O
+-,O
+associated,O
+malformations,O
+such,O
+as,O
+frequent,O
+abortions,O
+,,O
+fetal,O
+edema,O
+,,O
+cystic,O
+hygroma,O
+,,O
+or,O
+cardiac,O
+defects,O
+,,O
+we,O
+studied,O
+Chrna1,B-Gene
+,,I-Gene
+Chrnb1,B-Gene
+,,I-Gene
+Chrnd,B-Gene
+,,I-Gene
+Chrng,B-Gene
+,,I-Gene
+and,O
+Rapsn,B-Gene
+in,O
+mouse,O
+embryos,O
+and,O
+found,O
+expression,O
+in,O
+skeletal,O
+muscles,O
+but,O
+also,O
+in,O
+early,O
+somite,O
+development,O
+.,O
+ , 
+This,O
+indicates,O
+that,O
+early,O
+developmental,O
+defects,O
+might,O
+be,O
+due,O
+to,O
+somite,O
+expression,O
+in,O
+addition,O
+to,O
+solely,O
+muscle,O
+-,O
+specific,O
+effects,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+complete,O
+or,O
+severe,O
+functional,O
+disruption,O
+of,O
+fetal,O
+AChR,B-Gene
+causes,O
+lethal,O
+multiple,O
+pterygium,O
+syndrome,O
+whereas,O
+milder,O
+alterations,O
+result,O
+in,O
+fetal,O
+hypokinesia,O
+with,O
+inborn,O
+contractures,O
+or,O
+a,O
+myasthenic,O
+syndrome,O
+later,O
+in,O
+life,O
+.,O
+ , 
+#15846561
+Heterozygous,O
+mutations,O
+of,O
+OTX2,B-Gene
+cause,O
+severe,O
+ocular,O
+malformations,O
+.,O
+ , 
+Major,O
+malformations,O
+of,O
+the,O
+human,O
+eye,O
+,,O
+including,O
+microphthalmia,O
+and,O
+anophthalmia,O
+,,O
+are,O
+examples,O
+of,O
+phenotypes,O
+that,O
+recur,O
+in,O
+families,O
+yet,O
+often,O
+show,O
+no,O
+clear,O
+Mendelian,O
+inheritance,O
+pattern,O
+.,O
+ , 
+Defining,O
+loci,O
+by,O
+mapping,O
+is,O
+therefore,O
+rarely,O
+feasible,O
+.,O
+ , 
+Using,O
+a,O
+candidate,O
+-,O
+gene,O
+approach,O
+,,O
+we,O
+have,O
+identified,O
+heterozygous,O
+coding,O
+-,O
+region,O
+changes,O
+in,O
+the,O
+homeobox,O
+gene,O
+OTX2,B-Gene
+in,O
+eight,O
+families,O
+with,O
+ocular,O
+malformations,O
+.,O
+ , 
+The,O
+expression,O
+pattern,O
+of,O
+OTX2,B-Gene
+in,O
+human,O
+embryos,O
+is,O
+consistent,O
+with,O
+the,O
+eye,O
+phenotypes,O
+observed,O
+in,O
+the,O
+patients,O
+,,O
+which,O
+range,O
+from,O
+bilateral,O
+anophthalmia,O
+to,O
+retinal,O
+defects,O
+resembling,O
+Leber,O
+congenital,O
+amaurosis,O
+and,O
+pigmentary,O
+retinopathy,O
+.,O
+ , 
+Magnetic,O
+resonance,O
+imaging,O
+scans,O
+revealed,O
+defects,O
+of,O
+the,O
+optic,O
+nerve,O
+,,O
+optic,O
+chiasm,O
+,,O
+and,O
+,,O
+in,O
+some,O
+cases,O
+,,O
+brain,O
+.,O
+ , 
+In,O
+two,O
+families,O
+,,O
+the,O
+mutations,O
+appear,O
+to,O
+have,O
+occurred,O
+de,O
+novo,O
+in,O
+severely,O
+affected,O
+offspring,O
+,,O
+and,O
+,,O
+in,O
+two,O
+other,O
+families,O
+,,O
+the,O
+mutations,O
+have,O
+been,O
+inherited,O
+from,O
+a,O
+gonosomal,O
+mosaic,O
+parent,O
+.,O
+ , 
+Data,O
+from,O
+these,O
+four,O
+families,O
+support,O
+a,O
+simple,O
+model,O
+in,O
+which,O
+OTX2,B-Gene
+heterozygous,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mutations,O
+cause,O
+ocular,O
+malformations,O
+.,O
+ , 
+Four,O
+additional,O
+families,O
+display,O
+complex,O
+inheritance,O
+patterns,O
+,,O
+suggesting,O
+that,O
+OTX2,B-Gene
+mutations,O
+alone,O
+may,O
+not,O
+lead,O
+to,O
+consistent,O
+phenotypes,O
+.,O
+ , 
+The,O
+high,O
+incidence,O
+of,O
+mosaicism,O
+and,O
+the,O
+reduced,O
+penetrance,O
+have,O
+implications,O
+for,O
+genetic,O
+counseling,O
+.,O
+ , 
+#11845408
+An,O
+autosomal,O
+recessive,O
+form,O
+of,O
+bilateral,O
+frontoparietal,O
+polymicrogyria,O
+maps,O
+to,O
+chromosome,O
+16q12.2,O
+-,O
+21,O
+.,O
+ , 
+Polymicrogyria,O
+is,O
+a,O
+cerebral,O
+cortical,O
+malformation,O
+that,O
+is,O
+grossly,O
+characterized,O
+by,O
+excessive,O
+cortical,O
+folding,O
+and,O
+microscopically,O
+characterized,O
+by,O
+abnormal,O
+cortical,O
+layering,O
+.,O
+ , 
+Although,O
+polymicrogyria,O
+appears,O
+to,O
+have,O
+one,O
+or,O
+more,O
+genetic,O
+causes,O
+,,O
+no,O
+polymicrogyria,O
+loci,O
+have,O
+been,O
+identified,O
+.,O
+ , 
+Here,O
+we,O
+describe,O
+the,O
+clinical,O
+and,O
+radiographic,O
+features,O
+of,O
+a,O
+new,O
+genetic,O
+form,O
+of,O
+polymicrogyria,O
+and,O
+localize,O
+the,O
+responsible,O
+gene,O
+.,O
+ , 
+We,O
+studied,O
+two,O
+consanguineous,O
+Palestinian,O
+pedigrees,O
+with,O
+an,O
+autosomal,O
+recessive,O
+form,O
+of,O
+bilateral,O
+frontoparietal,O
+polymicrogyria,O
+(,O
+BFPP,O
+),O
+,,O
+using,O
+linkage,O
+analysis,O
+.,O
+ , 
+Five,O
+affected,O
+children,O
+had,O
+moderate,O
+-,O
+to,O
+-,O
+severe,O
+mental,O
+retardation,O
+,,O
+developmental,O
+delay,O
+,,O
+and,O
+esotropia,O
+,,O
+and,O
+four,O
+of,O
+the,O
+five,O
+affected,O
+children,O
+developed,O
+seizures,O
+.,O
+ , 
+Brain,O
+magnetic,O
+-,O
+resonance,O
+imaging,O
+revealed,O
+polymicrogyria,O
+that,O
+was,O
+most,O
+prominent,O
+in,O
+the,O
+frontal,O
+and,O
+parietal,O
+lobes,O
+but,O
+involved,O
+other,O
+cortical,O
+areas,O
+as,O
+well,O
+.,O
+ , 
+A,O
+genomewide,O
+linkage,O
+screen,O
+revealed,O
+a,O
+single,O
+locus,O
+that,O
+was,O
+identical,O
+by,O
+descent,O
+in,O
+affected,O
+children,O
+in,O
+both,O
+families,O
+and,O
+showed,O
+a,O
+single,O
+disease,O
+-,O
+associated,O
+haplotype,O
+,,O
+suggesting,O
+a,O
+common,O
+founder,O
+mutation,O
+.,O
+ , 
+The,O
+locus,O
+for,O
+BFPP,O
+maps,O
+to,O
+chromosome,O
+16q12.2,O
+-,O
+21,O
+,,O
+with,O
+a,O
+minimal,O
+interval,O
+of,O
+17,O
+cM.,O
+For,O
+D16S514,O
+,,O
+the,O
+maximal,O
+pooled,O
+two,O
+-,O
+point,O
+LOD,O
+score,O
+was,O
+3.98,O
+,,O
+and,O
+the,O
+maximal,O
+multipoint,O
+LOD,O
+score,O
+was,O
+4.57,O
+.,O
+ , 
+This,O
+study,O
+provides,O
+the,O
+first,O
+genetic,O
+evidence,O
+that,O
+BFPP,O
+is,O
+an,O
+autosomal,O
+recessive,O
+disorder,O
+and,O
+serves,O
+as,O
+a,O
+starting,O
+point,O
+for,O
+the,O
+identification,O
+of,O
+the,O
+responsible,O
+gene,O
+.,O
+ , 
+#8651311
+Conclusion,O
+of,O
+LOD,O
+-,O
+score,O
+analysis,O
+for,O
+family,O
+data,O
+generated,O
+under,O
+two,O
+-,O
+locus,O
+models,O
+.,O
+ , 
+The,O
+power,O
+to,O
+detect,O
+linkage,O
+by,O
+the,O
+LOD,O
+-,O
+score,O
+method,O
+is,O
+investigated,O
+here,O
+for,O
+diseases,O
+that,O
+depend,O
+on,O
+the,O
+effects,O
+of,O
+two,O
+genes,O
+.,O
+ , 
+The,O
+classical,O
+strategy,O
+is,O
+,,O
+first,O
+,,O
+to,O
+detect,O
+a,O
+major,O
+-,O
+gene,O
+(,O
+MG,O
+),O
+effect,O
+by,O
+segregation,O
+analysis,O
+and,O
+,,O
+second,O
+,,O
+to,O
+seek,O
+for,O
+linkage,O
+with,O
+genetic,O
+markers,O
+by,O
+the,O
+LOD,O
+-,O
+score,O
+method,O
+using,O
+the,O
+MG,O
+parameters,O
+.,O
+ , 
+We,O
+already,O
+showed,O
+that,O
+segregation,O
+analysis,O
+can,O
+lead,O
+to,O
+evidence,O
+for,O
+a,O
+MG,O
+effect,O
+for,O
+many,O
+two,O
+-,O
+locus,O
+models,O
+,,O
+with,O
+the,O
+estimates,O
+of,O
+the,O
+MG,O
+parameters,O
+being,O
+very,O
+different,O
+from,O
+those,O
+of,O
+the,O
+two,O
+genes,O
+involved,O
+in,O
+the,O
+disease,O
+.,O
+ , 
+We,O
+show,O
+here,O
+that,O
+use,O
+of,O
+these,O
+MG,O
+parameter,O
+estimates,O
+in,O
+the,O
+LOD,O
+-,O
+score,O
+analysis,O
+may,O
+lead,O
+to,O
+a,O
+failure,O
+to,O
+detect,O
+linkage,O
+for,O
+some,O
+two,O
+-,O
+locus,O
+models,O
+.,O
+ , 
+For,O
+these,O
+models,O
+,,O
+use,O
+of,O
+the,O
+sib,O
+-,O
+pair,O
+method,O
+gives,O
+a,O
+non,O
+-,O
+negligible,O
+increase,O
+of,O
+power,O
+to,O
+detect,O
+linkage,O
+.,O
+ , 
+The,O
+linkage,O
+-,O
+homogeneity,O
+test,O
+among,O
+subsamples,O
+differing,O
+for,O
+the,O
+familial,O
+disease,O
+distribution,O
+provides,O
+evidence,O
+of,O
+parameter,O
+misspecification,O
+,,O
+when,O
+the,O
+MG,O
+parameters,O
+are,O
+used,O
+.,O
+ , 
+Moreover,O
+,,O
+for,O
+most,O
+of,O
+the,O
+models,O
+,,O
+use,O
+of,O
+the,O
+MG,O
+parameters,O
+in,O
+LOD,O
+-,O
+score,O
+analysis,O
+leads,O
+to,O
+a,O
+large,O
+bias,O
+in,O
+estimation,O
+of,O
+the,O
+recombination,O
+fraction,O
+and,O
+sometimes,O
+also,O
+to,O
+a,O
+rejection,O
+of,O
+linkage,O
+for,O
+the,O
+true,O
+recombination,O
+fraction,O
+.,O
+ , 
+A,O
+final,O
+important,O
+point,O
+is,O
+that,O
+a,O
+strong,O
+evidence,O
+of,O
+an,O
+MG,O
+effect,O
+,,O
+obtained,O
+by,O
+segregation,O
+analysis,O
+,,O
+does,O
+not,O
+necessarily,O
+imply,O
+that,O
+linkage,O
+will,O
+be,O
+detected,O
+for,O
+at,O
+least,O
+one,O
+of,O
+the,O
+two,O
+genes,O
+,,O
+even,O
+with,O
+the,O
+true,O
+parameters,O
+and,O
+with,O
+a,O
+close,O
+informative,O
+marker,O
+.,O
+ , 
+#20137772
+Autosomal,O
+-,O
+recessive,O
+hypophosphatemic,O
+rickets,O
+is,O
+associated,O
+with,O
+an,O
+inactivation,O
+mutation,O
+in,O
+the,O
+ENPP1,B-Gene
+gene,O
+.,O
+ , 
+Human,O
+disorders,O
+of,O
+phosphate,O
+(,O
+Pi,O
+),O
+handling,O
+and,O
+hypophosphatemic,O
+rickets,O
+have,O
+been,O
+shown,O
+to,O
+result,O
+from,O
+mutations,O
+in,O
+PHEX,B-Gene
+,,I-Gene
+FGF23,B-Gene
+,,I-Gene
+and,O
+DMP1,B-Gene
+,,I-Gene
+presenting,O
+as,O
+X,O
+-,O
+linked,O
+recessive,O
+,,O
+autosomal,O
+-,O
+dominant,O
+,,O
+and,O
+autosomal,O
+-,O
+recessive,O
+patterns,O
+,,O
+respectively,O
+.,O
+ , 
+We,O
+present,O
+the,O
+identification,O
+of,O
+an,O
+inactivating,O
+mutation,O
+in,O
+the,O
+ecto,O
+-,O
+nucleotide,O
+pyrophosphatase,B-Gene
+/,I-Gene
+phosphodiesterase,I-Gene
+1,I-Gene
+(,B-Gene
+ENPP1,I-Gene
+),I-Gene
+gene,O
+causing,O
+autosomal,O
+-,O
+recessive,O
+hypophosphatemic,O
+rickets,O
+(,O
+ARHR,O
+),O
+with,O
+phosphaturia,O
+by,O
+positional,O
+cloning,O
+.,O
+ , 
+ENPP1,B-Gene
+generates,O
+inorganic,O
+pyrophosphate,O
+(,O
+PPi,O
+),O
+,,O
+an,O
+essential,O
+physiologic,O
+inhibitor,O
+of,O
+calcification,O
+,,O
+and,O
+previously,O
+described,O
+inactivating,O
+mutations,O
+in,O
+this,O
+gene,O
+were,O
+shown,O
+to,O
+cause,O
+aberrant,O
+ectopic,O
+calcification,O
+disorders,O
+,,O
+whereas,O
+no,O
+aberrant,O
+calcifications,O
+were,O
+present,O
+in,O
+our,O
+patients,O
+.,O
+ , 
+Our,O
+surprising,O
+result,O
+suggests,O
+a,O
+different,O
+pathway,O
+involved,O
+in,O
+the,O
+generation,O
+of,O
+ARHR,O
+and,O
+possible,O
+additional,O
+functions,O
+for,O
+ENPP1,B-Gene
+.,I-Gene
+ , 
+#9259197
+Geographic,O
+distribution,O
+and,O
+regional,O
+origin,O
+of,O
+272,O
+cystic,B-Gene
+fibrosis,I-Gene
+mutations,O
+in,O
+European,O
+populations,O
+.,O
+ , 
+The,O
+Biomed,O
+CF,O
+Mutation,O
+Analysis,O
+Consortium,O
+.,O
+ , 
+The,O
+geographic,O
+distribution,O
+of,O
+272,O
+cystic,O
+fibrosis,O
+(,O
+CF,O
+),O
+mutations,O
+has,O
+been,O
+studied,O
+by,O
+assessing,O
+the,O
+origin,O
+of,O
+27,177,O
+CF,O
+chromosomes,O
+from,O
+29,O
+European,O
+countries,O
+and,O
+three,O
+countries,O
+from,O
+the,O
+North,O
+of,O
+Africa,O
+.,O
+ , 
+The,O
+most,O
+common,O
+mutations,O
+are,O
+delta,B-SNP
+F308,I-SNP
+(,O
+66.8,O
+%,O
+),O
+,,O
+G542X,B-SNP
+(,O
+2.6,O
+%,O
+),O
+,,O
+N1303,B-SNP
+K,I-SNP
+(,O
+1.6,O
+%,O
+),O
+,,O
+G551D,B-SNP
+(,O
+1.5,O
+%,O
+),O
+and,O
+W1282X,B-SNP
+(,O
+1.0,O
+%,O
+),O
+.,O
+ , 
+The,O
+delta,B-SNP
+F508,I-SNP
+mutation,O
+has,O
+the,O
+highest,O
+frequency,O
+in,O
+Denmark,O
+(,O
+87.2,O
+%,O
+),O
+and,O
+the,O
+lowest,O
+in,O
+Algeria,O
+(,O
+26.3,O
+%,O
+),O
+.,O
+ , 
+Mutation,O
+G542X,B-SNP
+is,O
+common,O
+in,O
+the,O
+Mediterranean,O
+countries,O
+,,O
+with,O
+a,O
+mean,O
+frequency,O
+of,O
+6.1,O
+%,O
+.,O
+ , 
+N1303,B-SNP
+K,I-SNP
+is,O
+found,O
+in,O
+most,O
+of,O
+the,O
+western,O
+and,O
+Mediterranean,O
+countries,O
+and,O
+has,O
+the,O
+highest,O
+frequency,O
+in,O
+Tunisia,O
+(,O
+17.2,O
+%,O
+),O
+.,O
+ , 
+The,O
+wide,O
+distribution,O
+of,O
+these,O
+mutations,O
+suggests,O
+an,O
+ancient,O
+origin,O
+.,O
+ , 
+G551D,B-SNP
+is,O
+common,O
+in,O
+north,O
+-,O
+west,O
+and,O
+central,O
+Europe,O
+,,O
+but,O
+is,O
+uncommon,O
+in,O
+other,O
+parts,O
+of,O
+Europe,O
+.,O
+ , 
+W1282X,B-SNP
+has,O
+the,O
+highest,O
+frequency,O
+in,O
+Israel,O
+(,O
+36.2,O
+%,O
+),O
+,,O
+being,O
+also,O
+common,O
+in,O
+most,O
+Mediterranean,O
+countries,O
+and,O
+north,O
+Africa,O
+.,O
+ , 
+Seventeen,O
+mutation,O
+have,O
+frequencies,O
+between,O
+0.1,O
+and,O
+0.9,O
+%,O
+,,O
+1717,B-SNP
+-,I-SNP
+1G-->A,I-SNP
+(,O
+0.83,O
+%,O
+),O
+,,O
+R553X,B-SNP
+(,O
+0.75,O
+%,O
+),O
+,,O
+R1162X,B-SNP
+(,O
+0.51,O
+%,O
+),O
+,,O
+621,B-SNP
++,I-SNP
+1G-->T,I-SNP
+(,O
+0.54,O
+%,O
+),O
+and,O
+2183AA-->G,B-SNP
+(,O
+0.36,O
+%,O
+),O
+,,O
+being,O
+the,O
+most,O
+common,O
+ones,O
+.,O
+ , 
+Some,O
+mutations,O
+reach,O
+relatively,O
+high,O
+frequencies,O
+in,O
+some,O
+extended,O
+geographic,O
+regions,O
+,,O
+such,O
+as,O
+mutation,O
+394delTT,B-SNP
+in,O
+northern,O
+Europe,O
+(,O
+1.1,O
+-,O
+28.8,O
+%,O
+),O
+,,O
+R117H,B-SNP
+in,O
+northwestern,O
+Europe,O
+(,O
+1.3,O
+-,O
+3.0,O
+%,O
+),O
+,,O
+R553X,B-SNP
+in,O
+central,O
+Europe,O
+(,O
+1.1,O
+-,O
+24.4,O
+%,O
+),O
+,,O
+1717,B-SNP
+-,I-SNP
+1G-->A,I-SNP
+in,O
+Belgium,O
+and,O
+France,O
+(,O
+1.1,O
+-,O
+5.3,O
+%,O
+),O
+,,O
+and,O
+2183AA-->G,B-SNP
+in,O
+Italy,O
+and,O
+Greece,O
+(,O
+3.2,O
+%,O
+),O
+.,O
+ , 
+Other,O
+mutations,O
+are,O
+only,O
+common,O
+in,O
+small,O
+regions,O
+:,O
+T338I,B-SNP
+(,O
+Sardinia,O
+),O
+,,O
+711,B-SNP
++,I-SNP
+1G-->T,I-SNP
+(,O
+Tunisia,O
+),O
+,,O
+R1162X,B-SNP
+(,O
+Algeria,O
+and,O
+north,O
+of,O
+Italy,O
+),O
+,,O
+1609delCA,B-SNP
+(,O
+east,O
+of,O
+Spain,O
+),O
+,,O
+1811,B-SNP
++,I-SNP
+1.6kbA-->G,I-SNP
+(,O
+southeastern,O
+Spain,O
+),O
+,,O
+R1066C,B-SNP
+(,O
+Portugal,O
+),O
+,,O
+S549R,B-SNP
+(,O
+Algeria,O
+),O
+,,O
+R334W,B-SNP
+(,O
+Crete,O
+),O
+,,O
+621,B-SNP
++,I-SNP
+1G-->T,I-SNP
+(,O
+Central,O
+Greece,O
+),O
+,,O
+3849,B-SNP
++,I-SNP
+10kbC-->T,I-SNP
+(,O
+Israel,O
+),O
+,,O
+2789,B-SNP
++,I-SNP
+5G-->A,I-SNP
+(,O
+south,O
+of,O
+Greece,O
+),O
+,,O
+451,B-SNP
++,I-SNP
+1G,I-SNP
+--,I-SNP
+A,I-SNP
+(,O
+Israel,O
+),O
+,,O
+R347P,B-SNP
+(,O
+south,O
+of,O
+Bulgaria,O
+),O
+,,O
+1677delTA,B-SNP
+(,O
+south,O
+of,O
+Bulgaria,O
+and,O
+Turkey,O
+),O
+,,O
+G85E,B-SNP
+(,O
+south,O
+of,O
+Greece,O
+),O
+,,O
+R347H,B-SNP
+(,O
+Turkey,O
+),O
+,,O
+3905insT,B-SNP
+(,O
+Switzerland,O
+),O
+,,O
+1078delT,B-SNP
+(,O
+Brittany,O
+),O
+,,O
+1898,B-SNP
++,I-SNP
+1G-->A,I-SNP
+(,O
+Wales,O
+),O
+,,O
+A455E,B-SNP
+(,O
+The,O
+Netherlands,O
+),O
+,,O
+delta,B-SNP
+I507,I-SNP
+(,O
+Brittany,O
+),O
+,,O
+3659delC,B-SNP
+(,O
+Sweden,O
+),O
+and,O
+R560,B-SNP
+T,I-SNP
+(,O
+northern,O
+Ireland,O
+),O
+.,O
+ , 
+Most,O
+of,O
+these,O
+mutations,O
+must,O
+have,O
+an,O
+origin,O
+and,O
+diffusion,O
+in,O
+the,O
+specific,O
+European,O
+population,O
+subgroup,O
+.,O
+ , 
+Overall,O
+55,O
+mutations,O
+are,O
+common,O
+in,O
+one,O
+or,O
+several,O
+countries,O
+or,O
+regions,O
+of,O
+Europe,O
+and,O
+217,O
+mutations,O
+are,O
+rare,O
+with,O
+relative,O
+frequencies,O
+of,O
+lower,O
+than,O
+1,O
+%,O
+in,O
+any,O
+of,O
+these,O
+regions,O
+and,O
+countries,O
+.,O
+ , 
+This,O
+information,O
+might,O
+facilitate,O
+mutation,O
+analysis,O
+of,O
+CF,O
+in,O
+the,O
+different,O
+regions,O
+of,O
+Europe,O
+.,O
+ , 
+#14681830
+Maternally,O
+inherited,O
+aminoglycoside,O
+-,O
+induced,O
+and,O
+nonsyndromic,O
+deafness,O
+is,O
+associated,O
+with,O
+the,O
+novel,O
+C1494,B-SNP
+T,I-SNP
+mutation,O
+in,O
+the,O
+mitochondrial,B-Gene
+12S,I-Gene
+rRNA,I-Gene
+gene,O
+in,O
+a,O
+large,O
+Chinese,O
+family,O
+.,O
+ , 
+We,O
+report,O
+here,O
+the,O
+characterization,O
+of,O
+a,O
+large,O
+Chinese,O
+family,O
+with,O
+maternally,O
+transmitted,O
+aminoglycoside,O
+-,O
+induced,O
+and,O
+nonsyndromic,O
+deafness,O
+.,O
+ , 
+In,O
+the,O
+absence,O
+of,O
+aminoglycosides,O
+,,O
+some,O
+matrilineal,O
+relatives,O
+in,O
+this,O
+family,O
+exhibited,O
+late,O
+-,O
+onset,O
+/,O
+progressive,O
+deafness,O
+,,O
+with,O
+a,O
+wide,O
+range,O
+of,O
+severity,O
+and,O
+age,O
+at,O
+onset,O
+.,O
+ , 
+Notably,O
+,,O
+the,O
+average,O
+age,O
+at,O
+onset,O
+of,O
+deafness,O
+has,O
+changed,O
+from,O
+55,O
+years,O
+(,O
+generation,O
+II,O
+),O
+to,O
+10,O
+years,O
+(,O
+generation,O
+IV,O
+),O
+.,O
+ , 
+Clinical,O
+data,O
+reveal,O
+that,O
+the,O
+administration,O
+of,O
+aminoglycosides,O
+can,O
+induce,O
+or,O
+worsen,O
+deafness,O
+in,O
+matrilineal,O
+relatives,O
+.,O
+ , 
+The,O
+age,O
+at,O
+the,O
+time,O
+of,O
+drug,O
+administration,O
+appears,O
+to,O
+be,O
+correlated,O
+with,O
+the,O
+severity,O
+of,O
+hearing,O
+loss,O
+experienced,O
+by,O
+affected,O
+individuals,O
+.,O
+ , 
+Sequence,O
+analysis,O
+of,O
+mitochondrial,O
+DNA,O
+in,O
+this,O
+pedigree,O
+identified,O
+a,O
+homoplasmic,O
+C,O
+-,O
+to,O
+-,O
+T,O
+transition,O
+at,O
+position,O
+1494,O
+(,B-SNP
+C1494,I-SNP
+T,I-SNP
+),I-SNP
+in,O
+the,O
+12S,B-Gene
+rRNA,I-Gene
+gene,O
+.,O
+ , 
+The,O
+C1494,B-SNP
+T,I-SNP
+mutation,O
+is,O
+expected,O
+to,O
+form,O
+a,O
+novel,O
+U1494,O
+-,O
+1555A,O
+base,O
+pair,O
+,,O
+which,O
+is,O
+in,O
+the,O
+same,O
+position,O
+as,O
+the,O
+C1494,O
+-,O
+1555,O
+G,O
+pair,O
+created,O
+by,O
+the,O
+deafness,O
+-,O
+associated,O
+A1555,B-SNP
+G,I-SNP
+mutation,O
+,,O
+at,O
+the,O
+highly,O
+conserved,O
+A,O
+site,O
+of,O
+12S,B-Gene
+rRNA,I-Gene
+.,I-Gene
+ , 
+Exposure,O
+to,O
+a,O
+high,O
+concentration,O
+of,O
+paromomycin,O
+or,O
+neomycin,O
+caused,O
+a,O
+variable,O
+but,O
+significant,O
+average,O
+increase,O
+in,O
+doubling,O
+time,O
+in,O
+lymphoblastoid,O
+cell,O
+lines,O
+derived,O
+from,O
+four,O
+symptomatic,O
+and,O
+two,O
+asymptomatic,O
+individuals,O
+in,O
+this,O
+family,O
+carrying,O
+the,O
+C1494,B-SNP
+T,I-SNP
+mutation,O
+when,O
+compared,O
+to,O
+four,O
+control,O
+cell,O
+lines,O
+.,O
+ , 
+Furthermore,O
+,,O
+a,O
+significant,O
+decrease,O
+in,O
+the,O
+rate,O
+of,O
+total,O
+oxygen,O
+consumption,O
+was,O
+observed,O
+in,O
+the,O
+mutant,O
+cell,O
+lines,O
+.,O
+ , 
+Thus,O
+,,O
+our,O
+data,O
+strongly,O
+support,O
+the,O
+idea,O
+that,O
+the,O
+A,O
+site,O
+of,O
+mitochondrial,O
+12S,O
+rRNA,O
+is,O
+the,O
+primary,O
+target,O
+for,O
+aminoglycoside,O
+-,O
+induced,O
+deafness,O
+.,O
+ , 
+These,O
+results,O
+also,O
+strongly,O
+suggest,O
+that,O
+the,O
+nuclear,O
+background,O
+plays,O
+a,O
+role,O
+in,O
+the,O
+aminoglycoside,O
+ototoxicity,O
+and,O
+in,O
+the,O
+development,O
+of,O
+the,O
+deafness,O
+phenotype,O
+associated,O
+with,O
+the,O
+C1494,B-SNP
+T,I-SNP
+mutation,O
+in,O
+the,O
+mitochondrial,B-Gene
+12S,I-Gene
+rRNA,I-Gene
+gene,O
+.,O
+ , 
+#16088919
+ATP1A2,B-Gene
+mutations,O
+in,O
+11,O
+families,O
+with,O
+familial,O
+hemiplegic,O
+migraine,O
+.,O
+ , 
+Familial,O
+hemiplegic,O
+migraine,O
+(,O
+FHM,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+form,O
+of,O
+migraine,O
+with,O
+aura,O
+.,O
+ , 
+The,O
+disease,O
+is,O
+caused,O
+by,O
+mutations,O
+of,O
+at,O
+least,O
+three,O
+genes,O
+among,O
+which,O
+two,O
+have,O
+been,O
+identified,O
+,,O
+CACNA1A,B-Gene
+and,O
+ATP1A2,B-Gene
+.,I-Gene
+ , 
+Very,O
+few,O
+mutations,O
+have,O
+been,O
+identified,O
+so,O
+far,O
+in,O
+ATP1A2,B-Gene
+.,I-Gene
+ , 
+We,O
+screened,O
+the,O
+coding,O
+sequence,O
+of,O
+ATP1A2,B-Gene
+in,O
+26,O
+unrelated,O
+FHM,O
+probands,O
+in,O
+whom,O
+CACNA1A,O
+screening,B-Gene
+was,O
+negative,O
+.,O
+ , 
+A,O
+total,O
+of,O
+eight,O
+different,O
+mutations,O
+were,O
+identified,O
+in,O
+11,O
+of,O
+the,O
+probands,O
+(,O
+41,O
+%,O
+),O
+,,O
+including,O
+six,O
+missense,O
+mutations,O
+,,O
+one,O
+small,O
+deletion,O
+leading,O
+to,O
+a,O
+frameshift,O
+,,O
+and,O
+one,O
+in,O
+frame,O
+deletion,O
+.,O
+ , 
+All,O
+were,O
+novel,O
+mutations,O
+.,O
+ , 
+Two,O
+mutations,O
+were,O
+recurrent,O
+,,O
+in,O
+three,O
+and,O
+two,O
+families,O
+,,O
+respectively,O
+.,O
+ , 
+Genotyping,O
+of,O
+94,O
+relatives,O
+of,O
+these,O
+11,O
+probands,O
+identified,O
+47,O
+mutation,O
+carriers,O
+,,O
+among,O
+whom,O
+36,O
+were,O
+clinically,O
+affected,O
+.,O
+ , 
+Sequencing,O
+of,O
+all,O
+23,O
+exons,O
+in,O
+an,O
+ethnically,O
+matched,O
+panel,O
+detected,O
+only,O
+one,O
+exonic,O
+coding,O
+polymorphism,O
+.,O
+ , 
+#19327736
+TMEM126A,B-Gene
+,,I-Gene
+encoding,O
+a,O
+mitochondrial,O
+protein,O
+,,O
+is,O
+mutated,O
+in,O
+autosomal,O
+-,O
+recessive,O
+nonsyndromic,O
+optic,O
+atrophy,O
+.,O
+ , 
+Nonsyndromic,O
+autosomal,O
+-,O
+recessive,O
+optic,O
+neuropathies,O
+are,O
+rare,O
+conditions,O
+of,O
+unknown,O
+genetic,O
+and,O
+molecular,O
+origin,O
+.,O
+ , 
+Using,O
+an,O
+approach,O
+of,O
+whole,O
+-,O
+genome,O
+homozygosity,O
+mapping,O
+and,O
+positional,O
+cloning,O
+,,O
+we,O
+have,O
+identified,O
+the,O
+first,O
+gene,O
+,,O
+to,O
+our,O
+knowledge,O
+,,O
+responsible,O
+for,O
+this,O
+condition,O
+,,O
+TMEM126A,B-Gene
+,,I-Gene
+in,O
+a,O
+large,O
+multiplex,O
+inbred,O
+Algerian,O
+family,O
+and,O
+subsequently,O
+in,O
+three,O
+other,O
+families,O
+originating,O
+from,O
+the,O
+Maghreb,O
+.,O
+ , 
+TMEM126A,B-Gene
+is,O
+conserved,O
+in,O
+higher,O
+eukaryotes,O
+and,O
+encodes,O
+a,O
+transmembrane,O
+mitochondrial,O
+protein,O
+of,O
+unknown,O
+function,O
+,,O
+supporting,O
+the,O
+view,O
+that,O
+mitochondrial,O
+dysfunction,O
+may,O
+be,O
+a,O
+hallmark,O
+of,O
+inherited,O
+optic,O
+neuropathies,O
+including,O
+isolated,O
+autosomal,O
+-,O
+recessive,O
+forms,O
+.,O
+ , 
+#15024732
+Analysis,O
+of,O
+the,O
+allele,O
+-,O
+specific,O
+expression,O
+of,O
+the,O
+mismatch,O
+repair,O
+gene,O
+MLH1,B-Gene
+using,O
+a,O
+simple,O
+DHPLC,O
+-,O
+Based,O
+Method,O
+.,O
+ , 
+Quantitative,O
+measures,O
+of,O
+allele,O
+-,O
+specific,O
+gene,O
+expression,O
+allow,O
+the,O
+indirect,O
+detection,O
+of,O
+mutations,O
+or,O
+sequence,O
+variants,O
+in,O
+regulatory,O
+elements,O
+or,O
+in,O
+other,O
+non,O
+-,O
+coding,O
+regions,O
+that,O
+may,O
+result,O
+in,O
+significant,O
+physiological,O
+or,O
+pathological,O
+changes,O
+of,O
+gene,O
+expression,O
+and,O
+may,O
+contribute,O
+to,O
+Mendelian,O
+or,O
+multifactorial,O
+disorders,O
+.,O
+ , 
+We,O
+have,O
+devised,O
+a,O
+simple,O
+method,O
+,,O
+based,O
+on,O
+RT,O
+-,O
+PCR,O
+and,O
+single,O
+nucleotide,O
+primer,O
+extension,O
+(,O
+SNuPE,O
+),O
+with,O
+unlabelled,O
+dideoxynucleotides,O
+,,O
+followed,O
+by,O
+DHPLC,O
+(,O
+denaturing,O
+high,O
+performance,O
+liquid,O
+chromatography,O
+),O
+.,O
+ , 
+We,O
+established,O
+optimal,O
+conditions,O
+for,O
+separation,O
+of,O
+the,O
+extended,O
+products,O
+corresponding,O
+to,O
+the,O
+alleles,O
+of,O
+the,O
+c.655A,B-SNP
+>,I-SNP
+G,I-SNP
+(,B-SNP
+p.,I-SNP
+Ile219Val,I-SNP
+),I-SNP
+SNP,O
+,,O
+which,O
+is,O
+the,O
+most,O
+frequent,O
+exonic,O
+polymorphism,O
+of,O
+MLH1,B-Gene
+.,I-Gene
+ , 
+We,O
+then,O
+genotyped,O
+99,O
+unrelated,O
+control,O
+subjects,O
+and,O
+measured,O
+the,O
+allele,O
+-,O
+specific,O
+MLH1,B-Gene
+expression,O
+in,O
+the,O
+40,O
+heterozygous,O
+controls,O
+found,O
+in,O
+this,O
+group,O
+.,O
+ , 
+This,O
+method,O
+allowed,O
+us,O
+to,O
+define,O
+a,O
+narrow,O
+range,O
+of,O
+normal,O
+biallelic,O
+expression,O
+of,O
+MLH1,B-Gene
+,,I-Gene
+each,O
+allele,O
+contributing,O
+between,O
+44.7,O
+%,O
+and,O
+55.3,O
+%,O
+of,O
+the,O
+total,O
+expression,O
+.,O
+ , 
+We,O
+then,O
+measured,O
+the,O
+allele,O
+-,O
+specific,O
+expression,O
+in,O
+hereditary,O
+nonpolyposis,O
+colorectal,O
+cancer,O
+(,O
+HNPCC,O
+),O
+patients,O
+with,O
+MLH1,B-Gene
+mRNAs,O
+bearing,O
+different,O
+stop,O
+-,O
+codon,O
+or,O
+frame,O
+-,O
+shift,O
+mutations,O
+,,O
+or,O
+in,O
+-,O
+frame,O
+deletions,O
+,,O
+in,O
+order,O
+to,O
+detect,O
+the,O
+effects,O
+of,O
+nonsense,O
+-,O
+mediated,O
+mRNA,O
+decay,O
+(,O
+NMD,O
+),O
+.,O
+ , 
+Defects,O
+that,O
+induce,O
+mRNA,O
+instability,O
+were,O
+identified,O
+unambiguously,O
+and,O
+the,O
+data,O
+were,O
+consistent,O
+with,O
+current,O
+models,O
+of,O
+NMD,O
+.,O
+ , 
+This,O
+study,O
+provides,O
+a,O
+sensitive,O
+tool,O
+to,O
+identify,O
+indirectly,O
+MLH1,B-Gene
+defects,O
+that,O
+may,O
+escape,O
+detection,O
+in,O
+genomic,O
+DNA,O
+screenings,O
+but,O
+result,O
+in,O
+a,O
+quantitative,O
+change,O
+at,O
+the,O
+mRNA,O
+level,O
+.,O
+ , 
+#16773577
+Familial,O
+osteoarthritis,O
+of,O
+the,O
+hip,O
+joint,O
+associated,O
+with,O
+acetabular,O
+dysplasia,O
+maps,O
+to,O
+chromosome,O
+13q,O
+.,O
+ , 
+Genetic,O
+factors,O
+have,O
+been,O
+implicated,O
+in,O
+osteoarthritis,O
+(,O
+OA,O
+),O
+,,O
+particularly,O
+in,O
+OA,O
+of,O
+the,O
+hip,O
+joint,O
+(,O
+hip,O
+OA,O
+),O
+.,O
+ , 
+Several,O
+instances,O
+of,O
+familial,O
+hip,O
+OA,O
+that,O
+show,O
+distinctive,O
+modes,O
+of,O
+inheritance,O
+but,O
+that,O
+differ,O
+from,O
+chondrodysplasia,O
+have,O
+been,O
+reported,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+the,O
+characterization,O
+of,O
+a,O
+large,O
+Japanese,O
+family,O
+with,O
+an,O
+inherited,O
+disease,O
+of,O
+the,O
+hip,O
+that,O
+is,O
+indistinguishable,O
+from,O
+common,O
+hip,O
+OA,O
+,,O
+as,O
+evidenced,O
+by,O
+clinical,O
+symptoms,O
+and,O
+radiographs,O
+of,O
+the,O
+joint,O
+.,O
+ , 
+This,O
+family,O
+contained,O
+eight,O
+patients,O
+in,O
+4,O
+generations,O
+.,O
+ , 
+Affected,O
+individuals,O
+develop,O
+pain,O
+in,O
+the,O
+hip,O
+joint,O
+during,O
+adolescence,O
+,,O
+and,O
+the,O
+disease,O
+progresses,O
+to,O
+severe,O
+crippling,O
+before,O
+age,O
+60,O
+years,O
+.,O
+ , 
+Patients,O
+generally,O
+are,O
+in,O
+good,O
+health,O
+,,O
+height,O
+is,O
+not,O
+reduced,O
+,,O
+and,O
+there,O
+is,O
+no,O
+extraskeletal,O
+involvement,O
+suggestive,O
+of,O
+chondrodysplasia,O
+.,O
+ , 
+The,O
+skeletal,O
+change,O
+is,O
+bilateral,O
+acetabular,O
+dysplasia,O
+followed,O
+by,O
+OA,O
+,,O
+which,O
+occurs,O
+after,O
+age,O
+approximately,O
+40,O
+years,O
+and,O
+is,O
+indistinguishable,O
+from,O
+idiopathic,O
+nonfamilial,O
+dysplastic,O
+hip,O
+OA,O
+.,O
+ , 
+This,O
+trait,O
+shows,O
+autosomal,O
+dominant,O
+inheritance,O
+,,O
+with,O
+a,O
+considerably,O
+consistent,O
+phenotype,O
+.,O
+ , 
+Genomewide,O
+screening,O
+revealed,O
+linkage,O
+at,O
+chromosome,O
+13q22,O
+,,O
+and,O
+haplotype,O
+analysis,O
+narrowed,O
+the,O
+locus,O
+to,O
+a,O
+6.0,O
+-,O
+cM,O
+interval,O
+between,O
+markers,O
+D13S1296,O
+and,O
+D13S162,O
+,,O
+with,O
+a,O
+maximal,O
+multipoint,O
+LOD,O
+score,O
+of,O
+3.57,O
+.,O
+ , 
+The,O
+family,O
+described,O
+here,O
+represents,O
+a,O
+novel,O
+genetic,O
+entity,O
+as,O
+a,O
+monogenic,O
+form,O
+of,O
+hip,O
+OA,O
+.,O
+ , 
+Its,O
+further,O
+characterization,O
+can,O
+aid,O
+in,O
+elucidating,O
+the,O
+etiology,O
+and,O
+pathogenesis,O
+of,O
+a,O
+common,O
+idiopathic,O
+form,O
+of,O
+OA,O
+.,O
+ , 
+#17847000
+Cowden,O
+syndrome,O
+-,O
+affected,O
+patients,O
+with,O
+PTEN,B-Gene
+promoter,O
+mutations,O
+demonstrate,O
+abnormal,O
+protein,O
+translation,O
+.,O
+ , 
+Germline,O
+mutations,O
+of,O
+PTEN,B-Gene
+(,O
+phosphatase,O
+and,O
+tensin,O
+homolog,O
+deleted,O
+on,O
+chromosome,O
+10,O
+),O
+are,O
+associated,O
+with,O
+the,O
+multihamartomatous,O
+disorder,O
+Cowden,O
+syndrome,O
+(,O
+CS,O
+),O
+.,O
+ , 
+Moreover,O
+,,O
+patients,O
+with,O
+CS,O
+with,O
+germline,O
+PTEN,B-Gene
+promoter,O
+mutations,O
+have,O
+aberrant,O
+PTEN,B-Gene
+protein,O
+expression,O
+and,O
+an,O
+increased,O
+frequency,O
+of,O
+breast,O
+cancer,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+examined,O
+the,O
+downstream,O
+effect,O
+of,O
+five,O
+PTEN,B-Gene
+promoter,O
+variants,O
+(,B-SNP
+-861G,I-SNP
+/,I-SNP
+T,I-SNP
+,,I-SNP
+-853C,B-SNP
+/,I-SNP
+G,I-SNP
+,,I-SNP
+-834C,B-SNP
+/,I-SNP
+T,I-SNP
+,,I-SNP
+-798G,B-SNP
+/,I-SNP
+C,I-SNP
+,,I-SNP
+and,O
+-764G,B-SNP
+/,I-SNP
+A,I-SNP
+),I-SNP
+that,O
+are,O
+not,O
+within,O
+any,O
+known,O
+cis,O
+-,O
+acting,O
+regulatory,O
+elements,O
+.,O
+ , 
+Clinically,O
+,,O
+all,O
+five,O
+of,O
+these,O
+patients,O
+have,O
+been,O
+given,O
+diagnoses,O
+of,O
+breast,O
+,,O
+thyroid,O
+,,O
+and/or,O
+endometrial,O
+cancer,O
+.,O
+ , 
+We,O
+demonstrated,O
+that,O
+protein,O
+binding,O
+to,O
+the,O
+PTEN,B-Gene
+promoter,O
+(,O
+-893,O
+to,O
+-755,O
+),O
+was,O
+not,O
+altered,O
+in,O
+the,O
+five,O
+variants,O
+when,O
+compared,O
+with,O
+the,O
+wild,O
+-,O
+type,O
+(,O
+WT,O
+),O
+promoter,O
+.,O
+ , 
+However,O
+,,O
+reporter,O
+assays,O
+indicated,O
+that,O
+three,O
+of,O
+the,O
+variants,O
+(,B-SNP
+-861G,I-SNP
+/,I-SNP
+T,I-SNP
+,,I-SNP
+-853C,B-SNP
+/,I-SNP
+G,I-SNP
+,,I-SNP
+and,O
+-764G,B-SNP
+/,I-SNP
+A,I-SNP
+),I-SNP
+demonstrated,O
+an,O
+~50,O
+%,O
+decrease,O
+in,O
+luciferase,O
+activity,O
+compared,O
+with,O
+the,O
+WT,O
+construct,O
+.,O
+ , 
+PTEN,B-Gene
+messenger,O
+RNA,O
+(,O
+mRNA,O
+),O
+levels,O
+were,O
+not,O
+altered,O
+in,O
+these,O
+variants,O
+,,O
+whereas,O
+secondary,O
+structure,O
+predictions,O
+indicated,O
+that,O
+different,O
+PTEN,B-Gene
+5,O
+',O
+untranslated,O
+region,O
+transcript,O
+-,O
+folding,O
+patterns,O
+exist,O
+in,O
+three,O
+variants,O
+,,O
+suggesting,O
+an,O
+inhibition,O
+of,O
+protein,O
+translation,O
+.,O
+ , 
+This,O
+was,O
+confirmed,O
+by,O
+PTEN,B-Gene
+protein,O
+analysis,O
+.,O
+ , 
+These,O
+data,O
+indicate,O
+that,O
+variants,O
+causing,O
+large,O
+mRNA,O
+secondary,O
+structure,O
+alterations,O
+result,O
+in,O
+an,O
+inhibition,O
+of,O
+protein,O
+translation,O
+and,O
+a,O
+decrease,O
+in,O
+PTEN,B-Gene
+protein,O
+expression,O
+.,O
+ , 
+These,O
+data,O
+emphasize,O
+the,O
+importance,O
+of,O
+PTEN,B-Gene
+promoter,O
+nucleotide,O
+variations,O
+and,O
+their,O
+ability,O
+to,O
+lead,O
+to,O
+CS,O
+progression,O
+by,O
+a,O
+novel,O
+regulatory,O
+mechanism,O
+.,O
+ , 
+Importantly,O
+,,O
+these,O
+patients,O
+have,O
+a,O
+high,O
+prevalence,O
+of,O
+breast,O
+,,O
+thyroid,O
+,,O
+and,O
+endometrial,O
+malignancies,O
+;,O
+thus,O
+,,O
+understanding,O
+of,O
+the,O
+mechanism,O
+of,O
+PTEN,B-Gene
+dysfunction,O
+in,O
+these,O
+patients,O
+will,O
+lead,O
+to,O
+more,O
+-,O
+sensitive,O
+molecular,O
+diagnostic,O
+and,O
+predictive,O
+testing,O
+and,O
+,,O
+ultimately,O
+,,O
+to,O
+rational,O
+targeted,O
+therapies,O
+to,O
+treat,O
+or,O
+prevent,O
+malignancy,O
+.,O
+ , 
+#1598916
+Uniparental,O
+disomy,O
+15,O
+resulting,O
+from,O
+",O
+correction,O
+",O
+of,O
+an,O
+initial,O
+trisomy,O
+15,O
+.,O
+ , 
+#17285591
+Partial,O
+duplication,O
+at,O
+AZFc,B-Gene
+on,O
+the,O
+Y,O
+chromosome,O
+is,O
+a,O
+risk,O
+factor,O
+for,O
+impaired,O
+spermatogenesis,O
+in,O
+Han,O
+Chinese,O
+in,O
+Taiwan,O
+.,O
+ , 
+The,O
+Azoospermia,O
+Factor,O
+c,O
+(,O
+AZFc,O
+),O
+region,O
+on,O
+the,O
+Y,O
+chromosome,O
+long,O
+arm,O
+is,O
+one,O
+of,O
+the,O
+least,O
+stable,O
+regions,O
+in,O
+the,O
+human,O
+genome,O
+.,O
+ , 
+It,O
+consists,O
+almost,O
+entirely,O
+of,O
+very,O
+long,O
+repeats,O
+and,O
+is,O
+prone,O
+to,O
+rearrangement,O
+.,O
+ , 
+Numerous,O
+structures,O
+at,O
+AZFc,O
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+been,O
+identified,O
+,,O
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+some,O
+of,O
+them,O
+have,O
+been,O
+reported,O
+to,O
+be,O
+associated,O
+with,O
+male,O
+infertility,O
+.,O
+ , 
+We,O
+screened,O
+580,O
+Han,O
+Chinese,O
+in,O
+Taiwan,O
+for,O
+AZFc,O
+deletion,O
+and,O
+duplication,O
+using,O
+three,O
+PCR,O
+assays,O
+,,O
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+characterized,O
+the,O
+DAZ,O
+genes,O
+in,O
+selected,O
+subjects,O
+with,O
+additional,O
+Southern,O
+analyses,O
+.,O
+ , 
+About,O
+9.5,O
+%,O
+of,O
+our,O
+subjects,O
+have,O
+AZFc,O
+partial,O
+deletion,O
+,,O
+2.8,O
+%,O
+have,O
+partial,O
+deletion,O
+followed,O
+by,O
+duplication,O
+,,O
+and,O
+1.7,O
+%,O
+have,O
+partial,O
+duplication,O
+.,O
+ , 
+The,O
+overall,O
+rearrangement,O
+frequencies,O
+vary,O
+significantly,O
+between,O
+different,O
+Y,O
+chromosome,O
+haplogroups,O
+(,O
+Yhgs,O
+),O
+,,O
+ranging,O
+from,O
+2.9,O
+%,O
+in,O
+O3e,O
+to,O
+100,O
+%,O
+in,O
+N,O
+and,O
+Q.,O
+All,O
+individuals,O
+in,O
+Yhg,O
+-,O
+N,O
+lack,O
+the,O
+sY1191,O
+marker,O
+,,O
+but,O
+one,O
+out,O
+of,O
+three,O
+of,O
+them,O
+actually,O
+have,O
+four,O
+DAZ,O
+genes,O
+,,O
+indicating,O
+further,O
+duplication,O
+after,O
+the,O
+b2,O
+/,O
+b3,O
+deletion,O
+.,O
+ , 
+Our,O
+additional,O
+screening,O
+of,O
+142,O
+oligospermic,O
+men,O
+and,O
+107,O
+fertile,O
+controls,O
+found,O
+no,O
+significant,O
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+in,O
+the,O
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+of,O
+the,O
+gr,O
+/,O
+gr,O
+and,O
+the,O
+b2,O
+/,O
+b3,O
+deletion,O
+.,O
+ , 
+However,O
+,,O
+the,O
+frequency,O
+of,O
+AZFc,O
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+duplication,O
+in,O
+the,O
+infertile,O
+group,O
+(,O
+7.0,O
+%,O
+),O
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+significantly,O
+higher,O
+than,O
+that,O
+in,O
+the,O
+fertile,O
+control,O
+group,O
+(,O
+0.9,O
+%,O
+),O
+and,O
+the,O
+general,O
+Taiwanese,O
+population,O
+(,O
+1.7,O
+%,O
+),O
+.,O
+ , 
+Our,O
+results,O
+indicate,O
+that,O
+AZFc,O
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+deletion,O
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+partial,O
+duplication,O
+are,O
+common,O
+polymorphisms,O
+in,O
+Han,O
+Chinese,O
+,,O
+and,O
+that,O
+the,O
+AZFc,O
+partial,O
+duplication,O
+,,O
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+not,O
+the,O
+AZFc,O
+partial,O
+deletion,O
+,,O
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+a,O
+risk,O
+factor,O
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+male,O
+infertility,O
+in,O
+the,O
+Taiwanese,O
+population,O
+.,O
+ , 
+#15776426
+Mutational,O
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+of,O
+the,O
+NPHP4,B-Gene
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+Nephronophthisis,O
+(,O
+NPH,O
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+genetic,O
+cause,O
+for,O
+end,O
+-,O
+stage,O
+renal,O
+disease,O
+in,O
+the,O
+first,O
+two,O
+decades,O
+of,O
+life,O
+.,O
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+Mutations,O
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+genes,O
+(,O
+NPHP1,O
+,,O
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+,,O
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+3,O
+),O
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+.,O
+ , 
+Extrarenal,O
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+,,O
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+as,O
+retinitis,O
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+(,O
+Senior,O
+-,O
+Loken,O
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+,,O
+SLS,O
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+type,O
+Cogan,O
+.,O
+ , 
+Recently,O
+,,O
+we,O
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+a,O
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+gene,O
+(,B-Gene
+NPHP4,I-Gene
+),I-Gene
+as,O
+mutated,O
+in,O
+NPH,B-Gene
+.,I-Gene
+ , 
+To,O
+date,O
+,,O
+a,O
+total,O
+of,O
+only,O
+13,O
+different,O
+NPHP4,B-Gene
+mutations,O
+have,O
+been,O
+described,O
+.,O
+ , 
+To,O
+determine,O
+the,O
+frequency,O
+of,O
+NPHP4,B-Gene
+mutations,O
+,,O
+we,O
+performed,O
+mutational,O
+analysis,O
+by,O
+direct,O
+sequencing,O
+of,O
+all,O
+30,O
+NPHP4,B-Gene
+exons,O
+in,O
+250,O
+different,O
+patients,O
+with,O
+isolated,O
+NPH,O
+,,O
+SLS,O
+,,O
+or,O
+Cogan,O
+syndrome,O
+ascertained,O
+worldwide,O
+over,O
+14,O
+years,O
+.,O
+ , 
+We,O
+identified,O
+23,O
+novel,O
+NPHP4,B-Gene
+sequence,O
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+in,O
+26/250,O
+different,O
+patients,O
+(,O
+10,O
+%,O
+),O
+.,O
+ , 
+Interestingly,O
+,,O
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+compound,O
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+of,O
+NPHP4,B-Gene
+in,O
+only,O
+6/250,O
+different,O
+patients,O
+(,O
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+%,O
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+but,O
+only,O
+one,O
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+NPHP4,B-Gene
+sequence,O
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+in,O
+20/250,O
+different,O
+patients,O
+(,O
+8,O
+%,O
+),O
+.,O
+ , 
+In,O
+the,O
+six,O
+patients,O
+with,O
+two,O
+NPHP4,B-Gene
+mutations,O
+,,O
+5/8,O
+mutations,O
+(,O
+63,O
+%,O
+),O
+were,O
+likely,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mutations,O
+,,O
+whereas,O
+in,O
+the,O
+20,O
+patients,O
+with,O
+only,O
+one,O
+sequence,O
+variant,O
+,,O
+only,O
+1/20,O
+(,O
+5,O
+%,O
+),O
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+a,O
+likely,O
+loss,O
+-,O
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+-,O
+function,O
+(,O
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+,,O
+truncating,O
+),O
+mutation,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+:,O
+i,O
+),O
+two,O
+recessive,O
+mutations,O
+in,O
+NPHP4,B-Gene
+are,O
+a,O
+rare,O
+cause,O
+of,O
+nephronophthisis,O
+;,O
+ii,O
+),O
+single,O
+heterozygous,O
+NPHP4,B-Gene
+sequence,O
+variants,O
+are,O
+three,O
+times,O
+more,O
+prevalent,O
+than,O
+two,O
+recessive,O
+mutations,O
+;,O
+iii,O
+),O
+there,O
+is,O
+no,O
+genotype,O
+/,O
+phenotype,O
+correlation,O
+;,O
+iv,O
+),O
+there,O
+must,O
+exist,O
+further,O
+genes,O
+causing,O
+nephronophthisis,O
+,,O
+since,O
+in,O
+224/250,O
+(,O
+90,O
+%,O
+),O
+patients,O
+,,O
+no,O
+sequence,O
+variants,O
+in,O
+either,O
+of,O
+the,O
+four,O
+NPH,B-Gene
+genes,O
+were,O
+detected,O
+.,O
+ , 
+#8352283
+Better,O
+data,O
+analysis,O
+through,O
+data,O
+exploration,O
+.,O
+ , 
+#21922597
+Fine,O
+-,O
+tiling,O
+array,O
+CGH,O
+to,O
+improve,O
+diagnostics,O
+for,O
+α-,O
+and,O
+β,O
+-,O
+thalassemia,O
+rearrangements,O
+.,O
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+Implementation,O
+of,O
+multiplex,O
+ligation,O
+-,O
+dependent,O
+probe,O
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+(,O
+MLPA,O
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+for,O
+thalassemia,O
+causing,O
+deletions,O
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+lead,O
+to,O
+the,O
+detection,O
+of,O
+new,O
+rearrangements,O
+.,O
+ , 
+Knowledge,O
+of,O
+the,O
+exact,O
+breakpoint,O
+sequences,O
+should,O
+give,O
+more,O
+insight,O
+into,O
+the,O
+molecular,O
+mechanisms,O
+underlying,O
+these,O
+rearrangements,O
+,,O
+and,O
+would,O
+facilitate,O
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+design,O
+of,O
+gap,O
+-,O
+PCRs,O
+.,O
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+We,O
+have,O
+designed,O
+a,O
+custom,O
+fine,O
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+array,O
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+oligonucleotides,O
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+complete,O
+globin,O
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+.,O
+ , 
+We,O
+hybridized,O
+27,O
+DNA,O
+samples,O
+containing,O
+newly,O
+identified,O
+deletions,O
+and,O
+nine,O
+positive,O
+controls,O
+.,O
+ , 
+We,O
+designed,O
+specific,O
+primers,O
+to,O
+amplify,O
+relatively,O
+short,O
+fragments,O
+containing,O
+the,O
+breakpoint,O
+sequence,O
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+analyzed,O
+these,O
+by,O
+direct,O
+sequencing,O
+.,O
+ , 
+Results,O
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+nine,O
+positive,O
+controls,O
+showed,O
+that,O
+array,O
+comparative,O
+genomic,O
+hybridization,O
+(,O
+aCGH,O
+),O
+is,O
+suitable,O
+to,O
+detect,O
+small,O
+and,O
+large,O
+rearrangements,O
+.,O
+ , 
+We,O
+were,O
+able,O
+to,O
+locate,O
+all,O
+breakpoints,O
+to,O
+a,O
+region,O
+of,O
+approximately,O
+2,O
+kb,O
+.,O
+ , 
+We,O
+designed,O
+breakpoint,O
+primers,O
+for,O
+22,O
+cases,O
+and,O
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+successful,O
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+19,O
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+.,O
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+For,O
+12,O
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+these,O
+,,O
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+the,O
+breakpoints,O
+were,O
+determined,O
+.,O
+ , 
+Seven,O
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+these,O
+deletions,O
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+reported,O
+before,O
+.,O
+ , 
+aCGH,O
+is,O
+a,O
+valuable,O
+tool,O
+for,O
+high,O
+-,O
+resolution,O
+breakpoint,O
+characterization,O
+.,O
+ , 
+The,O
+combination,O
+of,O
+MLPA,O
+and,O
+aCGH,O
+has,O
+lead,O
+to,O
+relatively,O
+cheap,O
+and,O
+easy,O
+to,O
+perform,O
+PCR,O
+assays,O
+,,O
+which,O
+might,O
+be,O
+of,O
+use,O
+for,O
+laboratories,O
+as,O
+an,O
+alternative,O
+for,O
+MLPA,O
+in,O
+populations,O
+where,O
+only,O
+a,O
+limited,O
+number,O
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+specific,O
+deletions,O
+occur,O
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+high,O
+frequency,O
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+#10712225
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+of,O
+a,O
+maternal,O
+allele,O
+with,O
+36,O
+CAG,O
+repeats,O
+causes,O
+Huntington,O
+disease,O
+in,O
+two,O
+sisters,O
+.,O
+ , 
+Large,O
+intergenerational,O
+repeat,O
+expansions,O
+of,O
+the,O
+CAG,O
+trinucleotide,O
+repeat,O
+in,O
+the,O
+HD,B-Gene
+gene,O
+have,O
+been,O
+well,O
+documented,O
+for,O
+the,O
+male,O
+germline,O
+.,O
+ , 
+We,O
+describe,O
+a,O
+recurrent,O
+large,O
+expansion,O
+of,O
+a,O
+maternal,O
+allele,O
+with,O
+36,O
+CAG,O
+repeats,O
+(,O
+to,O
+66,O
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+57,O
+repeats,O
+,,O
+respectively,O
+,,O
+in,O
+two,O
+daughters,O
+),O
+associated,O
+with,O
+onset,O
+of,O
+Huntington,O
+disease,O
+(,O
+HD,O
+),O
+in,O
+the,O
+second,O
+and,O
+third,O
+decade,O
+in,O
+a,O
+family,O
+without,O
+history,O
+of,O
+HD,O
+.,O
+ , 
+Our,O
+findings,O
+give,O
+evidence,O
+of,O
+a,O
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+in,O
+the,O
+unaffected,O
+mother,O
+.,O
+ , 
+We,O
+hypothesize,O
+that,O
+large,O
+expansions,O
+also,O
+occur,O
+in,O
+the,O
+female,O
+germline,O
+and,O
+that,O
+a,O
+negative,O
+selection,O
+of,O
+oocytes,O
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+long,O
+repeats,O
+might,O
+explain,O
+the,O
+different,O
+instability,O
+behavior,O
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+ , 
+#9718357
+NTBC,B-Gene
+and,O
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+ , 
+#9633815
+Spectrum,O
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+fumarylacetoacetate,B-Gene
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+tyrosinemia,O
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+Hereditary,O
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+(,O
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+(,O
+FAH,O
+),O
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+ , 
+To,O
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+molecular,O
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+of,O
+tyrosinemia,O
+,,O
+the,O
+geographic,O
+distribution,O
+and,O
+the,O
+genotype,O
+-,O
+phenotype,O
+relationship,O
+,,O
+we,O
+have,O
+analyzed,O
+the,O
+FAH,O
+genotype,O
+of,O
+25,O
+HT1,O
+patients,O
+.,O
+ , 
+Mutation,O
+screening,O
+was,O
+performed,O
+by,O
+PCR,O
+amplification,O
+of,O
+exons,O
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+-,O
+14,O
+of,O
+the,O
+FAH,B-Gene
+gene,O
+,,O
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+by,O
+SSCP,O
+analysis,O
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+direct,O
+sequencing,O
+of,O
+the,O
+amplified,O
+exons,O
+.,O
+ , 
+Fourteen,O
+different,O
+mutations,O
+were,O
+found,O
+,,O
+of,O
+which,O
+seven,O
+were,O
+novel,O
+,,O
+viz,O
+.,O
+ , 
+three,O
+missense,O
+mutations,O
+(,B-SNP
+G158D,I-SNP
+,,I-SNP
+P261L,B-SNP
+,,I-SNP
+F405H,B-SNP
+),I-SNP
+,,O
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+deletion,O
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+three,O
+nucleotides,O
+causing,O
+a,O
+deletion,O
+of,O
+serine,O
+(,B-SNP
+DEL366S,I-SNP
+),I-SNP
+and,O
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+splice,O
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+:,O
+IVS2,B-SNP
++,I-SNP
+1(g,I-SNP
+-,I-SNP
+t,I-SNP
+),I-SNP
+,,I-SNP
+IVS6,B-SNP
+-,I-SNP
+1(g,I-SNP
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+c,I-SNP
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+,,I-SNP
+IVS8,B-SNP
+-,I-SNP
+1(g,I-SNP
+-,I-SNP
+c,I-SNP
+),I-SNP
+.,I-SNP
+ , 
+The,O
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+IVS6,B-SNP
+-,I-SNP
+1(g,I-SNP
+-,I-SNP
+t,I-SNP
+),I-SNP
+and,O
+IVS12,B-SNP
++,I-SNP
+5(g,I-SNP
+-,I-SNP
+a,I-SNP
+),I-SNP
+were,O
+frequently,O
+found,O
+in,O
+countries,O
+around,O
+the,O
+Mediterranean,O
+and,O
+northwestern,O
+Europe,O
+,,O
+respectively,O
+.,O
+ , 
+No,O
+clear,O
+correlation,O
+between,O
+the,O
+genotype,O
+and,O
+the,O
+three,O
+major,O
+HT1,O
+subtypes,O
+could,O
+be,O
+established,O
+.,O
+ , 
+#17503333
+RAB23,B-Gene
+mutations,O
+in,O
+Carpenter,O
+syndrome,O
+imply,O
+an,O
+unexpected,O
+role,O
+for,O
+hedgehog,O
+signaling,O
+in,O
+cranial,O
+-,O
+suture,O
+development,O
+and,O
+obesity,O
+.,O
+ , 
+Carpenter,O
+syndrome,O
+is,O
+a,O
+pleiotropic,O
+disorder,O
+with,O
+autosomal,O
+recessive,O
+inheritance,O
+,,O
+the,O
+cardinal,O
+features,O
+of,O
+which,O
+include,O
+craniosynostosis,O
+,,O
+polysyndactyly,O
+,,O
+obesity,O
+,,O
+and,O
+cardiac,O
+defects,O
+.,O
+ , 
+Using,O
+homozygosity,O
+mapping,O
+,,O
+we,O
+found,O
+linkage,O
+to,O
+chromosome,O
+6p12.1,O
+-,O
+q12,O
+and,O
+,,O
+in,O
+15,O
+independent,O
+families,O
+,,O
+identified,O
+five,O
+different,O
+mutations,O
+(,O
+four,O
+truncating,O
+and,O
+one,O
+missense,O
+),O
+in,O
+RAB23,B-Gene
+,,I-Gene
+which,O
+encodes,O
+a,O
+member,O
+of,O
+the,O
+RAB,O
+guanosine,O
+triphosphatase,O
+(,O
+GTPase,O
+),O
+family,O
+of,O
+vesicle,O
+transport,O
+proteins,O
+and,O
+acts,O
+as,O
+a,O
+negative,O
+regulator,O
+of,O
+hedgehog,O
+(,O
+HH,O
+),O
+signaling,O
+.,O
+ , 
+In,O
+10,O
+patients,O
+,,O
+the,O
+disease,O
+was,O
+caused,O
+by,O
+homozygosity,O
+for,O
+the,O
+same,O
+nonsense,O
+mutation,O
+,,O
+L145X,B-SNP
+,,I-SNP
+that,O
+resides,O
+on,O
+a,O
+common,O
+haplotype,O
+,,O
+indicative,O
+of,O
+a,O
+founder,O
+effect,O
+in,O
+patients,O
+of,O
+northern,O
+European,O
+descent,O
+.,O
+ , 
+Surprisingly,O
+,,O
+nonsense,O
+mutations,O
+of,O
+Rab23,B-Gene
+in,O
+open,O
+brain,O
+mice,O
+cause,O
+recessive,O
+embryonic,O
+lethality,O
+with,O
+neural,O
+-,O
+tube,O
+defects,O
+,,O
+suggesting,O
+a,O
+species,O
+difference,O
+in,O
+the,O
+requirement,O
+for,O
+RAB23,B-Gene
+during,O
+early,O
+development,O
+.,O
+ , 
+The,O
+discovery,O
+of,O
+RAB23,B-Gene
+mutations,O
+in,O
+patients,O
+with,O
+Carpenter,O
+syndrome,O
+implicates,O
+HH,O
+signaling,O
+in,O
+cranial,O
+-,O
+suture,O
+biogenesis,O
+--,O
+an,O
+unexpected,O
+finding,O
+,,O
+given,O
+that,O
+craniosynostosis,O
+is,O
+not,O
+usually,O
+associated,O
+with,O
+mutations,O
+of,O
+other,O
+HH,O
+-,O
+pathway,O
+components,O
+--,O
+and,O
+provides,O
+a,O
+new,O
+molecular,O
+target,O
+for,O
+studies,O
+of,O
+obesity,O
+.,O
+ , 
+#10094553
+Identification,O
+of,O
+twenty,O
+-,O
+one,O
+new,O
+mutations,O
+in,O
+the,O
+factor,B-Gene
+IX,I-Gene
+gene,O
+by,O
+SSCP,O
+analysis,O
+.,O
+ , 
+In,O
+this,O
+study,O
+we,O
+have,O
+analyzed,O
+the,O
+factor,B-Gene
+IX,I-Gene
+gene,O
+from,O
+84,O
+hemophilia,O
+B,O
+patients,O
+of,O
+Spanish,O
+origin,O
+.,O
+ , 
+It,O
+included,O
+single,O
+-,O
+strand,O
+conformation,O
+polymorphism,O
+(,O
+SSCP,O
+),O
+analysis,O
+of,O
+all,O
+functional,O
+regions,O
+of,O
+the,O
+gene,O
+and,O
+further,O
+sequencing,O
+of,O
+all,O
+fragments,O
+showing,O
+abnormal,O
+migration,O
+.,O
+ , 
+In,O
+76,O
+patients,O
+(,O
+90.4,O
+%,O
+),O
+,,O
+it,O
+was,O
+possible,O
+to,O
+identify,O
+molecular,O
+alterations,O
+leading,O
+to,O
+the,O
+appearance,O
+of,O
+the,O
+disease,O
+.,O
+ , 
+Twenty,O
+-,O
+one,O
+new,O
+mutations,O
+were,O
+identified,O
+,,O
+including,O
+13,O
+missense,O
+mutations,O
+,,O
+two,O
+nonsense,O
+mutations,O
+,,O
+three,O
+splice,O
+-,O
+site,O
+mutations,O
+,,O
+one,O
+frameshift,O
+deletion,O
+,,O
+one,O
+frameshift,O
+insertion,O
+,,O
+and,O
+one,O
+non,O
+-,O
+frameshift,O
+deletion,O
+.,O
+ , 
+The,O
+approach,O
+appears,O
+to,O
+be,O
+very,O
+suitable,O
+for,O
+molecular,O
+diagnosis,O
+of,O
+hemophilia,O
+B.,O
+ , 
+#7717407
+Human,B-Gene
+T,I-Gene
+-,I-Gene
+cell,I-Gene
+receptor,I-Gene
+V,I-Gene
+beta,I-Gene
+gene,O
+polymorphism,O
+and,O
+multiple,O
+sclerosis,O
+.,O
+ , 
+Population,O
+-,O
+based,O
+genetic,O
+associations,O
+have,O
+been,O
+reported,O
+between,O
+RFLPs,O
+detected,O
+with,O
+probes,O
+corresponding,O
+to,O
+the,O
+genes,O
+encoding,O
+the,O
+beta,O
+chain,O
+of,O
+the,O
+T,O
+-,O
+cell,O
+receptor,O
+for,O
+antigen,O
+(,O
+TCRB,O
+),O
+and,O
+a,O
+variety,O
+of,O
+autoimmune,O
+disorders,O
+.,O
+ , 
+In,O
+the,O
+case,O
+of,O
+multiple,O
+sclerosis,O
+(,O
+MS,O
+),O
+,,O
+these,O
+studies,O
+have,O
+localized,O
+a,O
+putative,O
+disease,O
+-,O
+associated,O
+gene,O
+to,O
+a,O
+region,O
+of,O
+approximately,O
+110,O
+kb,O
+in,O
+length,O
+,,O
+located,O
+within,O
+the,O
+TCRB,B-Gene
+locus,O
+.,O
+ , 
+In,O
+the,O
+current,O
+study,O
+,,O
+all,O
+14,O
+known,O
+TCRBV,O
+(,O
+variable,O
+region,O
+),O
+genes,O
+within,O
+the,O
+region,O
+of,O
+localization,O
+were,O
+mapped,O
+and,O
+identified,O
+.,O
+ , 
+The,O
+nucleotide,O
+sequences,O
+of,O
+these,O
+genes,O
+were,O
+determined,O
+in,O
+a,O
+panel,O
+of,O
+six,O
+MS,O
+patients,O
+and,O
+six,O
+healthy,O
+controls,O
+,,O
+who,O
+were,O
+human,O
+-,O
+leukocyte,O
+antigen,O
+and,O
+TCRB,O
+-,O
+RFLP,O
+haplotype,O
+matched,O
+.,O
+ , 
+Nine,O
+of,O
+the,O
+14,O
+TCRBV,O
+genes,O
+studied,O
+showed,O
+evidence,O
+of,O
+polymorphism,O
+.,O
+ , 
+PCR,O
+-,O
+based,O
+assays,O
+for,O
+each,O
+of,O
+these,O
+polymorphic,O
+genes,O
+were,O
+developed,O
+,,O
+and,O
+allele,O
+and,O
+genotype,O
+frequencies,O
+were,O
+determined,O
+in,O
+a,O
+panel,O
+of,O
+DNA,O
+samples,O
+from,O
+48,O
+MS,O
+patients,O
+and,O
+60,O
+control,O
+individuals,O
+.,O
+ , 
+No,O
+significant,O
+differences,O
+in,O
+allele,O
+,,O
+genotype,O
+,,O
+or,O
+phenotype,O
+frequencies,O
+were,O
+observed,O
+between,O
+the,O
+MS,O
+patients,O
+and,O
+controls,O
+for,O
+any,O
+of,O
+the,O
+14,O
+TCRBV,O
+-,O
+gene,O
+polymorphisms,O
+studied,O
+.,O
+ , 
+In,O
+light,O
+of,O
+the,O
+extensive,O
+linkage,O
+disequilibrium,O
+across,O
+the,O
+region,O
+studied,O
+,,O
+the,O
+saturating,O
+numbers,O
+of,O
+polymorphisms,O
+examined,O
+,,O
+and,O
+the,O
+direct,O
+sequence,O
+analysis,O
+of,O
+all,O
+BV,O
+genes,O
+in,O
+the,O
+region,O
+,,O
+these,O
+results,O
+suggest,O
+that,O
+it,O
+is,O
+unlikely,O
+that,O
+germ,O
+-,O
+line,O
+polymorphism,O
+in,O
+the,O
+TCRBV,O
+locus,O
+makes,O
+a,O
+major,O
+contribution,O
+to,O
+MS,O
+susceptibility.(ABSTRACT,O
+TRUNCATED,O
+AT,O
+250,O
+WORDS,O
+),O
+ , 
+#8318991
+Hunter,O
+syndrome,O
+:,O
+gene,O
+deletions,O
+and,O
+rearrangements,O
+.,O
+ , 
+#9012405
+A,O
+mutation,O
+in,O
+the,O
+XPB,B-Gene
+/,I-Gene
+ERCC3,I-Gene
+DNA,O
+repair,O
+transcription,O
+gene,O
+,,O
+associated,O
+with,O
+trichothiodystrophy,O
+.,O
+ , 
+Trichothiodystrophy,O
+(,O
+TTD,O
+),O
+is,O
+a,O
+rare,O
+,,O
+autosomal,O
+recessive,O
+disorder,O
+characterized,O
+by,O
+sulfur,O
+-,O
+deficient,O
+brittle,O
+hair,O
+and,O
+nails,O
+,,O
+mental,O
+retardation,O
+,,O
+impaired,O
+sexual,O
+development,O
+,,O
+and,O
+ichthyosis,O
+.,O
+ , 
+Photosensitivity,O
+has,O
+been,O
+reported,O
+in,O
+approximately,O
+50,O
+%,O
+of,O
+the,O
+cases,O
+,,O
+but,O
+no,O
+skin,O
+cancer,O
+is,O
+associated,O
+with,O
+TTD,O
+.,O
+ , 
+Virtually,O
+all,O
+photosensitive,O
+TTD,O
+patients,O
+have,O
+a,O
+deficiency,O
+in,O
+the,O
+nucleotide,O
+excision,O
+repair,O
+(,O
+NER,O
+),O
+of,O
+UV,O
+-,O
+induced,O
+DNA,O
+damage,O
+that,O
+is,O
+indistinguishable,O
+from,O
+that,O
+of,O
+xeroderma,O
+pigmentosum,O
+(,O
+XP,O
+),O
+complementation,O
+group,O
+D,O
+(,O
+XP,O
+-,O
+D,O
+),O
+patients,O
+.,O
+ , 
+DNA,O
+repair,O
+defects,O
+in,O
+XP,O
+-,O
+D,O
+are,O
+associated,O
+with,O
+two,O
+additional,O
+,,O
+quite,O
+different,O
+diseases,O
+;,O
+XP,O
+,,O
+a,O
+sun,O
+-,O
+sensitive,O
+and,O
+cancer,O
+-,O
+prone,O
+repair,O
+disorder,O
+,,O
+and,O
+Cockayne,O
+syndrome,O
+(,O
+CS,O
+),O
+,,O
+a,O
+photosensitive,O
+condition,O
+characterized,O
+by,O
+physical,O
+and,O
+mental,O
+retardation,O
+and,O
+wizened,O
+facial,O
+appearance,O
+.,O
+ , 
+One,O
+photosensitive,O
+TTD,O
+case,O
+constitutes,O
+a,O
+new,O
+repair,O
+-,O
+deficient,O
+complementation,O
+group,O
+,,O
+TTD,O
+-,O
+A.,O
+Remarkably,O
+,,O
+both,O
+TTD,O
+-,O
+A,O
+and,O
+XP,O
+-,O
+D,O
+defects,O
+are,O
+associated,O
+with,O
+subunits,O
+of,O
+TFIIH,O
+,,O
+a,O
+basal,O
+transcription,O
+factor,O
+with,O
+a,O
+second,O
+function,O
+in,O
+DNA,O
+repair,O
+.,O
+ , 
+Thus,O
+,,O
+mutations,O
+in,O
+TFIIH,O
+components,O
+may,O
+,,O
+on,O
+top,O
+of,O
+a,O
+repair,O
+defect,O
+,,O
+also,O
+cause,O
+transcriptional,O
+insufficiency,O
+,,O
+which,O
+may,O
+explain,O
+part,O
+of,O
+the,O
+non,O
+-,O
+XP,O
+clinical,O
+features,O
+of,O
+TTD,O
+.,O
+ , 
+Besides,O
+XPD,O
+and,O
+TTDA,O
+,,O
+the,O
+XPB,B-Gene
+gene,O
+product,O
+is,O
+also,O
+part,O
+of,O
+TFIIH,O
+.,O
+ , 
+To,O
+date,O
+,,O
+three,O
+patients,O
+with,O
+the,O
+remarkable,O
+conjunction,O
+of,O
+XP,O
+and,O
+CS,O
+but,O
+not,O
+TTD,O
+have,O
+been,O
+assigned,O
+to,O
+XP,O
+complementation,O
+group,O
+B,O
+(,O
+XP,O
+-,O
+B,O
+),O
+.,O
+ , 
+Here,O
+we,O
+present,O
+the,O
+characterization,O
+of,O
+the,O
+NER,O
+defect,O
+in,O
+two,O
+mild,O
+TTD,O
+patients,O
+(,O
+TTD6VI,O
+and,O
+TTD4VI,O
+),O
+and,O
+confirm,O
+the,O
+assignment,O
+to,O
+X,O
+-,O
+PB,O
+.,O
+ , 
+The,O
+causative,O
+mutation,O
+was,O
+found,O
+to,O
+be,O
+a,O
+single,O
+base,O
+substitution,O
+resulting,O
+in,O
+a,O
+missense,O
+mutation,O
+(,B-SNP
+T119P,I-SNP
+),I-SNP
+in,O
+a,O
+region,O
+of,O
+the,O
+XPB,B-Gene
+protein,O
+completely,O
+conserved,O
+in,O
+yeast,O
+,,O
+Drosophila,O
+,,O
+mouse,O
+,,O
+and,O
+man,O
+.,O
+ , 
+These,O
+findings,O
+define,O
+a,O
+third,O
+TTD,O
+complementation,O
+group,O
+,,O
+extend,O
+the,O
+clinical,O
+heterogeneity,O
+associated,O
+with,O
+XP,O
+-,O
+B,O
+,,O
+stress,O
+the,O
+exclusive,O
+relationship,O
+between,O
+TTD,O
+and,O
+mutations,O
+in,O
+subunits,O
+of,O
+repair,O
+/,O
+transcription,O
+factor,O
+TFIIH,B-Gene
+,,I-Gene
+and,O
+strongly,O
+support,O
+the,O
+concept,O
+of,O
+",O
+transcription,O
+syndromes,O
+.,O
+",O
+ , 
+#20333758
+Functional,O
+analysis,O
+of,O
+mutations,O
+in,O
+the,O
+ATP,O
+loop,O
+of,O
+the,O
+Wilson,O
+disease,O
+copper,O
+transporter,O
+,,O
+ , 
+ATP7B.,B-Gene
+Wilson,O
+disease,O
+(,O
+WND,O
+),O
+is,O
+an,O
+autosomal,O
+recessive,O
+disorder,O
+resulting,O
+from,O
+mutation,O
+of,O
+ATP7B.,B-Gene
+Transport,O
+of,O
+copper,O
+by,O
+ATP7B,B-Gene
+from,O
+the,O
+trans,O
+-,O
+Golgi,O
+of,O
+hepatocytes,O
+into,O
+apical,O
+membrane,O
+-,O
+trafficked,O
+vesicles,O
+for,O
+excretion,O
+in,O
+the,O
+bile,O
+is,O
+the,O
+major,O
+means,O
+of,O
+copper,O
+elimination,O
+from,O
+the,O
+body,O
+.,O
+ , 
+Although,O
+copper,O
+is,O
+an,O
+essential,O
+nutrient,O
+,,O
+homeostasis,O
+must,O
+be,O
+carefully,O
+maintained,O
+.,O
+ , 
+If,O
+homeostasis,O
+is,O
+disrupted,O
+,,O
+copper,O
+can,O
+accumulate,O
+within,O
+the,O
+liver,O
+,,O
+kidney,O
+,,O
+cornea,O
+,,O
+and/or,O
+brain,O
+.,O
+ , 
+The,O
+range,O
+of,O
+organs,O
+affected,O
+leads,O
+to,O
+clinical,O
+heterogeneity,O
+and,O
+difficulty,O
+in,O
+WND,O
+diagnosis,O
+.,O
+ , 
+Sequencing,O
+of,O
+ATP7B,B-Gene
+is,O
+an,O
+important,O
+adjunct,O
+for,O
+diagnosis,O
+but,O
+has,O
+led,O
+to,O
+the,O
+discovery,O
+of,O
+many,O
+novel,O
+missense,O
+variants,O
+.,O
+ , 
+Although,O
+prediction,O
+programs,O
+are,O
+available,O
+,,O
+functional,O
+characterization,O
+is,O
+essential,O
+for,O
+determining,O
+the,O
+consequence,O
+of,O
+novel,O
+variants,O
+.,O
+ , 
+We,O
+have,O
+tested,O
+12,O
+missense,O
+variants,O
+localized,O
+to,O
+the,O
+ATP,O
+loop,O
+of,O
+ATP7B,B-Gene
+and,O
+compared,O
+three,O
+predictive,O
+programs,O
+(,O
+SIFT,O
+,,O
+PolyPhen,O
+,,O
+and,O
+Align,O
+-,O
+GVGD,O
+),O
+.,O
+ , 
+We,O
+found,O
+p.,B-SNP
+L1043P,I-SNP
+,,I-SNP
+p.,B-SNP
+G1000R,I-SNP
+,,I-SNP
+p.,B-SNP
+G1101R,I-SNP
+,,I-SNP
+p.,B-SNP
+I1102,I-SNP
+T,I-SNP
+,,I-SNP
+p.,B-SNP
+V1239,I-SNP
+G,I-SNP
+,,I-SNP
+and,O
+p.,B-SNP
+D1267V,I-SNP
+deleterious,O
+;,O
+p.,B-SNP
+G1176E,I-SNP
+and,O
+p.,B-SNP
+G1287S,I-SNP
+intermediate,O
+;,O
+p.,B-SNP
+E1173,I-SNP
+G,I-SNP
+temperature,O
+sensitive,O
+;,O
+p.,B-SNP
+T991,I-SNP
+M,I-SNP
+and,O
+p.,B-SNP
+I1148,I-SNP
+T,I-SNP
+mild,O
+;,O
+and,O
+p.,B-SNP
+R1228,I-SNP
+T,I-SNP
+functioning,O
+as,O
+wild,O
+type,O
+.,O
+ , 
+We,O
+found,O
+that,O
+SIFT,O
+most,O
+often,O
+agreed,O
+with,O
+functional,O
+data,O
+(,O
+92,O
+%,O
+),O
+,,O
+compared,O
+with,O
+PolyPhen,O
+(,O
+83,O
+%,O
+),O
+and,O
+Align,O
+-,O
+GVGD,O
+(,O
+67,O
+%,O
+),O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+variants,O
+found,O
+to,O
+negatively,O
+affect,O
+function,O
+likely,O
+contribute,O
+to,O
+the,O
+WND,O
+phenotype,O
+in,O
+patients,O
+.,O
+ , 
+#20186687
+Loss,O
+-,O
+of,O
+-,O
+function,O
+of,O
+MYO5B,B-Gene
+is,O
+the,O
+main,O
+cause,O
+of,O
+microvillus,O
+inclusion,O
+disease,O
+:,O
+15,O
+novel,O
+mutations,O
+and,O
+a,O
+CaCo-2,O
+RNAi,O
+cell,O
+model,O
+.,O
+ , 
+Autosomal,O
+recessive,O
+microvillus,O
+inclusion,O
+disease,O
+(,O
+MVID,O
+),O
+is,O
+characterized,O
+by,O
+an,O
+intractable,O
+diarrhea,O
+starting,O
+within,O
+the,O
+first,O
+few,O
+weeks,O
+of,O
+life,O
+.,O
+ , 
+The,O
+hallmarks,O
+of,O
+MVID,O
+are,O
+a,O
+lack,O
+of,O
+microvilli,O
+on,O
+the,O
+surface,O
+of,O
+villous,O
+enterocytes,O
+,,O
+occurrence,O
+of,O
+intracellular,O
+vacuoles,O
+lined,O
+by,O
+microvilli,O
+(,O
+microvillus,O
+inclusions,O
+),O
+,,O
+and,O
+the,O
+cytoplasmic,O
+accumulation,O
+of,O
+periodic,O
+acid,O
+-,O
+Schiff,O
+(,O
+PAS)-positive,O
+vesicles,O
+in,O
+enterocytes,O
+.,O
+ , 
+Recently,O
+,,O
+we,O
+identified,O
+mutations,O
+in,O
+MYO5B,B-Gene
+,,I-Gene
+encoding,O
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+unconventional,O
+type,O
+Vb,O
+myosin,O
+motor,O
+protein,O
+,,O
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+a,O
+first,O
+cohort,O
+of,O
+nine,O
+MVID,O
+patients,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+identified,O
+15,O
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+nonsense,O
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+missense,O
+mutations,O
+in,O
+MYO5B,B-Gene
+in,O
+11,O
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+patients,O
+.,O
+ , 
+Fluorescence,O
+microscopy,O
+,,O
+Western,O
+blotting,O
+,,O
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+electron,O
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+applied,O
+to,O
+analyze,O
+the,O
+effects,O
+of,O
+MYO5B,B-Gene
+siRNA,O
+knock,O
+-,O
+down,O
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+,,O
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+border,O
+possessing,O
+CaCo-2,O
+cells,O
+.,O
+ , 
+Loss,O
+of,O
+surface,O
+microvilli,O
+,,O
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+formation,O
+of,O
+microvillus,O
+inclusions,O
+,,O
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+enrichment,O
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+PAS,O
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+positive,O
+endomembrane,O
+compartments,O
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+induced,O
+in,O
+polarized,O
+,,O
+filter,O
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+grown,O
+CaCo-2,O
+cells,O
+,,O
+following,O
+MYO5B,B-Gene
+knock,O
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+down,O
+.,O
+ , 
+Our,O
+data,O
+indicate,O
+that,O
+MYO5B,O
+mutations,B-Gene
+are,O
+a,O
+major,O
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+of,O
+microvillus,O
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+MYO5B,B-Gene
+knock,O
+-,O
+down,O
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+of,O
+the,O
+cellular,O
+phenotype,O
+in,O
+vitro,O
+,,O
+thus,O
+independently,O
+showing,O
+loss,O
+of,O
+MYO5B,B-Gene
+function,O
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+microvillus,O
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+disease,O
+.,O
+ , 
+#15747259
+No,O
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+evidence,O
+of,O
+linkage,O
+for,O
+restless,O
+legs,O
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+chromosome,O
+9p,O
+.,O
+ , 
+#1301933
+Rapid,O
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+genomic,O
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+saliva,O
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+polymerase,O
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+.,O
+ , 
+#19944400
+Deletions,O
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+LRRC50,B-Gene
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+.,O
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+Genetic,O
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+destructive,O
+airway,O
+disease,O
+,,O
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+,,O
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+,,O
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+,,O
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+dyskinesia,O
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+PCD,O
+),O
+.,O
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+The,O
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+(,O
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+regulation,O
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+.,O
+ , 
+Here,O
+,,O
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+that,O
+large,O
+genomic,O
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+,,O
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+LRRC50,B-Gene
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+Functional,O
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+LRRC50,B-Gene
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+DNAH5-,B-Gene
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+containing,O
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+On,O
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+basis,O
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+these,O
+findings,O
+,,O
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+assume,O
+that,O
+LRRC50,B-Gene
+plays,O
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+#7977348
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+In,O
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+#11139239
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+Total,O
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+These,O
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+5,O
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+Splicing,O
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+A,O
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+The,O
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+;,O
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+5,O
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+6,O
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+;,O
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+(,O
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+),O
+A368fsX24,B-SNP
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+c.1102delGinsTTATAC,I-SNP
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+,,O
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+IVS4,B-SNP
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+1G,I-SNP
+>,I-SNP
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+c.639,I-SNP
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+.,O
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+Q279R,B-SNP
+mutation,O
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+she,O
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+the,O
+classic,O
+phenotype,O
+since,O
+the,O
+age,O
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+8,O
+years,O
+,,O
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+case,O
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+into,O
+women,O
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+severe,O
+phenotype,O
+observed,O
+in,O
+classically,O
+affected,O
+males,O
+.,O
+ , 
+Mutation,O
+analysis,O
+provided,O
+precise,O
+identification,O
+for,O
+30,O
+heterozygotes,O
+among,O
+female,O
+relatives,O
+and,O
+detection,O
+of,O
+a,O
+de,O
+novo,O
+mutation,O
+.,O
+ , 
+The,O
+molecular,O
+studies,O
+on,O
+Spanish,O
+Fabry,O
+patients,O
+here,O
+reported,O
+further,O
+contribute,O
+to,O
+the,O
+identification,O
+of,O
+new,O
+mutations,O
+in,O
+this,O
+disease,O
+,,O
+and,O
+allow,O
+reliable,O
+detection,O
+of,O
+heterozygotes,O
+which,O
+has,O
+consequences,O
+for,O
+genetic,O
+counselling,O
+and,O
+for,O
+treatment,O
+.,O
+ , 
+#18674750
+WW,O
+-,O
+domain,O
+-,O
+containing,O
+oxidoreductase,O
+is,O
+associated,O
+with,O
+low,O
+plasma,O
+HDL,O
+-,O
+C,O
+levels,O
+.,O
+ , 
+Low,O
+serum,O
+HDL,O
+-,O
+cholesterol,O
+(,O
+HDL,O
+-,O
+C,O
+),O
+is,O
+a,O
+major,O
+risk,O
+factor,O
+for,O
+coronary,O
+artery,O
+disease,O
+.,O
+ , 
+We,O
+performed,O
+targeted,O
+genotyping,O
+of,O
+a,O
+12.4,O
+Mb,O
+linked,O
+region,O
+on,O
+16q,O
+to,O
+test,O
+for,O
+association,O
+with,O
+low,O
+HDL,O
+-,O
+C,O
+by,O
+using,O
+a,O
+regional,O
+-,O
+tag,O
+SNP,O
+strategy,O
+.,O
+ , 
+We,O
+identified,O
+one,O
+SNP,O
+,,O
+rs2548861,O
+,,O
+in,O
+the,O
+WW,B-Gene
+-,I-Gene
+domain,I-Gene
+-,I-Gene
+containing,I-Gene
+oxidoreductase,I-Gene
+(,B-Gene
+WWOX,I-Gene
+),I-Gene
+gene,O
+with,O
+region,O
+-,O
+wide,O
+significance,O
+for,O
+low,O
+HDL,O
+-,O
+C,O
+in,O
+dyslipidemic,O
+families,O
+of,O
+Mexican,O
+and,O
+European,O
+descent,O
+and,O
+in,O
+low,O
+-,O
+HDL,O
+-,O
+C,O
+cases,O
+and,O
+controls,O
+of,O
+European,O
+descent,O
+(,O
+p,O
+=,O
+6.9,O
+x,O
+10(-7,O
+),O
+),O
+.,O
+ , 
+We,O
+extended,O
+our,O
+investigation,O
+to,O
+the,O
+population,O
+level,O
+by,O
+using,O
+two,O
+independent,O
+unascertained,O
+population,O
+-,O
+based,O
+Finnish,O
+cohorts,O
+,,O
+the,O
+cross,O
+-,O
+sectional,O
+METSIM,O
+cohort,O
+of,O
+4,463,O
+males,O
+and,O
+the,O
+prospective,O
+Young,O
+Finns,O
+cohort,O
+of,O
+2,265,O
+subjects,O
+.,O
+ , 
+The,O
+combined,O
+analysis,O
+provided,O
+p,O
+=,O
+4,O
+x,O
+10(-4,O
+),O
+to,O
+2,O
+x,O
+10(-5,O
+),O
+.,O
+ , 
+Importantly,O
+,,O
+in,O
+the,O
+prospective,O
+cohort,O
+,,O
+we,O
+observed,O
+a,O
+significant,O
+longitudinal,O
+association,O
+of,O
+rs2548861,O
+with,O
+HDL,O
+-,O
+C,O
+levels,O
+obtained,O
+at,O
+four,O
+different,O
+time,O
+points,O
+over,O
+21,O
+years,O
+(,O
+p,O
+=,O
+0.003,O
+),O
+,,O
+and,O
+the,O
+T,O
+risk,O
+allele,O
+explained,O
+1.5,O
+%,O
+of,O
+the,O
+variance,O
+in,O
+HDL,O
+-,O
+C,O
+levels,O
+.,O
+ , 
+The,O
+rs2548861,O
+resides,O
+in,O
+a,O
+highly,O
+conserved,O
+region,O
+in,O
+intron,O
+8,O
+of,O
+WWOX,B-Gene
+.,I-Gene
+ , 
+Results,O
+from,O
+our,O
+in,O
+vitro,O
+reporter,O
+assay,O
+and,O
+electrophoretic,O
+mobility,O
+-,O
+shift,O
+assay,O
+demonstrate,O
+that,O
+this,O
+region,O
+functions,O
+as,O
+a,O
+cis,O
+-,O
+regulatory,O
+element,O
+whose,O
+associated,O
+rs2548861,O
+SNP,O
+has,O
+a,O
+specific,O
+allelic,O
+effect,O
+and,O
+that,O
+the,O
+region,O
+forms,O
+an,O
+allele,O
+-,O
+specific,O
+DNA,O
+-,O
+nuclear,O
+-,O
+factor,O
+complex,O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+analyses,O
+of,O
+9,798,O
+subjects,O
+show,O
+significant,O
+association,O
+between,O
+HDL,O
+-,O
+C,O
+and,O
+a,O
+WWOX,B-Gene
+variant,O
+with,O
+an,O
+allele,O
+-,O
+specific,O
+cis,O
+-,O
+regulatory,O
+function,O
+.,O
+ , 
+#10441582
+A,O
+second,O
+gene,O
+for,O
+autosomal,O
+dominant,O
+Möbius,O
+syndrome,O
+is,O
+localized,O
+to,O
+chromosome,O
+10q,O
+,,O
+in,O
+a,O
+Dutch,O
+family,O
+.,O
+ , 
+Möbius,O
+syndrome,O
+(,O
+MIM,O
+157900,O
+),O
+consists,O
+of,O
+a,O
+congenital,O
+paresis,O
+or,O
+paralysis,O
+of,O
+the,O
+VIIth,O
+(,O
+facial,O
+),O
+cranial,O
+nerve,O
+,,O
+frequently,O
+accompanied,O
+by,O
+dysfunction,O
+of,O
+other,O
+cranial,O
+nerves,O
+.,O
+ , 
+The,O
+abducens,O
+nerve,O
+is,O
+typically,O
+affected,O
+,,O
+and,O
+often,O
+,,O
+also,O
+,,O
+the,O
+hypoglossal,O
+nerve,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+orofacial,O
+and,O
+limb,O
+malformations,O
+,,O
+defects,O
+of,O
+the,O
+musculoskeletal,O
+system,O
+,,O
+and,O
+mental,O
+retardation,O
+are,O
+seen,O
+in,O
+patients,O
+with,O
+Möbius,O
+syndrome,O
+.,O
+ , 
+Most,O
+cases,O
+are,O
+sporadic,O
+,,O
+but,O
+familial,O
+recurrence,O
+can,O
+occur,O
+.,O
+ , 
+Different,O
+modes,O
+of,O
+inheritance,O
+are,O
+suggested,O
+by,O
+different,O
+pedigrees,O
+.,O
+ , 
+Genetic,O
+heterogeneity,O
+of,O
+Möbius,O
+syndrome,O
+has,O
+been,O
+suggested,O
+by,O
+cytogenetic,O
+studies,O
+and,O
+linkage,O
+analysis,O
+.,O
+ , 
+Previously,O
+,,O
+we,O
+identified,O
+a,O
+locus,O
+on,O
+chromosome,O
+3q21,O
+-,O
+22,O
+,,O
+in,O
+a,O
+large,O
+Dutch,O
+family,O
+with,O
+Möbius,O
+syndrome,O
+consisting,O
+essentially,O
+of,O
+autosomal,O
+dominant,O
+asymmetric,O
+bilateral,O
+facial,O
+paresis,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+linkage,O
+analysis,O
+in,O
+a,O
+second,O
+large,O
+Dutch,O
+family,O
+with,O
+autosomal,O
+dominant,O
+inherited,O
+facial,O
+paresis,O
+.,O
+ , 
+After,O
+exclusion,O
+of,O
+>,O
+90,O
+%,O
+of,O
+the,O
+genome,O
+,,O
+we,O
+identified,O
+the,O
+locus,O
+on,O
+the,O
+long,O
+arm,O
+of,O
+chromosome,O
+10,O
+in,O
+this,O
+family,O
+,,O
+demonstrating,O
+genetic,O
+heterogeneity,O
+of,O
+this,O
+condition,O
+.,O
+ , 
+The,O
+reduced,O
+penetrance,O
+suggests,O
+that,O
+at,O
+least,O
+some,O
+of,O
+the,O
+sporadic,O
+cases,O
+might,O
+be,O
+familial,O
+.,O
+ , 
+#19664745
+Dominant,O
+renin,B-Gene
+gene,O
+mutations,O
+associated,O
+with,O
+early,O
+-,O
+onset,O
+hyperuricemia,O
+,,O
+anemia,O
+,,O
+and,O
+chronic,O
+kidney,O
+failure,O
+.,O
+ , 
+Through,O
+linkage,O
+analysis,O
+and,O
+candidate,O
+gene,O
+sequencing,O
+,,O
+we,O
+identified,O
+three,O
+unrelated,O
+families,O
+with,O
+the,O
+autosomal,O
+-,O
+dominant,O
+inheritance,O
+of,O
+early,O
+onset,O
+anemia,O
+,,O
+hypouricosuric,O
+hyperuricemia,O
+,,O
+progressive,O
+kidney,O
+failure,O
+,,O
+and,O
+mutations,O
+resulting,O
+either,O
+in,O
+the,O
+deletion,O
+(,B-SNP
+p.,I-SNP
+Leu16del,I-SNP
+),I-SNP
+or,O
+the,O
+amino,O
+acid,O
+exchange,O
+(,B-SNP
+p.,I-SNP
+Leu16Arg,I-SNP
+),I-SNP
+of,O
+a,O
+single,O
+leucine,O
+residue,O
+in,O
+the,O
+signal,O
+sequence,O
+of,O
+renin,B-Gene
+.,I-Gene
+ , 
+Both,O
+mutations,O
+decrease,O
+signal,O
+sequence,O
+hydrophobicity,O
+and,O
+are,O
+predicted,O
+by,O
+bioinformatic,O
+analyses,O
+to,O
+damage,O
+targeting,O
+and,O
+cotranslational,O
+translocation,O
+of,O
+preprorenin,O
+into,O
+the,O
+endoplasmic,O
+reticulum,O
+(,O
+ER,O
+),O
+.,O
+ , 
+Transfection,O
+and,O
+in,O
+vitro,O
+studies,O
+confirmed,O
+that,O
+both,O
+mutations,O
+affect,O
+ER,O
+translocation,O
+and,O
+processing,O
+of,O
+nascent,O
+preprorenin,O
+,,O
+resulting,O
+either,O
+in,O
+reduced,O
+(,B-SNP
+p.,I-SNP
+Leu16del,I-SNP
+),I-SNP
+or,O
+abolished,O
+(,B-SNP
+p.,I-SNP
+Leu16Arg,I-SNP
+),I-SNP
+prorenin,O
+and,O
+renin,O
+biosynthesis,O
+and,O
+secretion,O
+.,O
+ , 
+Expression,O
+of,O
+renin,B-Gene
+and,O
+other,O
+components,O
+of,O
+the,O
+renin,O
+-,O
+angiotensin,O
+system,O
+was,O
+decreased,O
+accordingly,O
+in,O
+kidney,O
+biopsy,O
+specimens,O
+from,O
+affected,O
+individuals,O
+.,O
+ , 
+Cells,O
+stably,O
+expressing,O
+the,O
+p.,B-SNP
+Leu16del,I-SNP
+protein,O
+showed,O
+activated,O
+ER,O
+stress,O
+,,O
+unfolded,O
+protein,O
+response,O
+,,O
+and,O
+reduced,O
+growth,O
+rate,O
+.,O
+ , 
+It,O
+is,O
+likely,O
+that,O
+expression,O
+of,O
+the,O
+mutant,O
+proteins,O
+has,O
+a,O
+dominant,O
+toxic,O
+effect,O
+gradually,O
+reducing,O
+the,O
+viability,O
+of,O
+renin,O
+-,O
+expressing,O
+cells,O
+.,O
+ , 
+This,O
+alters,O
+the,O
+intrarenal,O
+renin,O
+-,O
+angiotensin,O
+system,O
+and,O
+the,O
+juxtaglomerular,O
+apparatus,O
+functionality,O
+and,O
+leads,O
+to,O
+nephron,O
+dropout,O
+and,O
+progressive,O
+kidney,O
+failure,O
+.,O
+ , 
+Our,O
+findings,O
+provide,O
+insight,O
+into,O
+the,O
+functionality,O
+of,O
+renin,O
+-,O
+angiotensin,O
+system,O
+and,O
+stress,O
+the,O
+importance,O
+of,O
+renin,B-Gene
+analysis,O
+in,O
+families,O
+and,O
+individuals,O
+with,O
+early,O
+onset,O
+hyperuricemia,O
+,,O
+anemia,O
+,,O
+and,O
+progressive,O
+kidney,O
+failure,O
+.,O
+ , 
+#7977368
+Mutations,O
+in,O
+argininosuccinate,B-Gene
+synthetase,I-Gene
+mRNA,O
+of,O
+Japanese,O
+patients,O
+,,O
+causing,O
+classical,O
+citrullinemia,O
+.,O
+ , 
+Citrullinemia,O
+is,O
+an,O
+autosomal,O
+recessive,O
+disease,O
+caused,O
+by,O
+a,O
+genetic,O
+deficiency,O
+of,O
+argininosuccinate,B-Gene
+synthetase,I-Gene
+.,I-Gene
+ , 
+In,O
+order,O
+to,O
+characterize,O
+mutations,O
+in,O
+Japanese,O
+patients,O
+with,O
+classical,O
+citrullinemia,O
+,,O
+RNA,O
+isolated,O
+from,O
+10,O
+unrelated,O
+patients,O
+was,O
+reverse,O
+-,O
+transcribed,O
+,,O
+and,O
+cDNA,O
+amplified,O
+by,O
+PCR,O
+was,O
+cloned,O
+and,O
+sequenced,O
+.,O
+ , 
+The,O
+10,O
+mutations,O
+identified,O
+included,O
+6,O
+missense,O
+mutations,O
+(,B-SNP
+A118,I-SNP
+T,I-SNP
+,,I-SNP
+A192V,B-SNP
+,,I-SNP
+R272C,B-SNP
+,,I-SNP
+G280R,B-SNP
+,,I-SNP
+R304W,B-SNP
+,,I-SNP
+and,O
+R363L,B-SNP
+),I-SNP
+,,O
+2,O
+mutations,O
+associated,O
+with,O
+an,O
+absence,O
+of,O
+an,O
+exon,O
+7,O
+or,O
+exon,O
+13,O
+,,O
+1,O
+mutation,O
+with,O
+a,O
+deletion,O
+of,O
+the,O
+first,O
+7,O
+bp,O
+in,O
+exon,O
+16,O
+(,O
+which,O
+might,O
+be,O
+caused,O
+by,O
+abnormal,O
+splicing,O
+),O
+,,O
+and,O
+1,O
+mutation,O
+with,O
+an,O
+insertion,O
+of,O
+37,O
+bp,O
+within,O
+exons,O
+15,O
+and,O
+16,O
+in,O
+cDNA,O
+.,O
+ , 
+The,O
+insertion,O
+mutation,O
+and,O
+the,O
+five,O
+missense,O
+mutations,O
+(,B-SNP
+R304W,I-SNP
+being,O
+excluded,O
+),O
+are,O
+new,O
+mutations,O
+described,O
+in,O
+the,O
+present,O
+paper,O
+.,O
+ , 
+These,O
+are,O
+in,O
+addition,O
+to,O
+14,O
+mutations,O
+(,O
+9,O
+missense,O
+mutations,O
+,,O
+4,O
+mutations,O
+associated,O
+with,O
+an,O
+absence,O
+of,O
+an,O
+exon,O
+in,O
+mRNA,O
+,,O
+and,O
+1,O
+splicing,O
+mutation,O
+),O
+that,O
+we,O
+identified,O
+previously,O
+in,O
+mainly,O
+American,O
+patients,O
+with,O
+neonatal,O
+citrullinemia,O
+.,O
+ , 
+Two,O
+of,O
+these,O
+20,O
+mutations,O
+,,O
+a,O
+deletion,O
+of,O
+exon,O
+13,O
+sequence,O
+and,O
+a,O
+7,O
+-,O
+bp,O
+deletion,O
+in,O
+exon,O
+16,O
+,,O
+were,O
+common,O
+to,O
+Japanese,O
+and,O
+American,O
+populations,O
+from,O
+different,O
+ethnic,O
+backgrounds,O
+;,O
+however,O
+,,O
+other,O
+mutations,O
+were,O
+unique,O
+to,O
+each,O
+population,O
+.,O
+ , 
+Furthermore,O
+,,O
+the,O
+presence,O
+of,O
+a,O
+frequent,O
+mutation,O
+--,O
+the,O
+exon,O
+7,O
+deletion,O
+mutation,O
+in,O
+mRNA,O
+,,O
+which,O
+accounts,O
+for,O
+10,O
+of,O
+23,O
+affected,O
+alleles,O
+--,O
+was,O
+demonstrated,O
+in,O
+Japanese,O
+citrullinemia,O
+.,O
+ , 
+This,O
+differs,O
+from,O
+the,O
+situation,O
+in,O
+the,O
+United,O
+States,O
+,,O
+where,O
+there,O
+was,O
+far,O
+greater,O
+heterogeneity,O
+of,O
+mutations,O
+.,O
+ , 
+#11309687
+A,O
+confidence,O
+-,O
+set,O
+approach,O
+for,O
+finding,O
+tightly,O
+linked,O
+genomic,O
+regions,O
+.,O
+ , 
+As,O
+more,O
+studies,O
+adopt,O
+the,O
+approach,O
+of,O
+whole,O
+-,O
+genome,O
+screening,O
+,,O
+geneticists,O
+are,O
+faced,O
+with,O
+the,O
+challenge,O
+of,O
+having,O
+to,O
+interpret,O
+results,O
+from,O
+traditional,O
+approaches,O
+that,O
+were,O
+not,O
+designed,O
+for,O
+genome,O
+-,O
+scan,O
+data,O
+.,O
+ , 
+Frequently,O
+,,O
+two,O
+-,O
+point,O
+analysis,O
+by,O
+the,O
+LOD,O
+method,O
+is,O
+performed,O
+to,O
+search,O
+for,O
+signals,O
+of,O
+linkage,O
+throughout,O
+the,O
+genome,O
+,,O
+for,O
+each,O
+of,O
+hundreds,O
+or,O
+even,O
+thousands,O
+of,O
+markers,O
+.,O
+ , 
+This,O
+practice,O
+has,O
+raised,O
+the,O
+question,O
+of,O
+how,O
+to,O
+adjust,O
+the,O
+significance,O
+level,O
+for,O
+the,O
+fact,O
+that,O
+multiple,O
+tests,O
+are,O
+being,O
+performed,O
+.,O
+ , 
+Various,O
+recommendations,O
+have,O
+been,O
+made,O
+,,O
+but,O
+no,O
+consensus,O
+has,O
+emerged,O
+.,O
+ , 
+In,O
+this,O
+article,O
+,,O
+we,O
+propose,O
+a,O
+new,O
+method,O
+,,O
+the,O
+confidence,O
+-,O
+set,O
+approach,O
+,,O
+that,O
+circumvents,O
+the,O
+need,O
+to,O
+correct,O
+for,O
+the,O
+level,O
+of,O
+significance,O
+according,O
+to,O
+the,O
+number,O
+of,O
+markers,O
+tested,O
+.,O
+ , 
+In,O
+the,O
+search,O
+for,O
+the,O
+gene,O
+location,O
+of,O
+a,O
+monogenic,O
+disorder,O
+,,O
+multiplicity,O
+adjustment,O
+is,O
+not,O
+needed,O
+in,O
+order,O
+to,O
+maintain,O
+the,O
+desired,O
+level,O
+of,O
+confidence,O
+.,O
+ , 
+For,O
+complex,O
+diseases,O
+involving,O
+multiple,O
+genes,O
+,,O
+one,O
+needs,O
+only,O
+to,O
+adjust,O
+the,O
+level,O
+of,O
+significance,O
+according,O
+to,O
+the,O
+number,O
+of,O
+disease,O
+genes,O
+--,O
+a,O
+much,O
+smaller,O
+number,O
+than,O
+the,O
+number,O
+of,O
+markers,O
+in,O
+a,O
+genome,O
+screen,O
+-,O
+to,O
+ensure,O
+a,O
+predetermined,O
+genomewide,O
+confidence,O
+level,O
+.,O
+ , 
+Furthermore,O
+,,O
+our,O
+formulation,O
+of,O
+the,O
+tests,O
+enables,O
+us,O
+to,O
+localize,O
+disease,O
+genes,O
+to,O
+small,O
+genomic,O
+regions,O
+,,O
+an,O
+extremely,O
+desirable,O
+feature,O
+that,O
+the,O
+traditional,O
+LOD,O
+method,O
+lacks,O
+.,O
+ , 
+Our,O
+simulation,O
+study,O
+shows,O
+that,O
+,,O
+for,O
+sib,O
+-,O
+pair,O
+data,O
+,,O
+even,O
+when,O
+the,O
+coverage,O
+probability,O
+of,O
+the,O
+confidence,O
+set,O
+is,O
+chosen,O
+to,O
+be,O
+as,O
+high,O
+as,O
+99,O
+%,O
+,,O
+our,O
+approach,O
+is,O
+able,O
+to,O
+implicate,O
+only,O
+the,O
+markers,O
+that,O
+are,O
+closely,O
+linked,O
+to,O
+the,O
+disease,O
+genes,O
+.,O
+ , 
+#8328462
+beta,B-Gene
+-,I-Gene
+Hexosaminidase,I-Gene
+isozymes,O
+from,O
+cells,O
+cotransfected,O
+with,O
+alpha,O
+and,O
+beta,O
+cDNA,O
+constructs,O
+:,O
+analysis,O
+of,O
+the,O
+alpha,O
+-,O
+subunit,O
+missense,O
+mutation,O
+associated,O
+with,O
+the,O
+adult,O
+form,O
+of,O
+Tay,O
+-,O
+Sachs,O
+disease,O
+.,O
+ , 
+In,O
+vitro,O
+mutagenesis,O
+and,O
+transient,O
+expression,O
+in,O
+COS,O
+cells,O
+has,O
+been,O
+used,O
+to,O
+associate,O
+a,O
+missense,O
+mutation,O
+with,O
+a,O
+clinical,O
+or,O
+biochemical,O
+phenotype,O
+.,O
+ , 
+Mutations,O
+affecting,O
+the,O
+alpha,O
+-,O
+subunit,O
+of,O
+beta,B-Gene
+-,I-Gene
+hexosaminidase,I-Gene
+A,I-Gene
+(,O
+alpha,O
+beta,O
+),O
+(,O
+E.C.3.2.1.52,O
+),O
+result,O
+in,O
+Tay,O
+-,O
+Sachs,O
+disease,O
+.,O
+ , 
+Because,O
+hexosaminidase,B-Gene
+A,I-Gene
+is,O
+heterodimeric,O
+,,O
+analysis,O
+of,O
+alpha,O
+-,O
+chain,O
+mutations,O
+is,O
+not,O
+straightforward,O
+.,O
+ , 
+We,O
+examine,O
+three,O
+approaches,O
+utilizing,O
+previously,O
+identified,O
+mutations,O
+affecting,O
+alpha,O
+-,O
+chain,O
+folding,O
+.,O
+ , 
+These,O
+involve,O
+transfection,O
+of,O
+(,O
+1,O
+),O
+the,O
+alpha,O
+cDNA,O
+alone,O
+;,O
+(,O
+2,O
+),O
+a,O
+beta,O
+cDNA,O
+construct,O
+encoding,O
+a,O
+beta,O
+-,O
+subunit,O
+substituted,O
+at,O
+a,O
+position,O
+homologous,O
+to,O
+that,O
+of,O
+the,O
+alpha,O
+-,O
+subunit,O
+,,O
+and,O
+(,O
+3,O
+),O
+both,O
+alpha,O
+and,O
+beta,O
+cDNAs,O
+.,O
+ , 
+The,O
+latter,O
+two,O
+procedures,O
+amplified,O
+residual,O
+activity,O
+levels,O
+over,O
+that,O
+of,O
+patient,O
+samples,O
+,,O
+an,O
+effect,O
+not,O
+previously,O
+found,O
+with,O
+mutations,O
+affecting,O
+an,O
+",O
+active,O
+",O
+alpha,O
+Arg,O
+residue,O
+.,O
+ , 
+This,O
+effect,O
+may,O
+help,O
+to,O
+discriminate,O
+between,O
+protein,O
+-,O
+folding,O
+and,O
+active,O
+-,O
+site,O
+mutations,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+,,O
+with,O
+proper,O
+controls,O
+,,O
+the,O
+latter,O
+method,O
+of,O
+cotransfection,O
+can,O
+be,O
+used,O
+to,O
+evaluate,O
+the,O
+effects,O
+and,O
+perhaps,O
+to,O
+predict,O
+the,O
+clinical,O
+course,O
+of,O
+some,O
+alpha,O
+-,O
+chain,O
+mutations,O
+.,O
+ , 
+Using,O
+this,O
+technique,O
+,,O
+we,O
+demonstrate,O
+that,O
+the,O
+adult,O
+-,O
+onset,O
+Tay,O
+-,O
+Sachs,O
+mutation,O
+,,O
+alpha,O
+Gly,B-SNP
+--,I-SNP
+>,I-SNP
+Ser269,I-SNP
+,,I-SNP
+does,O
+not,O
+directly,O
+affect,O
+alpha,O
+beta,O
+dimerization,O
+but,O
+exerts,O
+an,O
+indirect,O
+effect,O
+on,O
+the,O
+dimer,O
+through,O
+destabilizing,O
+the,O
+folded,O
+alpha,O
+-,O
+subunit,O
+at,O
+physiological,O
+temperatures,O
+.,O
+ , 
+Two,O
+other,O
+alpha,O
+mutations,O
+linked,O
+to,O
+more,O
+severe,O
+phenotypes,O
+appear,O
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+inhibit,O
+the,O
+initial,O
+folding,O
+of,O
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+subunit,O
+.,O
+ , 
+#9375854
+Analysis,O
+of,O
+multiple,O
+mitochondrial,O
+DNA,O
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+(,O
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+sporadic,O
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+is,O
+morphologically,O
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+by,O
+inflammatory,O
+cell,O
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+and,O
+rimmed,O
+vacuoles,O
+in,O
+muscle,O
+fibers,O
+.,O
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+Mitochondrial,O
+changes,O
+are,O
+regularly,O
+present,O
+with,O
+ragged,O
+-,O
+red,O
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+of,O
+cytochrome,O
+c,O
+oxidase,O
+.,O
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+In,O
+these,O
+muscle,O
+fiber,O
+segments,O
+,,O
+there,O
+is,O
+accumulation,O
+of,O
+mitochondria,O
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+mitochondrial,O
+DNA,O
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+There,O
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+in,O
+different,O
+muscle,O
+fibers,O
+.,O
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+In,O
+this,O
+study,O
+,,O
+we,O
+have,O
+sequenced,O
+for,O
+the,O
+first,O
+time,O
+the,O
+multiple,O
+mtDNA,O
+deletions,O
+in,O
+muscle,O
+from,O
+four,O
+patients,O
+with,O
+IBM,O
+.,O
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+The,O
+deletion,O
+breakpoints,O
+were,O
+sequenced,O
+from,O
+cloned,O
+polymerase,O
+chain,O
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+(,O
+PCR)-amplified,O
+mtDNA,O
+fragments,O
+.,O
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+The,O
+sequencing,O
+was,O
+performed,O
+directly,O
+from,O
+the,O
+bacterial,O
+colonies,O
+used,O
+for,O
+cloning,O
+.,O
+ , 
+Of,O
+122,O
+analyzed,O
+clones,O
+,,O
+33,O
+different,O
+deletions,O
+were,O
+identified,O
+.,O
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+The,O
+majority,O
+of,O
+these,O
+have,O
+not,O
+previously,O
+been,O
+described,O
+.,O
+ , 
+There,O
+was,O
+a,O
+marked,O
+predominance,O
+of,O
+deletion,O
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+in,O
+certain,O
+regions,O
+of,O
+mtDNA,O
+.,O
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+These,O
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+breakpoint,O
+regions,O
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+similar,O
+to,O
+those,O
+described,O
+in,O
+other,O
+conditions,O
+with,O
+multiple,O
+deletions,O
+,,O
+such,O
+as,O
+autosomal,O
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+progressive,O
+external,O
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+(,O
+adPEO,O
+),O
+and,O
+normal,O
+aging,O
+,,O
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+those,O
+described,O
+in,O
+diseases,O
+due,O
+to,O
+single,O
+deletions,O
+such,O
+as,O
+Kearns,O
+-,O
+Sayre,O
+syndrome,O
+and,O
+sporadic,O
+PEO,O
+.,O
+ , 
+These,O
+findings,O
+indicate,O
+that,O
+common,O
+factors,O
+are,O
+involved,O
+in,O
+the,O
+development,O
+of,O
+multiple,O
+mtDNA,O
+deletions,O
+in,O
+IBM,O
+,,O
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+,,O
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+.,O
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+#9222768
+Novel,O
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+4,O
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+CFTR,B-Gene
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+in,O
+an,O
+Algerian,O
+patient,O
+.,O
+ , 
+#7981715
+Complex,O
+arylsulfatase,O
+A,O
+alleles,O
+causing,O
+metachromatic,O
+leukodystrophy,O
+.,O
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+Metachromatic,O
+leukodystrophy,O
+is,O
+a,O
+lysosomal,O
+storage,O
+disorder,O
+caused,O
+by,O
+the,O
+deficiency,O
+of,O
+arylsulfatase,O
+A.,O
+Sequencing,O
+of,O
+the,O
+arylsulfatase,O
+A,O
+genes,O
+of,O
+a,O
+patient,O
+affected,O
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+late,O
+infantile,O
+metachromatic,O
+leukodystrophy,O
+revealed,O
+that,O
+the,O
+patient,O
+is,O
+a,O
+compound,O
+heterozygote,O
+of,O
+two,O
+alleles,O
+carrying,O
+two,O
+deleterious,O
+mutation,O
+each,O
+.,O
+ , 
+One,O
+allele,O
+bears,O
+a,O
+splice,O
+donor,O
+site,O
+mutation,O
+together,O
+with,O
+two,O
+polymorphisms,O
+and,O
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+(,B-SNP
+Gly122,I-SNP
+>,I-SNP
+Ser,I-SNP
+),I-SNP
+.,O
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+The,O
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+Gly122,B-SNP
+>,I-SNP
+Ser,I-SNP
+substitution,O
+have,O
+been,O
+described,O
+recently,O
+but,O
+on,O
+different,O
+alleles,O
+.,O
+ , 
+The,O
+other,O
+allele,O
+carries,O
+two,O
+missense,O
+mutations,O
+causing,O
+a,O
+Gly154,B-SNP
+>,I-SNP
+Asp,I-SNP
+and,O
+a,O
+Pro167,B-SNP
+>,I-SNP
+Arg,I-SNP
+substitution,O
+.,O
+ , 
+When,O
+arylsulfatase,O
+A,O
+cDNAs,O
+carrying,O
+these,O
+mutations,O
+separately,O
+or,O
+in,O
+combination,O
+were,O
+transfected,O
+into,O
+baby,O
+hamster,O
+kidney,O
+cells,O
+expression,O
+of,O
+arylsulfatase,O
+A,O
+activity,O
+could,O
+not,O
+be,O
+detected,O
+.,O
+ , 
+Linkage,O
+of,O
+mutations,O
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+verified,O
+by,O
+sequencing,O
+of,O
+the,O
+parental,O
+DNAs,O
+.,O
+ , 
+Biosynthesis,O
+studies,O
+performed,O
+with,O
+the,O
+patients,O
+',O
+fibroblasts,O
+show,O
+that,O
+the,O
+enzyme,O
+carrying,O
+both,O
+mutations,O
+is,O
+synthesized,O
+in,O
+almost,O
+normal,O
+amounts,O
+but,O
+is,O
+rapidly,O
+degraded,O
+in,O
+an,O
+early,O
+biosynthetic,O
+compartment,O
+.,O
+ , 
+The,O
+occurence,O
+of,O
+two,O
+disease,O
+causing,O
+mutations,O
+on,O
+the,O
+same,O
+allele,O
+is,O
+a,O
+novel,O
+phenomenon,O
+in,O
+metachromatic,O
+leukodystrophy,O
+and,O
+as,O
+far,O
+as,O
+lysosomal,O
+storage,O
+diseases,O
+are,O
+concerned,O
+have,O
+so,O
+far,O
+only,O
+been,O
+described,O
+in,O
+Fabry,O
+disease,O
+and,O
+in,O
+the,O
+complex,O
+glucocerebrosidase,O
+alleles,O
+associated,O
+with,O
+Gaucher,O
+disease,O
+.,O
+ , 
+#16532386
+Genome,O
+scan,O
+for,O
+loci,O
+predisposing,O
+to,O
+anxiety,O
+disorders,O
+using,O
+a,O
+novel,O
+multivariate,O
+approach,O
+:,O
+strong,O
+evidence,O
+for,O
+a,O
+chromosome,O
+4,O
+risk,O
+locus,O
+.,O
+ , 
+We,O
+conducted,O
+a,O
+10,O
+-,O
+centimorgan,O
+linkage,O
+autosomal,O
+genome,O
+scan,O
+in,O
+a,O
+set,O
+of,O
+19,O
+extended,O
+American,O
+pedigrees,O
+(,O
+219,O
+subjects,O
+),O
+ascertained,O
+through,O
+probands,O
+with,O
+panic,O
+disorder,O
+.,O
+ , 
+Several,O
+anxiety,O
+disorders,O
+--,O
+including,O
+social,O
+phobia,O
+,,O
+agoraphobia,O
+,,O
+and,O
+simple,O
+phobia,O
+--,O
+in,O
+addition,O
+to,O
+panic,O
+disorder,O
+segregate,O
+in,O
+these,O
+families,O
+.,O
+ , 
+In,O
+previous,O
+studies,O
+of,O
+this,O
+sample,O
+,,O
+linkage,O
+analyses,O
+were,O
+based,O
+separately,O
+on,O
+each,O
+of,O
+the,O
+individual,O
+categorical,O
+affection,O
+diagnoses,O
+.,O
+ , 
+Given,O
+the,O
+substantial,O
+comorbidity,O
+between,O
+anxiety,O
+disorders,O
+and,O
+their,O
+probable,O
+shared,O
+genetic,O
+liability,O
+,,O
+it,O
+is,O
+clear,O
+that,O
+this,O
+method,O
+discards,O
+a,O
+considerable,O
+amount,O
+of,O
+information,O
+.,O
+ , 
+In,O
+this,O
+article,O
+,,O
+we,O
+propose,O
+a,O
+new,O
+approach,O
+that,O
+considers,O
+panic,O
+disorder,O
+,,O
+simple,O
+phobia,O
+,,O
+social,O
+phobia,O
+,,O
+and,O
+agoraphobia,O
+as,O
+expressions,O
+of,O
+the,O
+same,O
+multivariate,O
+,,O
+putatively,O
+genetically,O
+influenced,O
+trait,O
+.,O
+ , 
+We,O
+applied,O
+the,O
+most,O
+powerful,O
+multipoint,O
+Haseman,O
+-,O
+Elston,O
+method,O
+,,O
+using,O
+the,O
+grade,O
+of,O
+membership,O
+score,O
+generated,O
+from,O
+a,O
+fuzzy,O
+clustering,O
+of,O
+these,O
+phenotypes,O
+as,O
+the,O
+dependent,O
+variable,O
+in,O
+Haseman,O
+-,O
+Elston,O
+regression,O
+.,O
+ , 
+One,O
+region,O
+on,O
+chromosome,O
+4q31,O
+-,O
+q34,O
+,,O
+at,O
+marker,O
+D4S413,O
+(,O
+with,O
+multipoint,O
+and,O
+single,O
+-,O
+point,O
+nominal,O
+P,O
+values,O
+<,O
+.00001,O
+),O
+,,O
+showed,O
+strong,O
+evidence,O
+of,O
+linkage,O
+(,O
+genomewide,O
+significance,O
+at,O
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+neuropeptide,B-Gene
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+(,O
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+-,O
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+-,O
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+.,O
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+Our,O
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+,,O
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+least,O
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+.,O
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+This,O
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+be,O
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+-,O
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+#17024664
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+44.0+/-10.9,O
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+39.7+/-10.3,O
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+),O
+.,O
+ , 
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+the,O
+association,O
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+with,O
+missense,O
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+stratifying,O
+missense,O
+mutations,O
+into,O
+those,O
+that,O
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+in,O
+substitution,O
+of,O
+a,O
+surface,O
+amino,O
+acid,O
+and,O
+those,O
+that,O
+disrupted,O
+structural,O
+integrity,O
+demonstrated,O
+that,O
+surface,O
+amino,O
+acid,O
+substitutions,O
+conferred,O
+a,O
+higher,O
+pheochromocytoma,O
+risk,O
+.,O
+ , 
+Age,O
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+(,O
+P=0.001,O
+),O
+,,O
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+-,O
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+and,O
+RCC,O
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+P=0.0008,O
+,,O
+respectively,O
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+a,O
+nonsense,O
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+mutation,O
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+in,O
+those,O
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+deletions,O
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+missense,O
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+that,O
+disrupted,O
+the,O
+structural,O
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+VHL,O
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+#23084292
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+3,701,O
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+7,199,O
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+Our,O
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+the,O
+use,O
+of,O
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+Bayesian,O
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+criterion,O
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+),O
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+NOTCH4,B-Gene
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+multiple,O
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+SNPs,O
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+,,O
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+a,O
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+.,O
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+With,O
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+able,O
+to,O
+identify,O
+a,O
+model,O
+that,O
+was,O
+an,O
+overwhelmingly,O
+better,O
+fit,O
+to,O
+the,O
+data,O
+than,O
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+(,O
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+[,O
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+50,O
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+(,O
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+#11799475
+Evidence,O
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+.,O
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+Eating,O
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+(,O
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+192,O
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+AN,O
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+food,O
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+.,O
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+When,O
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+.,O
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+The,O
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+#9452048
+Identification,O
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+#11781875
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+These,O
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+(,B-Gene
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+These,O
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+resulting,O
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+database,O
+.,O
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+Family,O
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+comprehensive,O
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+useful,O
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+For,O
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+The,O
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+This,O
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+#15338459
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+#18429048
+Haplotype,O
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+Gaucher,O
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+GBA,O
+gene,O
+.,O
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+Most,O
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+However,O
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+reported,O
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+patients,O
+homozygous,O
+for,O
+the,O
+[,B-SNP
+D409H;H255Q,B-SNP
+],I-SNP
+double,O
+mutant,O
+allele,O
+(,O
+HGVS,O
+-,O
+approved,O
+nomenclature,O
+,,O
+p.[D448H;H294Q,B-SNP
+],I-SNP
+),I-SNP
+present,O
+a,O
+more,O
+severe,O
+phenotype,O
+than,O
+patients,O
+homozygous,O
+for,O
+the,O
+relatively,O
+common,O
+D409H,B-SNP
+mutation,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+confirmed,O
+the,O
+detrimental,O
+cumulative,O
+effect,O
+of,O
+these,O
+two,O
+mutations,O
+at,O
+the,O
+enzymatic,O
+activity,O
+level,O
+by,O
+the,O
+heterologous,O
+expression,O
+of,O
+the,O
+single,O
+and,O
+double,O
+mutant,O
+alleles,O
+.,O
+ , 
+Additionally,O
+,,O
+we,O
+found,O
+a,O
+high,O
+frequency,O
+of,O
+the,O
+[,B-SNP
+D409H;H255Q,B-SNP
+],I-SNP
+allele,O
+in,O
+patients,O
+from,O
+the,O
+Balkans,O
+and,O
+the,O
+Adriatic,O
+area,O
+of,O
+Italy,O
+.,O
+ , 
+This,O
+prompted,O
+us,O
+to,O
+perform,O
+a,O
+haplotype,O
+analysis,O
+,,O
+using,O
+five,O
+microsatellite,O
+polymorphisms,O
+close,O
+to,O
+the,O
+GBA,O
+gene,O
+,,O
+to,O
+determine,O
+the,O
+origin,O
+of,O
+this,O
+allele,O
+.,O
+ , 
+The,O
+results,O
+of,O
+the,O
+37,O
+chromosomes,O
+analysed,O
+showed,O
+that,O
+most,O
+of,O
+them,O
+share,O
+a,O
+common,O
+haplotype,O
+and,O
+are,O
+consistent,O
+with,O
+a,O
+single,O
+origin,O
+in,O
+the,O
+Balkans,O
+and,O
+the,O
+Adriatic,O
+area,O
+of,O
+Italy,O
+for,O
+the,O
+[,B-SNP
+D409H;H255Q,B-SNP
+],I-SNP
+allele,O
+.,O
+ , 
+#15146469
+Novel,O
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+recurrent,O
+mutations,O
+in,O
+the,O
+NF1,B-Gene
+gene,O
+in,O
+Italian,O
+patients,O
+with,O
+neurofibromatosis,O
+type,O
+1,O
+.,O
+ , 
+Neurofibromatosis,O
+type,O
+1,O
+(,O
+NF1,O
+),O
+is,O
+one,O
+of,O
+the,O
+most,O
+common,O
+autosomal,O
+dominant,O
+disorders,O
+in,O
+humans,O
+,,O
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+1,O
+in,O
+3500,O
+individuals,O
+.,O
+ , 
+NF1,B-Gene
+is,O
+a,O
+fully,O
+penetrant,O
+exhibiting,O
+a,O
+mutation,O
+rate,O
+some,O
+10,O
+-,O
+fold,O
+higher,O
+compared,O
+to,O
+most,O
+other,O
+disease,O
+genes,O
+.,O
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+As,O
+a,O
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+,,O
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+.,O
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+Mutation,O
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+large,O
+size,O
+of,O
+NF1,B-Gene
+gene,O
+,,O
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+of,O
+pseudogenes,O
+and,O
+the,O
+great,O
+variety,O
+of,O
+lesions,O
+.,O
+ , 
+In,O
+the,O
+present,O
+study,O
+we,O
+attempted,O
+to,O
+delineate,O
+the,O
+NF1,O
+mutational,O
+spectrum,O
+in,O
+the,O
+Italian,O
+population,O
+reporting,O
+four,O
+-,O
+year,O
+experience,O
+with,O
+the,O
+direct,O
+analysis,O
+of,O
+the,O
+whole,O
+NF1,B-Gene
+coding,O
+region,O
+in,O
+110,O
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+by,O
+NF1,B-Gene
+.,I-Gene
+ , 
+For,O
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+patient,O
+,,O
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+whole,O
+coding,O
+sequence,O
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+all,O
+splice,O
+sites,O
+were,O
+studied,O
+for,O
+mutations,O
+,,O
+either,O
+by,O
+the,O
+protein,O
+truncation,O
+test,O
+(,O
+PTT,O
+),O
+,,O
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+,,O
+most,O
+often,O
+,,O
+by,O
+denaturing,O
+high,O
+performance,O
+liquid,O
+chromatography,O
+(,O
+DHPLC,O
+),O
+.,O
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+Mutations,O
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+in,O
+75,O
+(,O
+68,O
+%,O
+),O
+patients,O
+.,O
+ , 
+Twenty,O
+-,O
+two,O
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+were,O
+found,O
+to,O
+be,O
+novel,O
+.,O
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+The,O
+detection,O
+rate,O
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+the,O
+different,O
+methods,O
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+7/18,O
+(,O
+39,O
+%,O
+),O
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+PTT,O
+,,O
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+68/103,O
+(,O
+66,O
+%,O
+),O
+for,O
+DHPLC,O
+.,O
+ , 
+The,O
+mutations,O
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+evenly,O
+distributed,O
+along,O
+the,O
+NF1,O
+coding,O
+sequence,O
+.,O
+ , 
+Thirty,O
+-,O
+two,O
+of,O
+the,O
+75,O
+unrelated,O
+NF1,O
+patients,O
+in,O
+which,O
+germline,O
+mutations,O
+were,O
+identified,O
+(,O
+32/75,O
+,,O
+43,O
+%,O
+),O
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+23,O
+different,O
+recurrent,O
+mutations,O
+.,O
+ , 
+Fifteen,O
+sequence,O
+variants,O
+likely,O
+to,O
+represent,O
+non,O
+-,O
+pathogenic,O
+polymorphisms,O
+were,O
+observed,O
+at,O
+the,O
+NF1,O
+locus,O
+.,O
+ , 
+Genotype,O
+-,O
+phenotype,O
+analysis,O
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+unable,O
+to,O
+detect,O
+any,O
+obvious,O
+correlation,O
+.,O
+ , 
+#11668643
+Seven,O
+novel,O
+mutations,O
+in,O
+the,O
+ORNT1,B-Gene
+gene,O
+(,B-Gene
+SLC25A15,I-Gene
+),I-Gene
+in,O
+patients,O
+with,O
+hyperornithinemia,O
+,,O
+hyperammonemia,O
+,,O
+and,O
+homocitrullinuria,O
+syndrome,O
+.,O
+ , 
+Eight,O
+unrelated,O
+Italian,O
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+the,O
+hyperornithinemia,O
+,,O
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+,,O
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+(,O
+HHH,O
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+analyzed,O
+for,O
+mutations,O
+in,O
+the,O
+ORNT1,B-Gene
+gene,O
+.,O
+ , 
+Seven,O
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+mutations,O
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+identified,O
+(,B-SNP
+Q89X,I-SNP
+,,I-SNP
+G27R,B-SNP
+,,I-SNP
+G190D,B-SNP
+,,I-SNP
+R275Q,B-SNP
+,,I-SNP
+c.861insG,B-SNP
+,,I-SNP
+c.164insA,B-SNP
+,,I-SNP
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+IVS5,B-SNP
++,I-SNP
+1G-->A,I-SNP
+),I-SNP
+.,O
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+Other,O
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+a,O
+heterozygous,O
+deletion,O
+of,O
+a,O
+phenylalanine,O
+residue,O
+(,B-SNP
+F188del,I-SNP
+),I-SNP
+in,O
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+allele,O
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+the,O
+R179X,B-SNP
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+two,O
+.,O
+ , 
+The,O
+G27R,B-SNP
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+carried,O
+by,O
+two,O
+patients,O
+.,O
+ , 
+Analyses,O
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+ORNT1,B-Gene
+mRNA,O
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+patients,O
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+that,O
+mutant,O
+alleles,O
+were,O
+stable,O
+and,O
+of,O
+the,O
+predicted,O
+size,O
+.,O
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+The,O
+current,O
+study,O
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+ORNT1,B-Gene
+gene,O
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+#8981970
+Expression,O
+of,O
+DAZ,B-Gene
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+an,O
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+factor,O
+candidate,O
+,,O
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+.,O
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+#8723698
+Simple,O
+detection,O
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+a,O
+(,O
+Finnish,O
+),O
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+1,I-Gene
+mutation,O
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+#8102508
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+neonatal,O
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+a,O
+new,O
+locus,O
+on,O
+chromosome,O
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+.,O
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+The,O
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+neonatal,O
+convulsions,O
+(,O
+BFNC,O
+),O
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+a,O
+rare,O
+autosomal,O
+dominant,O
+disorder,O
+characterized,O
+by,O
+unprovoked,O
+seizures,O
+in,O
+the,O
+first,O
+few,O
+weeks,O
+of,O
+life,O
+.,O
+ , 
+One,O
+locus,O
+for,O
+BFNC,B-Gene
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+mapped,O
+to,O
+chromosome,O
+20,O
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+several,O
+pedigrees,O
+,,O
+but,O
+we,O
+have,O
+excluded,O
+linkage,O
+to,O
+chromosome,O
+20,O
+in,O
+one,O
+large,O
+kindred,O
+.,O
+ , 
+In,O
+order,O
+to,O
+identify,O
+this,O
+novel,O
+BFNC,B-Gene
+locus,O
+,,O
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+repeat,O
+markers,O
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+throughout,O
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+genome,O
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+to,O
+screen,O
+this,O
+family,O
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+Maximum,O
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+This,O
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+#15726498
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+map,O
+approximately,O
+900,O
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+approximately,O
+1.3,O
+Mb,O
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+of,O
+SOX9,B-Gene
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+(,O
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+semilethal,O
+skeletal,O
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+.,O
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+In,O
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+sex,O
+-,O
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+(,B-Gene
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+1,O
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+SOX9,B-Gene
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+.,O
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+Here,O
+,,O
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+,,O
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+Robin,O
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+.,O
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+Both,O
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+have,O
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+The,O
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+maps,O
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+900,O
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+of,O
+SOX9,B-Gene
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+bacterial,O
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+breakpoints,O
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+two,O
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+mild,O
+CD,O
+.,O
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+We,O
+also,O
+report,O
+a,O
+prenatal,O
+identification,O
+of,O
+acampomelic,O
+CD,O
+with,O
+male,O
+-,O
+to,O
+-,O
+female,O
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+a,O
+fetus,O
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+t(4;7;8;17)(4qter-->4p15.1::17q25.1,O
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+Surprisingly,O
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+17q,O
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+approximately,O
+1.3,O
+Mb,O
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+of,O
+SOX9,B-Gene
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+this,O
+the,O
+longest,O
+-,O
+range,O
+position,O
+effect,O
+found,O
+in,O
+the,O
+field,O
+of,O
+human,O
+genetics,O
+and,O
+the,O
+first,O
+report,O
+of,O
+a,O
+patient,O
+with,O
+CD,O
+with,O
+the,O
+chromosome,O
+breakpoint,O
+mapping,O
+3,O
+',O
+of,O
+SOX9,B-Gene
+.,I-Gene
+ , 
+By,O
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+the,O
+Regulatory,O
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+score,O
+in,O
+conjunction,O
+with,O
+analysis,O
+of,O
+the,O
+rearrangement,O
+breakpoints,O
+,,O
+we,O
+identified,O
+a,O
+candidate,O
+upstream,O
+cis,O
+-,O
+regulatory,O
+element,O
+,,O
+SOX9cre1,O
+.,O
+ , 
+We,O
+provide,O
+evidence,O
+that,O
+this,O
+1.1,O
+-,O
+kb,O
+evolutionarily,O
+conserved,O
+element,O
+and,O
+the,O
+downstream,O
+breakpoint,O
+region,O
+colocalize,O
+with,O
+SOX9,B-Gene
+in,O
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+interphase,O
+nucleus,O
+,,O
+despite,O
+being,O
+located,O
+1.1,O
+Mb,O
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+1.3,O
+Mb,O
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+of,O
+it,O
+,,O
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+.,O
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+The,O
+potential,O
+molecular,O
+mechanism,O
+responsible,O
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+position,O
+effect,O
+is,O
+discussed,O
+.,O
+ , 
+#19462467
+Molecular,O
+profiling,O
+of,O
+the,O
+",O
+plexinome,O
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+Plexins,O
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+high,O
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+Functional,O
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+metastasis,O
+.,O
+ , 
+Yet,O
+,,O
+it,O
+is,O
+largely,O
+unknown,O
+whether,O
+plexin,O
+genes,O
+are,O
+genetically,O
+altered,O
+in,O
+human,O
+tumors,O
+.,O
+ , 
+We,O
+performed,O
+a,O
+comprehensive,O
+gene,O
+copy,O
+analysis,O
+and,O
+mutational,O
+profiling,O
+of,O
+all,O
+nine,O
+members,O
+of,O
+the,O
+plexin,O
+gene,O
+family,O
+(,O
+plexinome,O
+),O
+,,O
+in,O
+melanomas,O
+and,O
+pancreatic,O
+ductal,O
+adenocarcinomas,O
+(,O
+PDACs,O
+),O
+,,O
+which,O
+are,O
+characterized,O
+by,O
+high,O
+metastatic,O
+potential,O
+and,O
+poor,O
+prognosis,O
+.,O
+ , 
+Gene,O
+copy,O
+analysis,O
+detected,O
+amplification,O
+of,O
+PLXNA4,B-Gene
+in,O
+melanomas,O
+,,O
+whereas,O
+copy,O
+number,O
+losses,O
+of,O
+multiple,O
+plexin,O
+genes,O
+were,O
+seen,O
+in,O
+PDACs,O
+.,O
+ , 
+Somatic,O
+mutations,O
+were,O
+detected,O
+in,O
+PLXNA4,B-Gene
+,,O
+PLXNB3,B-Gene
+,,I-Gene
+and,O
+PLXNC1,B-Gene
+;,I-Gene
+providing,O
+the,O
+first,O
+evidence,O
+that,O
+these,O
+plexins,O
+are,O
+mutated,O
+in,O
+human,O
+cancer,O
+.,O
+ , 
+Functional,O
+assays,O
+in,O
+cellular,O
+models,O
+revealed,O
+that,O
+some,O
+of,O
+these,O
+missense,O
+mutations,O
+result,O
+in,O
+loss,O
+of,O
+plexin,O
+function,O
+.,O
+ , 
+For,O
+instance,O
+,,O
+c.1613G,B-SNP
+>,I-SNP
+A,I-SNP
+,,I-SNP
+p.,B-SNP
+R538H,I-SNP
+mutation,O
+in,O
+the,O
+extracellular,O
+domain,O
+of,O
+PLXNB3,B-Gene
+prevented,O
+binding,O
+of,O
+the,O
+ligand,O
+Sema5A.,O
+ , 
+Moreover,O
+,,O
+although,O
+PLXNA4,O
+signaling,O
+can,O
+inhibit,O
+tumor,O
+cell,O
+migration,O
+,,O
+the,O
+mutated,O
+c.5206C,B-SNP
+>,I-SNP
+T,I-SNP
+,,I-SNP
+p.,B-SNP
+H1736Y,I-SNP
+allele,O
+had,O
+lost,O
+this,O
+activity,O
+.,O
+ , 
+Our,O
+study,O
+is,O
+the,O
+first,O
+systematic,O
+analysis,O
+of,O
+the,O
+",O
+plexinome,O
+",O
+in,O
+human,O
+tumors,O
+,,O
+and,O
+indicates,O
+that,O
+multiple,O
+mutated,O
+plexins,O
+may,O
+be,O
+involved,O
+in,O
+cancer,O
+progression,O
+.,O
+ , 
+#8940284
+Using,O
+the,O
+expectation,O
+or,O
+the,O
+distribution,O
+of,O
+the,O
+identity,O
+by,O
+descent,O
+for,O
+mapping,O
+quantitative,O
+trait,O
+loci,O
+under,O
+the,O
+random,O
+model,O
+.,O
+ , 
+We,O
+examine,O
+the,O
+ability,O
+of,O
+four,O
+implementations,O
+of,O
+the,O
+random,O
+model,O
+to,O
+map,O
+quantitative,O
+trait,O
+loci,O
+(,O
+QTLs,O
+),O
+.,O
+ , 
+The,O
+implementations,O
+use,O
+either,O
+the,O
+expectation,O
+or,O
+the,O
+distribution,O
+of,O
+the,O
+identity,O
+-,O
+by,O
+-,O
+descent,O
+value,O
+at,O
+a,O
+putative,O
+QTL,O
+and,O
+either,O
+a,O
+2,O
+x,O
+1,O
+vector,O
+of,O
+sib,O
+-,O
+pair,O
+traits,O
+or,O
+their,O
+scalar,O
+difference,O
+.,O
+ , 
+When,O
+the,O
+traits,O
+of,O
+both,O
+sibs,O
+are,O
+used,O
+,,O
+there,O
+is,O
+little,O
+difference,O
+between,O
+the,O
+expectation,O
+and,O
+distribution,O
+methods,O
+,,O
+while,O
+the,O
+expectation,O
+method,O
+suffers,O
+in,O
+both,O
+precision,O
+and,O
+power,O
+when,O
+the,O
+difference,O
+between,O
+traits,O
+is,O
+used,O
+.,O
+ , 
+This,O
+is,O
+consistent,O
+with,O
+the,O
+prediction,O
+that,O
+the,O
+difference,O
+between,O
+the,O
+expectation,O
+and,O
+distribution,O
+methods,O
+is,O
+inversely,O
+proportional,O
+to,O
+the,O
+amount,O
+of,O
+information,O
+available,O
+for,O
+mapping,O
+.,O
+ , 
+We,O
+find,O
+,,O
+though,O
+,,O
+that,O
+the,O
+amount,O
+of,O
+information,O
+must,O
+be,O
+very,O
+low,O
+for,O
+this,O
+difference,O
+to,O
+be,O
+noticeable,O
+.,O
+ , 
+This,O
+is,O
+exemplified,O
+when,O
+both,O
+marker,O
+loci,O
+are,O
+fixed,O
+.,O
+ , 
+In,O
+this,O
+case,O
+,,O
+while,O
+the,O
+expectation,O
+method,O
+is,O
+powerless,O
+to,O
+detect,O
+the,O
+QTL,O
+,,O
+the,O
+distribution,O
+method,O
+can,O
+still,O
+detect,O
+the,O
+presence,O
+(,O
+but,O
+not,O
+the,O
+position,O
+),O
+of,O
+the,O
+QTL,O
+59,O
+%,O
+of,O
+the,O
+time,O
+(,O
+when,O
+using,O
+trait,O
+values,O
+),O
+or,O
+14,O
+%,O
+of,O
+the,O
+time,O
+(,O
+when,O
+using,O
+trait,O
+differences,O
+),O
+.,O
+ , 
+We,O
+also,O
+note,O
+a,O
+confounding,O
+between,O
+estimates,O
+of,O
+the,O
+QTL,O
+,,O
+polygenic,O
+,,O
+and,O
+error,O
+variance,O
+.,O
+ , 
+The,O
+degree,O
+of,O
+confounding,O
+is,O
+small,O
+when,O
+the,O
+vector,O
+of,O
+trait,O
+values,O
+is,O
+used,O
+but,O
+can,O
+be,O
+substantial,O
+when,O
+the,O
+expectation,O
+method,O
+and,O
+trait,O
+differences,O
+are,O
+used,O
+.,O
+ , 
+We,O
+discuss,O
+this,O
+in,O
+light,O
+of,O
+the,O
+general,O
+ability,O
+of,O
+the,O
+random,O
+model,O
+to,O
+partition,O
+these,O
+components,O
+.,O
+ , 
+#12489041
+Distribution,O
+patterns,O
+of,O
+postmortem,O
+damage,O
+in,O
+human,O
+mitochondrial,O
+DNA,O
+.,O
+ , 
+The,O
+distribution,O
+of,O
+postmortem,O
+damage,O
+in,O
+mitochondrial,O
+DNA,O
+retrieved,O
+from,O
+37,O
+ancient,O
+human,O
+DNA,O
+samples,O
+was,O
+analyzed,O
+by,O
+cloning,O
+and,O
+was,O
+compared,O
+with,O
+a,O
+selection,O
+of,O
+published,O
+animal,O
+data,O
+.,O
+ , 
+A,O
+relative,O
+rate,O
+of,O
+damage,O
+(,O
+rho(v,O
+),O
+),O
+was,O
+calculated,O
+for,O
+nucleotide,O
+positions,O
+within,O
+the,O
+human,B-Gene
+hypervariable,I-Gene
+region,I-Gene
+1,I-Gene
+(,B-Gene
+HVR1,I-Gene
+),I-Gene
+and,O
+cytochrome,B-Gene
+oxidase,I-Gene
+subunit,I-Gene
+III,I-Gene
+genes,O
+.,O
+ , 
+A,O
+comparison,O
+of,O
+damaged,O
+sites,O
+within,O
+and,O
+between,O
+the,O
+regions,O
+reveals,O
+that,O
+damage,O
+hotspots,O
+exist,O
+and,O
+that,O
+,,O
+in,O
+the,O
+HVR1,B-Gene
+,,I-Gene
+these,O
+correlate,O
+with,O
+sites,O
+known,O
+to,O
+have,O
+high,O
+in,O
+vivo,O
+mutation,O
+rates,O
+.,O
+ , 
+Conversely,O
+,,O
+HVR1,B-Gene
+subregions,O
+with,O
+known,O
+structural,O
+function,O
+,,O
+such,O
+as,O
+MT5,O
+,,O
+have,O
+lower,O
+in,O
+vivo,O
+mutation,O
+rates,O
+and,O
+lower,O
+postmortem,O
+-,O
+damage,O
+rates,O
+.,O
+ , 
+The,O
+postmortem,O
+data,O
+also,O
+identify,O
+a,O
+possible,O
+functional,O
+subregion,O
+of,O
+the,O
+HVR1,B-Gene
+,,I-Gene
+termed,O
+",O
+low,O
+-,O
+diversity,O
+1,O
+,,O
+",O
+through,O
+the,O
+lack,O
+of,O
+sequence,O
+damage,O
+.,O
+ , 
+The,O
+amount,O
+of,O
+postmortem,O
+damage,O
+observed,O
+in,O
+mitochondrial,O
+coding,O
+regions,O
+was,O
+significantly,O
+lower,O
+than,O
+in,O
+the,O
+HVR1,B-Gene
+,,I-Gene
+and,O
+,,O
+although,O
+hotspots,O
+were,O
+noted,O
+,,O
+these,O
+did,O
+not,O
+correlate,O
+with,O
+codon,O
+position,O
+.,O
+ , 
+Finally,O
+,,O
+a,O
+simple,O
+method,O
+for,O
+the,O
+identification,O
+of,O
+incorrect,O
+archaeological,O
+haplogroup,O
+designations,O
+is,O
+introduced,O
+,,O
+on,O
+the,O
+basis,O
+of,O
+the,O
+observed,O
+spectrum,O
+of,O
+postmortem,O
+damage,O
+.,O
+ , 
+#8981950
+Hereditary,O
+multiple,O
+exostoses,O
+(,O
+EXT,O
+):,O
+mutational,O
+studies,O
+of,O
+familial,O
+EXT1,O
+cases,O
+and,O
+EXT,O
+-,O
+associated,O
+malignancies,O
+.,O
+ , 
+Hereditary,O
+multiple,O
+exostoses,O
+(,O
+EXT,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+disorder,O
+characterized,O
+by,O
+the,O
+formation,O
+of,O
+cartilage,O
+-,O
+capped,O
+prominences,O
+that,O
+develop,O
+from,O
+the,O
+growth,O
+centers,O
+of,O
+the,O
+long,O
+bones,O
+.,O
+ , 
+EXT,O
+is,O
+genetically,O
+heterogeneous,O
+,,O
+with,O
+three,O
+loci,O
+,,O
+currently,O
+identified,O
+on,O
+chromosomes,O
+8q24.1,O
+,,O
+11p13,O
+,,O
+and,O
+19q,O
+.,O
+ , 
+The,O
+EXT1,B-Gene
+gene,O
+,,O
+located,O
+on,O
+chromosome,O
+8q24.1,O
+,,O
+has,O
+been,O
+cloned,O
+and,O
+is,O
+encoded,O
+by,O
+a,O
+3.4,O
+-,O
+kb,O
+cDNA,O
+.,O
+ , 
+Five,O
+mutations,O
+in,O
+the,O
+EXT1,B-Gene
+gene,O
+have,O
+been,O
+identified,O
+--,O
+four,O
+germ,O
+-,O
+line,O
+mutations,O
+,,O
+including,O
+two,O
+unrelated,O
+families,O
+with,O
+the,O
+same,O
+mutation,O
+,,O
+and,O
+one,O
+somatic,O
+mutation,O
+in,O
+a,O
+patient,O
+with,O
+chondrosarcoma,O
+.,O
+ , 
+Four,O
+of,O
+the,O
+mutations,O
+identified,O
+resulted,O
+in,O
+frameshifts,O
+and,O
+premature,O
+termination,O
+codons,O
+,,O
+while,O
+the,O
+fifth,O
+mutation,O
+resulted,O
+in,O
+a,O
+substitution,O
+of,O
+leucine,O
+for,O
+arginine,O
+.,O
+ , 
+Loss,O
+of,O
+heterozygosity,O
+(,O
+LOH,O
+),O
+analysis,O
+of,O
+chondrosarcomas,O
+and,O
+chondroblastomas,O
+revealed,O
+multiple,O
+LOH,O
+events,O
+at,O
+loci,O
+on,O
+chromosomes,O
+3q,O
+,,O
+8q,O
+,,O
+10q,O
+,,O
+and,O
+19q,O
+.,O
+ , 
+One,O
+sporadic,O
+chondrosarcoma,O
+demonstrated,O
+LOH,O
+for,O
+EXT1,B-Gene
+and,O
+EXT3,B-Gene
+,,I-Gene
+while,O
+a,O
+second,O
+underwent,O
+LOH,O
+for,O
+EXT2,B-Gene
+and,O
+chromosome,O
+10,O
+.,O
+ , 
+A,O
+third,O
+chondrosarcoma,O
+underwent,O
+LOH,O
+for,O
+EXT1,B-Gene
+and,O
+chromosome,O
+3q,O
+.,O
+ , 
+These,O
+results,O
+agree,O
+with,O
+previous,O
+findings,O
+that,O
+mutations,O
+at,O
+EXT1,B-Gene
+and,O
+multiple,O
+genetic,O
+events,O
+that,O
+include,O
+LOH,O
+at,O
+other,O
+loci,O
+may,O
+be,O
+required,O
+for,O
+the,O
+development,O
+of,O
+chondrosarcoma,O
+.,O
+ , 
+#9683585
+Germ,O
+-,O
+line,O
+mutation,O
+analysis,O
+in,O
+patients,O
+with,O
+multiple,O
+endocrine,O
+neoplasia,O
+type,O
+1,O
+and,O
+related,O
+disorders,O
+.,O
+ , 
+Multiple,O
+endocrine,O
+neoplasia,O
+type,O
+1,O
+(,O
+MEN1,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+syndrome,O
+predisposing,O
+to,O
+tumors,O
+of,O
+the,O
+parathyroid,O
+,,O
+endocrine,O
+pancreas,O
+,,O
+anterior,O
+pituitary,O
+,,O
+adrenal,O
+glands,O
+,,O
+and,O
+diffuse,O
+neuroendocrine,O
+tissues,O
+.,O
+ , 
+The,O
+MEN1,B-Gene
+gene,O
+has,O
+been,O
+assigned,O
+,,O
+by,O
+linkage,O
+analysis,O
+and,O
+loss,O
+of,O
+heterozygosity,O
+,,O
+to,O
+chromosome,O
+11q13,O
+and,O
+recently,O
+has,O
+been,O
+identified,O
+by,O
+positional,O
+cloning,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+a,O
+total,O
+of,O
+84,O
+families,O
+and/or,O
+isolated,O
+patients,O
+with,O
+either,O
+MEN1,B-Gene
+or,O
+MEN1,O
+-,O
+related,O
+inherited,O
+endocrine,O
+tumors,O
+were,O
+screened,O
+for,O
+MEN1,O
+germ,O
+-,O
+line,O
+mutations,O
+,,O
+by,O
+heteroduplex,O
+and,O
+sequence,O
+analysis,O
+of,O
+the,O
+MEN1,B-Gene
+gene,O
+-,O
+coding,O
+region,O
+and,O
+untranslated,O
+exon,O
+1,O
+.,O
+ , 
+Germ,O
+-,O
+line,O
+MEN1,B-Gene
+alterations,O
+were,O
+identified,O
+in,O
+47/54,O
+(,O
+87,O
+%,O
+),O
+MEN1,B-Gene
+families,O
+,,O
+in,O
+9/11,O
+(,O
+82,O
+%,O
+),O
+isolated,O
+MEN1,B-Gene
+patients,O
+,,O
+and,O
+in,O
+only,O
+6/19,O
+(,O
+31.5,O
+%,O
+),O
+atypical,O
+MEN1,O
+-,O
+related,O
+inherited,O
+cases,O
+.,O
+ , 
+We,O
+characterized,O
+52,O
+distinct,O
+mutations,O
+in,O
+a,O
+total,O
+of,O
+62,O
+MEN1,B-Gene
+germ,O
+-,O
+line,O
+alterations,O
+.,O
+ , 
+Thirty,O
+-,O
+five,O
+of,O
+the,O
+52,O
+mutations,O
+were,O
+frameshifts,O
+and,O
+nonsense,O
+mutations,O
+predicted,O
+to,O
+encode,O
+for,O
+a,O
+truncated,O
+MEN1,B-Gene
+protein,O
+.,O
+ , 
+We,O
+identified,O
+eight,O
+missense,O
+mutations,O
+and,O
+five,O
+in,O
+-,O
+frame,O
+deletions,O
+over,O
+the,O
+entire,O
+coding,O
+sequence,O
+.,O
+ , 
+Six,O
+mutations,O
+were,O
+observed,O
+more,O
+than,O
+once,O
+in,O
+familial,O
+MEN1,B-Gene
+.,I-Gene
+ , 
+Haplotype,O
+analysis,O
+in,O
+families,O
+with,O
+identical,O
+mutations,O
+indicate,O
+that,O
+these,O
+occurrences,O
+reflected,O
+mainly,O
+independent,O
+mutational,O
+events,O
+.,O
+ , 
+No,O
+MEN1,B-Gene
+germ,O
+-,O
+line,O
+mutations,O
+were,O
+found,O
+in,O
+7/54,O
+(,O
+13,O
+%,O
+),O
+ , 
+MEN1,B-Gene
+families,O
+,,O
+in,O
+2/11,O
+(,O
+18,O
+%,O
+),O
+isolated,O
+MEN1,B-Gene
+cases,O
+,,O
+in,O
+13/19,O
+(,O
+68,O
+.,O
+5,O
+%,O
+),O
+MEN1,O
+-,O
+related,O
+cases,O
+,,O
+and,O
+in,O
+a,O
+kindred,O
+with,O
+familial,O
+isolated,O
+hyperparathyroidism,O
+.,O
+ , 
+Two,O
+hundred,O
+twenty,O
+gene,O
+carriers,O
+(,O
+167,O
+affected,O
+and,O
+53,O
+unaffected,O
+),O
+were,O
+identified,O
+.,O
+ , 
+No,O
+evidence,O
+of,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+was,O
+found,O
+.,O
+ , 
+Age,O
+-,O
+related,O
+penetrance,O
+was,O
+estimated,O
+to,O
+be,O
+>,O
+95,O
+%,O
+at,O
+age,O
+>,O
+30,O
+years,O
+.,O
+ , 
+Our,O
+results,O
+add,O
+to,O
+the,O
+diversity,O
+of,O
+MEN1,B-Gene
+germ,O
+-,O
+line,O
+mutations,O
+and,O
+provide,O
+new,O
+tools,O
+in,O
+genetic,O
+screening,O
+of,O
+MEN1,B-Gene
+and,O
+clinically,O
+related,O
+cases,O
+.,O
+ , 
+#18767143
+The,O
+FBN2,B-Gene
+gene,O
+:,O
+new,O
+mutations,O
+,,O
+locus,O
+-,O
+specific,O
+database,O
+(,O
+Universal,O
+Mutation,O
+Database,O
+FBN2,B-Gene
+),I-Gene
+,,O
+and,O
+genotype,O
+-,O
+phenotype,O
+correlations,O
+.,O
+ , 
+Congenital,O
+contractural,O
+arachnodactyly,O
+(,O
+CCA,O
+),O
+is,O
+an,O
+extremely,O
+rare,O
+disease,O
+,,O
+due,O
+to,O
+mutations,O
+in,O
+the,O
+FBN2,B-Gene
+gene,O
+encoding,O
+fibrillin-2,B-Gene
+.,I-Gene
+ , 
+Another,O
+member,O
+of,O
+the,O
+fibrillin,O
+family,O
+,,O
+the,O
+FBN1,B-Gene
+gene,O
+,,O
+is,O
+involved,O
+in,O
+a,O
+broad,O
+phenotypic,O
+continuum,O
+of,O
+connective,O
+-,O
+tissue,O
+disorders,O
+including,O
+Marfan,O
+syndrome,O
+.,O
+ , 
+Identifying,O
+not,O
+only,O
+what,O
+is,O
+in,O
+common,O
+but,O
+also,O
+what,O
+differentiates,O
+these,O
+two,O
+proteins,O
+should,O
+enable,O
+us,O
+to,O
+better,O
+comprehend,O
+their,O
+respective,O
+functions,O
+and,O
+better,O
+understand,O
+the,O
+multitude,O
+of,O
+diseases,O
+in,O
+which,O
+these,O
+two,O
+genes,O
+are,O
+involved,O
+.,O
+ , 
+In,O
+1995,O
+we,O
+created,O
+a,O
+locus,O
+-,O
+specific,O
+database,O
+(,O
+LSDB,O
+),O
+for,O
+FBN1,B-Gene
+mutations,O
+with,O
+the,O
+Universal,O
+Mutation,O
+Database,O
+(,O
+UMD,O
+),O
+tool,O
+.,O
+ , 
+To,O
+facilitate,O
+comparison,O
+of,O
+identified,O
+mutations,O
+in,O
+these,O
+two,O
+genes,O
+and,O
+search,O
+for,O
+specific,O
+functional,O
+areas,O
+,,O
+we,O
+created,O
+an,O
+LSDB,O
+for,O
+the,O
+FBN2,B-Gene
+gene,O
+:,O
+the,O
+UMD,O
+-,B-Gene
+FBN2,I-Gene
+database,O
+.,O
+ , 
+This,O
+database,O
+lists,O
+26,O
+published,O
+and,O
+six,O
+newly,O
+identified,O
+mutations,O
+that,O
+mainly,O
+comprise,O
+missense,O
+and,O
+splice,O
+-,O
+site,O
+mutations,O
+.,O
+ , 
+Although,O
+the,O
+number,O
+of,O
+described,O
+FBN2,B-Gene
+mutations,O
+was,O
+low,O
+,,O
+the,O
+frequency,O
+of,O
+joint,O
+dislocation,O
+was,O
+significantly,O
+higher,O
+with,O
+missense,O
+mutations,O
+when,O
+compared,O
+to,O
+splice,O
+site,O
+mutations,O
+.,O
+ , 
+#11813133
+A,O
+polymorphism,O
+in,O
+the,O
+human,O
+UGRP1,B-Gene
+gene,O
+promoter,O
+that,O
+regulates,O
+transcription,O
+is,O
+associated,O
+with,O
+an,O
+increased,O
+risk,O
+of,O
+asthma,O
+.,O
+ , 
+Several,O
+traits,O
+associated,O
+with,O
+asthma,O
+phenotypes,O
+,,O
+such,O
+as,O
+high,O
+total,O
+serum,O
+immunoglobulin,O
+E,O
+and,O
+bronchial,O
+hyperresponsiveness,O
+,,O
+have,O
+been,O
+linked,O
+by,O
+numerous,O
+genome,O
+-,O
+screen,O
+studies,O
+and,O
+linkage,O
+analyses,O
+to,O
+markers,O
+on,O
+human,O
+chromosome,O
+5q31,O
+-,O
+q34,O
+.,O
+ , 
+In,O
+the,O
+present,O
+article,O
+,,O
+we,O
+describe,O
+UGRP1,B-Gene
+(,O
+encoding,O
+uteroglobin,B-Gene
+-,I-Gene
+related,I-Gene
+protein,I-Gene
+1,I-Gene
+),I-Gene
+as,O
+one,O
+of,O
+asthma,O
+-,O
+susceptibility,O
+genes,O
+that,O
+is,O
+located,O
+on,O
+chromosome,O
+5q31,O
+-,O
+q32,O
+.,O
+ , 
+UGRP1,B-Gene
+is,O
+a,O
+homodimeric,O
+secretory,O
+protein,O
+of,O
+17,O
+kDa,O
+and,O
+is,O
+expressed,O
+only,O
+in,O
+lung,O
+and,O
+trachea,O
+.,O
+ , 
+The,O
+G,B-SNP
+--,I-SNP
+>,I-SNP
+A,I-SNP
+polymorphism,I-SNP
+was,I-SNP
+identified,I-SNP
+at,I-SNP
+-112,I-SNP
+bp,I-SNP
+in,O
+the,O
+human,O
+UGRP1,B-Gene
+gene,O
+promoter,O
+.,O
+ , 
+The,O
+-112A,O
+allele,O
+is,O
+responsible,O
+for,O
+a,O
+24,O
+%,O
+reduction,O
+in,O
+the,O
+promoter,O
+activity,O
+in,O
+relation,O
+to,O
+the,O
+-112,O
+G,O
+allele,O
+,,O
+as,O
+examined,O
+by,O
+transfection,O
+analysis,O
+.,O
+ , 
+Electrophoretic,O
+mobility,O
+-,O
+shift,O
+analysis,O
+revealed,O
+that,O
+an,O
+unknown,O
+nuclear,O
+factor,O
+binds,O
+to,O
+the,O
+region,O
+around,O
+-112,O
+bp,O
+.,O
+ , 
+The,O
+binding,O
+affinity,O
+with,O
+the,O
+-112A,O
+oligonucleotide,O
+was,O
+reduced,O
+by,O
+approximately,O
+one,O
+half,O
+,,O
+as,O
+compared,O
+with,O
+the,O
+-112,O
+G,O
+oligonucleotide,O
+.,O
+ , 
+In,O
+a,O
+case,O
+-,O
+control,O
+study,O
+using,O
+169,O
+Japanese,O
+individuals,O
+(,O
+84,O
+patients,O
+with,O
+asthma,O
+and,O
+85,O
+healthy,O
+control,O
+individuals,O
+),O
+,,O
+those,O
+with,O
+a,O
+-112A,O
+allele,O
+(,O
+G,O
+/,O
+A,O
+or,O
+A,O
+/,O
+A,O
+),O
+were,O
+4.1,O
+times,O
+more,O
+likely,O
+to,O
+have,O
+asthma,O
+than,O
+were,O
+those,O
+with,O
+the,O
+wild,O
+-,O
+type,O
+allele,O
+(,O
+G,O
+/,O
+G,O
+),O
+.,O
+ , 
+#8116617
+Paternal,O
+isodisomy,O
+for,O
+chromosome,O
+5,O
+in,O
+a,O
+child,O
+with,O
+spinal,O
+muscular,O
+atrophy,O
+.,O
+ , 
+Paternal,O
+isodisomy,O
+for,O
+chromosome,O
+5,O
+was,O
+detected,O
+in,O
+a,O
+2,O
+-,O
+year,O
+-,O
+old,O
+boy,O
+with,O
+type,O
+III,O
+spinal,O
+muscular,O
+atrophy,O
+(,B-Gene
+SMA,I-Gene
+),I-Gene
+,,O
+an,O
+autosomal,O
+recessive,O
+degenerative,O
+disorder,O
+of,O
+alpha,O
+motor,O
+neurons,O
+,,O
+known,O
+to,O
+map,O
+to,O
+5q11.2,O
+-,O
+13.3,O
+.,O
+ , 
+Examination,O
+of,O
+17,O
+short,O
+-,O
+sequence,O
+repeat,O
+polymorphisms,O
+spanning,O
+5p15.1,O
+-,O
+15.3,O
+to,O
+5q33.3,O
+-,O
+qter,O
+produced,O
+no,O
+evidence,O
+of,O
+maternally,O
+inherited,O
+alleles,O
+.,O
+ , 
+Cytogenetic,O
+analysis,O
+revealed,O
+a,O
+normal,O
+male,O
+karyotype,O
+,,O
+and,O
+FISH,O
+with,O
+probes,O
+closely,O
+flanking,O
+the,O
+SMA,B-Gene
+locus,O
+confirmed,O
+the,O
+presence,O
+of,O
+two,O
+copies,O
+of,O
+chromosome,O
+5,O
+.,O
+ , 
+No,O
+developmental,O
+abnormalities,O
+,,O
+other,O
+than,O
+those,O
+attributable,O
+to,O
+classical,O
+childhood,O
+-,O
+onset,O
+SMA,B-Gene
+,,I-Gene
+were,O
+present,O
+.,O
+ , 
+While,O
+the,O
+absence,O
+of,O
+a,O
+maternally,O
+derived,O
+chromosome,O
+5,O
+could,O
+have,O
+produced,O
+the,O
+symptoms,O
+of,O
+SMA,B-Gene
+through,O
+the,O
+mechanisms,O
+of,O
+genomic,O
+imprinting,O
+,,O
+the,O
+lack,O
+of,O
+more,O
+global,O
+developmental,O
+abnormalities,O
+would,O
+be,O
+unusual,O
+.,O
+ , 
+Paternal,O
+transmission,O
+of,O
+two,O
+copies,O
+of,O
+a,O
+defective,O
+gene,O
+at,O
+the,O
+SMA,B-Gene
+locus,O
+seems,O
+to,O
+be,O
+the,O
+most,O
+likely,O
+cause,O
+of,O
+disease,O
+,,O
+but,O
+proof,O
+of,O
+this,O
+will,O
+have,O
+to,O
+await,O
+the,O
+identification,O
+of,O
+the,O
+SMA,B-Gene
+gene,O
+.,O
+ , 
+While,O
+uniparental,O
+isodisomy,O
+is,O
+a,O
+rare,O
+event,O
+,,O
+it,O
+must,O
+be,O
+considered,O
+as,O
+a,O
+possible,O
+mechanism,O
+involved,O
+in,O
+SMA,B-Gene
+when,O
+conducting,O
+prenatal,O
+testing,O
+and,O
+counseling,O
+for,O
+this,O
+disorder,O
+.,O
+ , 
+#7825575
+Likelihood,O
+methods,O
+for,O
+locating,O
+disease,O
+genes,O
+in,O
+nonequilibrium,O
+populations,O
+.,O
+ , 
+Until,O
+recently,O
+,,O
+attempts,O
+to,O
+map,O
+disease,O
+genes,O
+on,O
+the,O
+basis,O
+of,O
+population,O
+associations,O
+with,O
+linked,O
+markers,O
+have,O
+been,O
+based,O
+on,O
+expected,O
+values,O
+of,O
+linkage,O
+disequilibrium,O
+.,O
+ , 
+These,O
+methods,O
+suffer,O
+from,O
+the,O
+large,O
+variances,O
+imposed,O
+on,O
+disequilibrium,O
+measures,O
+by,O
+the,O
+evolutionary,O
+process,O
+,,O
+but,O
+a,O
+more,O
+serious,O
+problem,O
+for,O
+many,O
+diseases,O
+is,O
+that,O
+they,O
+assume,O
+an,O
+equilibrium,O
+population,O
+.,O
+ , 
+For,O
+diseases,O
+that,O
+arose,O
+only,O
+a,O
+few,O
+hundred,O
+generations,O
+ago,O
+,,O
+it,O
+is,O
+more,O
+appropriate,O
+to,O
+concentrate,O
+on,O
+the,O
+initial,O
+growth,O
+phase,O
+of,O
+the,O
+disease,O
+.,O
+ , 
+We,O
+invoke,O
+a,O
+Poisson,O
+branching,O
+process,O
+for,O
+this,O
+early,O
+growth,O
+,,O
+and,O
+estimate,O
+the,O
+likelihood,O
+for,O
+the,O
+recombination,O
+fraction,O
+between,O
+marker,O
+and,O
+disease,O
+loci,O
+,,O
+on,O
+the,O
+basis,O
+of,O
+simulated,O
+disease,O
+populations,O
+.,O
+ , 
+The,O
+limits,O
+of,O
+the,O
+resulting,O
+support,O
+intervals,O
+for,O
+the,O
+recombination,O
+fraction,O
+vary,O
+inversely,O
+with,O
+the,O
+age,O
+of,O
+the,O
+disease,O
+in,O
+generations,O
+.,O
+ , 
+We,O
+illustrate,O
+the,O
+procedure,O
+with,O
+data,O
+on,O
+cystic,O
+fibrosis,O
+and,O
+diastrophic,O
+dysplasia,O
+,,O
+for,O
+which,O
+the,O
+method,O
+appears,O
+appropriate,O
+,,O
+and,O
+for,O
+Friedreich,O
+ataxia,O
+and,O
+Huntington,O
+disease,O
+,,O
+for,O
+which,O
+it,O
+does,O
+not,O
+.,O
+ , 
+A,O
+valuable,O
+aspect,O
+of,O
+the,O
+method,O
+is,O
+the,O
+ability,O
+in,O
+some,O
+cases,O
+to,O
+compare,O
+likelihoods,O
+of,O
+the,O
+three,O
+orders,O
+for,O
+a,O
+disease,O
+locus,O
+and,O
+two,O
+linked,O
+marker,O
+loci,O
+.,O
+ , 
+#8198127
+The,O
+genetic,O
+locus,O
+for,O
+free,O
+sialic,O
+acid,O
+storage,O
+disease,O
+maps,O
+to,O
+the,O
+long,O
+arm,O
+of,O
+chromosome,O
+6,O
+.,O
+ , 
+Salla,O
+disease,O
+(,O
+SD,O
+),O
+,,O
+or,O
+adult,O
+-,O
+type,O
+free,O
+sialic,O
+acid,O
+storage,O
+disease,O
+,,O
+is,O
+an,O
+autosomal,O
+recessive,O
+lysosomal,O
+storage,O
+disorder,O
+characterized,O
+by,O
+impaired,O
+transport,O
+of,O
+free,O
+sialic,O
+acid,O
+across,O
+the,O
+lysosomal,O
+membrane,O
+and,O
+severe,O
+psychomotor,O
+retardation,O
+.,O
+ , 
+Random,O
+linkage,O
+analysis,O
+of,O
+a,O
+sample,O
+of,O
+27,O
+Finnish,O
+families,O
+allowed,O
+us,O
+to,O
+localize,O
+the,O
+SD,O
+locus,O
+to,O
+the,O
+long,O
+arm,O
+of,O
+chromosome,O
+6,O
+.,O
+ , 
+The,O
+highest,O
+lod,O
+score,O
+of,O
+8.95,O
+was,O
+obtained,O
+with,O
+a,O
+microsatellite,O
+marker,O
+of,O
+locus,O
+D6S286,O
+at,O
+theta,O
+=,O
+.00,O
+.,O
+ , 
+Evidence,O
+for,O
+linkage,O
+disequilibrium,O
+was,O
+observed,O
+between,O
+the,O
+SD,O
+locus,O
+and,O
+the,O
+alleles,O
+of,O
+three,O
+closely,O
+linked,O
+markers,O
+,,O
+suggesting,O
+that,O
+the,O
+length,O
+of,O
+the,O
+critical,O
+region,O
+for,O
+the,O
+SD,O
+locus,O
+is,O
+in,O
+the,O
+order,O
+of,O
+190,O
+kb,O
+.,O
+ , 
+#9399915
+Centromere,O
+DNA,O
+dynamics,O
+:,O
+latent,O
+centromeres,O
+and,O
+neocentromere,O
+formation,O
+.,O
+ , 
+#22570304
+Retinitis,O
+pigmentosa,O
+:,O
+More,O
+genes,O
+,,O
+more,O
+variants,O
+,,O
+more,O
+work,O
+.,O
+ , 
+#15024727
+Genetically,O
+heterogeneous,O
+selective,O
+intestinal,O
+malabsorption,O
+of,O
+vitamin,O
+B12,O
+:,O
+founder,O
+effects,O
+,,O
+consanguinity,O
+,,O
+and,O
+high,O
+clinical,O
+awareness,O
+explain,O
+aggregations,O
+in,O
+Scandinavia,O
+and,O
+the,O
+Middle,O
+East,O
+.,O
+ , 
+Selective,O
+intestinal,O
+malabsorption,O
+of,O
+vitamin,O
+B(12,O
+),O
+causing,O
+juvenile,O
+megaloblastic,O
+anemia,O
+(,O
+MGA,O
+;,O
+MIM,O
+#,O
+261100,O
+),O
+is,O
+a,O
+recessively,O
+inherited,O
+disorder,O
+that,O
+is,O
+believed,O
+to,O
+be,O
+rare,O
+except,O
+for,O
+notable,O
+clusters,O
+of,O
+cases,O
+in,O
+Finland,O
+,,O
+Norway,O
+,,O
+and,O
+the,O
+Eastern,O
+Mediterranean,O
+region,O
+.,O
+ , 
+The,O
+disease,O
+can,O
+be,O
+caused,O
+by,O
+mutations,O
+in,O
+either,O
+the,O
+cubilin,B-Gene
+(,B-Gene
+CUBN,I-Gene
+;,I-Gene
+MGA1,B-Gene
+;,I-Gene
+MIM,O
+#,O
+602997,O
+),O
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+amnionless,B-Gene
+(,B-Gene
+AMN,I-Gene
+;,I-Gene
+MIM,O
+#,O
+605799,O
+),O
+gene,O
+.,O
+ , 
+To,O
+explain,O
+the,O
+peculiar,O
+geographical,O
+distribution,O
+,,O
+we,O
+hypothesized,O
+that,O
+mutations,O
+in,O
+one,O
+of,O
+the,O
+genes,O
+would,O
+mainly,O
+be,O
+responsible,O
+for,O
+the,O
+disease,O
+in,O
+Scandinavia,O
+,,O
+and,O
+mutations,O
+in,O
+the,O
+other,O
+gene,O
+in,O
+the,O
+Mediterranean,O
+region,O
+.,O
+ , 
+We,O
+studied,O
+42,O
+sibships,O
+and,O
+found,O
+all,O
+cases,O
+in,O
+Finland,O
+to,O
+be,O
+due,O
+to,O
+CUBN,B-Gene
+(,O
+three,O
+different,O
+mutations,O
+),O
+and,O
+all,O
+cases,O
+in,O
+Norway,O
+to,O
+be,O
+due,O
+to,O
+AMN,B-Gene
+(,O
+two,O
+different,O
+mutations,O
+),O
+,,O
+while,O
+in,O
+Turkey,O
+,,O
+Israel,O
+,,O
+and,O
+Saudi,O
+Arabia,O
+,,O
+there,O
+were,O
+two,O
+different,O
+AMN,B-Gene
+mutations,O
+and,O
+three,O
+different,O
+CUBN,B-Gene
+mutations,O
+.,O
+ , 
+Haplotype,O
+evidence,O
+excluded,O
+both,O
+CUBN,B-Gene
+and,O
+AMN,B-Gene
+conclusively,O
+in,O
+five,O
+families,O
+and,O
+tentatively,O
+in,O
+three,O
+families,O
+,,O
+suggesting,O
+the,O
+presence,O
+of,O
+at,O
+least,O
+one,O
+more,O
+gene,O
+locus,O
+that,O
+can,O
+cause,O
+MGA,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+the,O
+Scandinavian,O
+cases,O
+are,O
+typical,O
+examples,O
+of,O
+enrichment,O
+by,O
+founder,O
+effects,O
+,,O
+while,O
+in,O
+the,O
+Mediterranean,O
+region,O
+high,O
+degrees,O
+of,O
+consanguinity,O
+expose,O
+rare,O
+mutations,O
+in,O
+both,O
+genes,O
+.,O
+ , 
+We,O
+suggest,O
+that,O
+in,O
+both,O
+regions,O
+,,O
+physician,O
+awareness,O
+of,O
+this,O
+disease,O
+causes,O
+it,O
+to,O
+be,O
+more,O
+readily,O
+diagnosed,O
+than,O
+elsewhere,O
+;,O
+thus,O
+,,O
+it,O
+may,O
+well,O
+be,O
+more,O
+common,O
+worldwide,O
+than,O
+previously,O
+thought,O
+.,O
+ , 
+#10712209
+Combined,O
+analysis,O
+of,O
+hereditary,O
+prostate,O
+cancer,O
+linkage,O
+to,O
+1q24,O
+-,O
+25,O
+:,O
+results,O
+from,O
+772,O
+hereditary,O
+prostate,O
+cancer,O
+families,O
+from,O
+the,O
+International,O
+Consortium,O
+for,O
+Prostate,O
+Cancer,O
+Genetics,O
+.,O
+ , 
+A,O
+previous,O
+linkage,O
+study,O
+provided,O
+evidence,O
+for,O
+a,O
+prostate,O
+cancer,O
+-,O
+susceptibility,O
+locus,O
+at,O
+1q24,O
+-,O
+25,O
+.,O
+ , 
+Subsequent,O
+reports,O
+in,O
+additional,O
+collections,O
+of,O
+families,O
+have,O
+yielded,O
+conflicting,O
+results,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+evidence,O
+for,O
+locus,O
+heterogeneity,O
+has,O
+been,O
+provided,O
+by,O
+the,O
+identification,O
+of,O
+other,O
+putative,O
+hereditary,O
+prostate,O
+cancer,O
+loci,O
+on,O
+Xq27,O
+-,O
+28,O
+,,O
+1q42,O
+-,O
+43,O
+,,O
+and,O
+1p36,O
+.,O
+ , 
+The,O
+present,O
+study,O
+describes,O
+a,O
+combined,O
+analysis,O
+for,O
+six,O
+markers,O
+in,O
+the,O
+1q24,O
+-,O
+25,O
+region,O
+in,O
+772,O
+families,O
+affected,O
+by,O
+hereditary,O
+prostate,O
+cancer,O
+and,O
+ascertained,O
+by,O
+the,O
+members,O
+of,O
+the,O
+International,O
+Consortium,O
+for,O
+Prostate,O
+Cancer,O
+Genetics,O
+(,O
+ICPCG,O
+),O
+from,O
+North,O
+America,O
+,,O
+Australia,O
+,,O
+Finland,O
+,,O
+Norway,O
+,,O
+Sweden,O
+,,O
+and,O
+the,O
+United,O
+Kingdom,O
+.,O
+ , 
+Overall,O
+,,O
+there,O
+was,O
+some,O
+evidence,O
+for,O
+linkage,O
+,,O
+with,O
+a,O
+peak,O
+parametric,O
+multipoint,O
+LOD,O
+score,O
+assuming,O
+heterogeneity,O
+(,O
+HLOD,O
+),O
+of,O
+1.40,O
+(,O
+P=.01,O
+),O
+at,O
+D1S212,O
+.,O
+ , 
+The,O
+estimated,O
+proportion,O
+of,O
+families,O
+(,O
+alpha,O
+),O
+linked,O
+to,O
+the,O
+locus,O
+was.06,O
+(,O
+1,O
+-,O
+LOD,O
+support,O
+interval.01-.12,O
+),O
+.,O
+ , 
+This,O
+evidence,O
+was,O
+not,O
+observed,O
+by,O
+a,O
+nonparametric,O
+approach,O
+,,O
+presumably,O
+because,O
+of,O
+the,O
+extensive,O
+heterogeneity,O
+.,O
+ , 
+Further,O
+parametric,O
+analysis,O
+revealed,O
+a,O
+significant,O
+effect,O
+of,O
+the,O
+presence,O
+of,O
+male,O
+-,O
+to,O
+-,O
+male,O
+disease,O
+transmission,O
+within,O
+the,O
+families,O
+.,O
+ , 
+In,O
+the,O
+subset,O
+of,O
+491,O
+such,O
+families,O
+,,O
+the,O
+peak,O
+HLOD,O
+was,O
+2.56,O
+(,O
+P=.0006,O
+),O
+and,O
+alpha,O
+=,O
+.11,O
+ , 
+(,O
+1,O
+-,O
+LOD,O
+support,O
+interval.04-.19,O
+),O
+,,O
+compared,O
+with,O
+HLODs,O
+of,O
+0,O
+in,O
+the,O
+remaining,O
+281,O
+families,O
+.,O
+ , 
+Within,O
+the,O
+families,O
+with,O
+male,O
+-,O
+to,O
+-,O
+male,O
+disease,O
+transmission,O
+,,O
+alpha,O
+increased,O
+with,O
+the,O
+early,O
+mean,O
+age,O
+at,O
+diagnosis,O
+(,O
+<,O
+65,O
+years,O
+,,O
+alpha,O
+=,O
+.19,O
+,,O
+with,O
+1,O
+-,O
+LOD,O
+support,O
+interval.06-.34,O
+),O
+and,O
+the,O
+number,O
+of,O
+affected,O
+family,O
+members,O
+(,O
+five,O
+or,O
+more,O
+family,O
+members,O
+,,O
+alpha,O
+=,O
+.15,O
+,,O
+with,O
+1,O
+-,O
+LOD,O
+support,O
+interval.04-.28,O
+),O
+.,O
+ , 
+The,O
+highest,O
+value,O
+of,O
+alpha,O
+was,O
+observed,O
+for,O
+the,O
+48,O
+families,O
+that,O
+met,O
+all,O
+three,O
+criteria,O
+(,O
+peak,O
+HLOD,O
+=,O
+ , 
+2.25,O
+,,O
+P=.001,O
+,,O
+alpha=.29,O
+,,O
+with,O
+1,O
+-,O
+LOD,O
+support,O
+interval.08-.53,O
+),O
+ , 
+.,O
+ , 
+These,O
+results,O
+support,O
+the,O
+finding,O
+of,O
+a,O
+prostate,O
+cancer,O
+-,O
+susceptibility,O
+gene,O
+linked,O
+to,O
+1q24,O
+-,O
+25,O
+,,O
+albeit,O
+in,O
+a,O
+defined,O
+subset,O
+of,O
+prostate,O
+cancer,O
+families,O
+.,O
+ , 
+Although,O
+HPC1,B-Gene
+accounts,O
+for,O
+only,O
+a,O
+small,O
+proportion,O
+of,O
+all,O
+families,O
+affected,O
+by,O
+hereditary,O
+prostate,O
+cancer,O
+,,O
+it,O
+appears,O
+to,O
+play,O
+a,O
+more,O
+prominent,O
+role,O
+in,O
+the,O
+subset,O
+of,O
+families,O
+with,O
+several,O
+members,O
+affected,O
+at,O
+an,O
+early,O
+age,O
+and,O
+with,O
+male,O
+-,O
+to,O
+-,O
+male,O
+disease,O
+transmission,O
+.,O
+ , 
+#10486328
+Assignment,O
+of,O
+the,O
+locus,O
+for,O
+hydrolethalus,O
+syndrome,O
+to,O
+a,O
+highly,O
+restricted,O
+region,O
+on,O
+11q23,O
+-,O
+25,O
+.,O
+ , 
+Hydrolethalus,O
+syndrome,O
+is,O
+a,O
+recessively,O
+inherited,O
+lethal,O
+malformation,O
+syndrome,O
+characterized,O
+by,O
+hydrocephaly,O
+with,O
+absent,O
+midline,O
+structures,O
+of,O
+the,O
+brain,O
+,,O
+micrognathia,O
+,,O
+polydactyly,O
+,,O
+and,O
+several,O
+other,O
+abnormalities,O
+,,O
+mostly,O
+in,O
+the,O
+midline,O
+structures,O
+.,O
+ , 
+Hydrolethalus,O
+syndrome,O
+was,O
+described,O
+in,O
+1981,O
+in,O
+Finland,O
+,,O
+where,O
+the,O
+incidence,O
+is,O
+1:20,000,O
+.,O
+ , 
+Only,O
+a,O
+few,O
+cases,O
+have,O
+been,O
+reported,O
+elsewhere,O
+,,O
+and,O
+the,O
+pathogenesis,O
+has,O
+remained,O
+unknown,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+the,O
+assignment,O
+of,O
+the,O
+hydrolethalus,O
+syndrome,O
+locus,O
+to,O
+chromosome,O
+11q23,O
+-,O
+25,O
+in,O
+Finnish,O
+families,O
+.,O
+ , 
+The,O
+initial,O
+genome,O
+scan,O
+was,O
+performed,O
+using,O
+DNA,O
+samples,O
+from,O
+only,O
+15,O
+affected,O
+individuals,O
+.,O
+ , 
+In,O
+the,O
+next,O
+step,O
+,,O
+the,O
+hydrolethalus,O
+syndrome,O
+locus,O
+was,O
+assigned,O
+to,O
+an,O
+8.5,O
+-,O
+cM,O
+interval,O
+between,O
+markers,O
+D11S4144,O
+and,O
+D11S1351,O
+by,O
+linkage,O
+analysis,O
+in,O
+eight,O
+families,O
+.,O
+ , 
+Finally,O
+,,O
+the,O
+critical,O
+locus,O
+could,O
+be,O
+restricted,O
+by,O
+linkage,O
+disequilibrium,O
+and,O
+haplotype,O
+analyses,O
+to,O
+a,O
+0.5,O
+-,O
+1,O
+-,O
+cM,O
+region,O
+between,O
+markers,O
+D11S933,O
+and,O
+D11S934,O
+.,O
+ , 
+Genealogical,O
+studies,O
+performed,O
+in,O
+40,O
+families,O
+affected,O
+by,O
+hydrolethalus,O
+revealed,O
+no,O
+regional,O
+clustering,O
+,,O
+suggesting,O
+a,O
+relatively,O
+early,O
+introduction,O
+of,O
+the,O
+disease,O
+mutation,O
+into,O
+the,O
+Finnish,O
+population,O
+and,O
+the,O
+spreading,O
+of,O
+the,O
+mutation,O
+with,O
+the,O
+inhabitation,O
+of,O
+the,O
+late,O
+-,O
+settlement,O
+area,O
+.,O
+ , 
+#1539591
+A,O
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+dystrophin,O
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+C,O
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+terminal,O
+domains,O
+is,O
+localized,O
+at,O
+the,O
+muscle,O
+membrane,O
+.,O
+ , 
+A,O
+Duchenne,O
+muscular,O
+dystrophy,O
+patient,O
+who,O
+displayed,O
+near,O
+-,O
+normal,O
+dystrophin,O
+staining,O
+at,O
+the,O
+sarcolemma,O
+with,O
+N,O
+-,O
+terminal,O
+,,O
+but,O
+not,O
+with,O
+C,O
+-,O
+terminal,O
+,,O
+anti,O
+-,O
+dystrophin,O
+monoclonal,O
+antibodies,O
+was,O
+found,O
+to,O
+have,O
+a,O
+frameshift,O
+deletion,O
+of,O
+exons,O
+42,O
+and,O
+43,O
+.,O
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+This,O
+deletion,O
+introduces,O
+an,O
+early,O
+termination,O
+codon,O
+,,O
+and,O
+a,O
+225,O
+-,O
+kD,O
+protein,O
+was,O
+detected,O
+by,O
+western,O
+blotting,O
+with,O
+N,O
+-,O
+terminal,O
+antibodies,O
+only,O
+.,O
+ , 
+The,O
+results,O
+suggest,O
+that,O
+an,O
+N,O
+-,O
+terminal,O
+truncated,O
+dystrophin,O
+fragment,O
+encoded,O
+by,O
+exon,O
+1,O
+-,O
+41,O
+is,O
+able,O
+to,O
+associate,O
+with,O
+the,O
+muscle,O
+cell,O
+membrane,O
+.,O
+ , 
+The,O
+current,O
+idea,O
+that,O
+the,O
+C,O
+-,O
+terminal,O
+domains,O
+of,O
+dystrophin,O
+are,O
+important,O
+or,O
+essential,O
+for,O
+its,O
+integration,O
+with,O
+the,O
+sarcolemma,O
+may,O
+have,O
+to,O
+be,O
+reexamined,O
+in,O
+the,O
+light,O
+of,O
+these,O
+observations,O
+.,O
+ , 
+#10477429
+TP53,B-Gene
+mutation,O
+and,O
+haplotype,O
+analysis,O
+of,O
+two,O
+large,O
+African,O
+American,O
+families,O
+.,O
+ , 
+Two,O
+large,O
+apparently,O
+unrelated,O
+African,O
+American,O
+families,O
+with,O
+a,O
+high,O
+incidence,O
+of,O
+breast,O
+cancer,O
+and,O
+other,O
+tumors,O
+characteristic,O
+of,O
+Li,O
+-,O
+Fraumeni,O
+breast,O
+sarcoma,O
+cancer,O
+family,O
+syndrome,O
+were,O
+studied,O
+.,O
+ , 
+Mutation,O
+screening,O
+revealed,O
+that,O
+in,O
+both,O
+families,O
+the,O
+affected,O
+members,O
+carried,O
+a,O
+germline,O
+mutation,O
+of,O
+the,O
+TP53,B-Gene
+gene,O
+at,O
+codon,B-SNP
+133,I-SNP
+(,I-SNP
+ATG--,I-SNP
+>,I-SNP
+ACG,I-SNP
+,,I-SNP
+M133,B-SNP
+T,I-SNP
+),I-SNP
+.,O
+ , 
+In,O
+order,O
+to,O
+determine,O
+whether,O
+an,O
+ancestral,O
+haplotype,O
+was,O
+shared,O
+by,O
+these,O
+two,O
+families,O
+,,O
+polymorphic,O
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+TP53,B-Gene
+gene,O
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+.,O
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+Haplotype,O
+analysis,O
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+five,O
+markers,O
+revealed,O
+an,O
+identical,O
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+by,O
+the,O
+two,O
+families,O
+.,O
+ , 
+Loss,O
+of,O
+heterozygosity,O
+at,O
+the,O
+TP53,B-Gene
+locus,O
+in,O
+the,O
+probands,O
+',O
+tumor,O
+tissues,O
+from,O
+each,O
+family,O
+was,O
+observed,O
+;,O
+in,O
+each,O
+case,O
+,,O
+the,O
+retained,O
+allele,O
+carried,O
+the,O
+common,O
+haplotype,O
+.,O
+ , 
+The,O
+frequency,O
+of,O
+this,O
+haplotype,O
+in,O
+the,O
+general,O
+African,O
+American,O
+population,O
+is,O
+<,O
+0.003,O
+.,O
+ , 
+This,O
+unique,O
+haplotype,O
+,,O
+combined,O
+with,O
+the,O
+rare,O
+TP53,B-Gene
+mutation,O
+,,O
+suggests,O
+that,O
+these,O
+African,O
+American,O
+families,O
+share,O
+a,O
+common,O
+ancestry,O
+.,O
+ , 
+This,O
+finding,O
+suggests,O
+that,O
+other,O
+African,O
+Americans,O
+may,O
+be,O
+carriers,O
+of,O
+this,O
+mutation,O
+and,O
+thus,O
+may,O
+be,O
+at,O
+risk,O
+of,O
+early,O
+-,O
+onset,O
+breast,O
+cancer,O
+or,O
+other,O
+cancers,O
+characteristic,O
+of,O
+the,O
+Li,O
+-,O
+Fraumeni,O
+breast,O
+sarcoma,O
+cancer,O
+family,O
+syndrome,O
+.,O
+ , 
+The,O
+finding,O
+of,O
+recurring,O
+mutations,O
+in,O
+African,O
+Americans,O
+may,O
+facilitate,O
+carrier,O
+screening,O
+and,O
+identification,O
+in,O
+this,O
+population,O
+.,O
+ , 
+#12497643
+Splice,O
+mutations,O
+in,O
+the,O
+p53,B-Gene
+gene,O
+:,O
+case,O
+report,O
+and,O
+review,O
+of,O
+the,O
+literature,O
+.,O
+ , 
+Splice,O
+mutations,O
+in,O
+the,O
+p53,B-Gene
+gene,O
+(,B-Gene
+TP53,I-Gene
+),I-Gene
+are,O
+described,O
+as,O
+rare,O
+events,O
+that,O
+occur,O
+at,O
+a,O
+frequency,O
+of,O
+less,O
+than,O
+1,O
+%,O
+.,O
+ , 
+Using,O
+a,O
+functional,O
+assay,O
+based,O
+on,O
+the,O
+transcriptional,O
+activity,O
+of,O
+p53,B-Gene
+and,O
+using,O
+RNA,O
+as,O
+starting,O
+material,O
+,,O
+we,O
+describe,O
+here,O
+a,O
+p53,B-Gene
+splice,O
+mutation,O
+that,O
+could,O
+not,O
+be,O
+detected,O
+by,O
+genomic,O
+sequencing,O
+.,O
+ , 
+This,O
+lack,O
+of,O
+detection,O
+is,O
+due,O
+to,O
+a,O
+deletion,O
+of,O
+the,O
+region,O
+complementary,O
+to,O
+primers,O
+commonly,O
+used,O
+for,O
+amplification,O
+.,O
+ , 
+Reviewing,O
+the,O
+literature,O
+,,O
+we,O
+show,O
+that,O
+p53,B-Gene
+splice,O
+mutations,O
+have,O
+been,O
+certainly,O
+underestimated,O
+and,O
+that,O
+careful,O
+strategy,O
+should,O
+be,O
+used,O
+for,O
+a,O
+complete,O
+mutational,O
+analysis,O
+of,O
+the,O
+p53,B-Gene
+gene,O
+.,O
+ , 
+Furthermore,O
+,,O
+some,O
+p53,B-Gene
+gene,O
+mutations,O
+described,O
+as,O
+",O
+neutral,O
+",O
+due,O
+to,O
+the,O
+absence,O
+of,O
+any,O
+amino,O
+-,O
+acid,O
+change,O
+are,O
+truly,O
+deleterious,O
+,,O
+as,O
+they,O
+affect,O
+gene,O
+splicing,O
+.,O
+ , 
+#17621639
+Detection,O
+of,O
+pathogenic,O
+gene,O
+copy,O
+number,O
+variations,O
+in,O
+patients,O
+with,O
+mental,O
+retardation,O
+by,O
+genomewide,O
+oligonucleotide,O
+array,O
+comparative,O
+genomic,O
+hybridization,O
+.,O
+ , 
+Genomic,O
+imbalance,O
+is,O
+a,O
+major,O
+cause,O
+of,O
+developmental,O
+disorders,O
+.,O
+ , 
+Microarray,O
+-,O
+based,O
+comparative,O
+genomic,O
+hybridization,O
+(,O
+aCGH,O
+),O
+has,O
+revealed,O
+frequent,O
+imbalances,O
+associated,O
+with,O
+clinical,O
+syndromes,O
+,,O
+but,O
+also,O
+a,O
+large,O
+number,O
+of,O
+copy,O
+number,O
+variations,O
+(,O
+CNVs,O
+),O
+,,O
+which,O
+have,O
+complicated,O
+the,O
+interpretation,O
+of,O
+results,O
+.,O
+ , 
+We,O
+studied,O
+100,O
+consecutive,O
+patients,O
+with,O
+unexplained,O
+mental,O
+retardation,O
+and,O
+a,O
+normal,O
+karyotype,O
+using,O
+several,O
+platforms,O
+of,O
+CGH,O
+arrays,O
+.,O
+ , 
+A,O
+genomewide,O
+array,O
+with,O
+44,290,O
+oligonucleotide,O
+probes,O
+(,O
+OaCGH44,O
+K,O
+),O
+detected,O
+imbalances,O
+in,O
+15,O
+%,O
+of,O
+cases,O
+studied,O
+with,O
+sizes,O
+ranged,O
+from,O
+459,O
+kb,O
+to,O
+19,O
+Mb,O
+while,O
+revealing,O
+a,O
+small,O
+number,O
+of,O
+CNVs,O
+(,O
+0.72,O
+/,O
+individual,O
+),O
+.,O
+ , 
+Another,O
+platform,O
+with,O
+approximately,O
+240,000,O
+oligonucleotide,O
+probes,O
+(,O
+OaCGH244,O
+K,O
+),O
+revealed,O
+a,O
+large,O
+number,O
+of,O
+CNVs,O
+(,O
+20,O
+/,O
+individual,O
+),O
+in,O
+selected,O
+cases,O
+and,O
+their,O
+normal,O
+parents,O
+.,O
+ , 
+We,O
+used,O
+a,O
+comprehensive,O
+approach,O
+for,O
+interpreting,O
+the,O
+results,O
+of,O
+aCGH,O
+,,O
+including,O
+consideration,O
+of,O
+the,O
+size,O
+,,O
+inheritance,O
+and,O
+gene,O
+content,O
+of,O
+CNVs,O
+,,O
+and,O
+consultation,O
+with,O
+an,O
+online,O
+Database,O
+of,O
+Genomic,O
+Variants,O
+(,O
+DGV,O
+),O
+and,O
+Online,O
+Mendelian,O
+Inheritance,O
+in,O
+Men,O
+(,O
+OMIM,O
+),O
+for,O
+information,O
+on,O
+the,O
+genes,O
+involved,O
+.,O
+ , 
+Our,O
+study,O
+suggests,O
+that,O
+genomewide,O
+oligonucleotide,O
+arrays,O
+such,O
+as,O
+the,O
+OaCGH44,O
+K,O
+platform,O
+can,O
+be,O
+used,O
+as,O
+a,O
+powerful,O
+diagnostic,O
+tool,O
+for,O
+detection,O
+of,O
+genomic,O
+imbalances,O
+associated,O
+with,O
+unexplained,O
+mental,O
+retardation,O
+or,O
+syndromic,O
+autism,O
+spectrum,O
+disorders,O
+.,O
+ , 
+It,O
+is,O
+interesting,O
+to,O
+note,O
+that,O
+a,O
+small,O
+number,O
+of,O
+common,O
+variants,O
+were,O
+revealed,O
+by,O
+OaCGH244,O
+K,O
+in,O
+some,O
+study,O
+subjects,O
+but,O
+not,O
+in,O
+their,O
+parents,O
+and,O
+that,O
+some,O
+inherited,O
+CNVs,O
+had,O
+altered,O
+breakpoints,O
+.,O
+ , 
+Further,O
+investigations,O
+on,O
+these,O
+alterations,O
+may,O
+provide,O
+useful,O
+information,O
+for,O
+understanding,O
+the,O
+mechanism,O
+of,O
+CNVs,O
+.,O
+ , 
+#11793474
+Integrating,O
+mutation,O
+data,O
+and,O
+structural,O
+analysis,O
+of,O
+the,O
+TP53,B-Gene
+tumor,O
+-,O
+suppressor,O
+protein,O
+.,O
+ , 
+TP53,B-Gene
+encodes,O
+p53,B-Gene
+,,I-Gene
+which,O
+is,O
+a,O
+nuclear,O
+phosphoprotein,O
+with,O
+cancer,O
+-,O
+inhibiting,O
+properties,O
+.,O
+ , 
+In,O
+response,O
+to,O
+DNA,O
+damage,O
+,,O
+p53,B-Gene
+is,O
+activated,O
+and,O
+mediates,O
+a,O
+set,O
+of,O
+antiproliferative,O
+responses,O
+including,O
+cell,O
+-,O
+cycle,O
+arrest,O
+and,O
+apoptosis,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+TP53,B-Gene
+gene,O
+are,O
+associated,O
+with,O
+more,O
+than,O
+50,O
+%,O
+of,O
+human,O
+cancers,O
+,,O
+and,O
+90,O
+%,O
+of,O
+these,O
+affect,O
+p53,O
+-,O
+DNA,O
+interactions,O
+,,O
+resulting,O
+in,O
+a,O
+partial,O
+or,O
+complete,O
+loss,O
+of,O
+transactivation,O
+functions,O
+.,O
+ , 
+These,O
+mutations,O
+affect,O
+the,O
+structural,O
+integrity,O
+and/or,O
+p53,B-Gene
+-,I-Gene
+DNA,O
+interactions,O
+,,O
+leading,O
+to,O
+the,O
+partial,O
+or,O
+complete,O
+loss,O
+of,O
+the,O
+protein,O
+'s,O
+function,O
+.,O
+ , 
+We,O
+report,O
+here,O
+the,O
+results,O
+of,O
+a,O
+systematic,O
+automated,O
+analysis,O
+of,O
+the,O
+effects,O
+of,O
+p53,B-Gene
+mutations,O
+on,O
+the,O
+structure,O
+of,O
+the,O
+core,O
+domain,O
+of,O
+the,O
+protein,O
+.,O
+ , 
+We,O
+found,O
+that,O
+304,O
+of,O
+the,O
+882,O
+(,O
+34.4,O
+%,O
+),O
+distinct,O
+mutations,O
+reported,O
+in,O
+the,O
+core,O
+domain,O
+can,O
+be,O
+explained,O
+in,O
+structural,O
+terms,O
+by,O
+their,O
+predicted,O
+effects,O
+on,O
+protein,O
+folding,O
+or,O
+on,O
+protein,O
+-,O
+DNA,O
+contacts,O
+.,O
+ , 
+The,O
+proportion,O
+of,O
+",O
+explained,O
+",O
+mutations,O
+increased,O
+to,O
+55.6,O
+%,O
+when,O
+substitutions,O
+of,O
+evolutionary,O
+conserved,O
+amino,O
+acids,O
+were,O
+included,O
+.,O
+ , 
+The,O
+automated,O
+method,O
+of,O
+structural,O
+analysis,O
+developed,O
+here,O
+may,O
+be,O
+applied,O
+to,O
+other,O
+frequently,O
+mutated,O
+gene,O
+mutations,O
+such,O
+as,O
+dystrophin,B-Gene
+,,I-Gene
+BRCA1,B-Gene
+,,I-Gene
+and,O
+G6PD,B-Gene
+.,I-Gene
+ , 
+#22473970
+A,O
+diagnostic,O
+genetic,O
+test,O
+for,O
+the,O
+physical,O
+mapping,O
+of,O
+germline,O
+rearrangements,O
+in,O
+the,O
+susceptibility,O
+breast,O
+cancer,O
+genes,O
+BRCA1,B-Gene
+and,O
+BRCA2,B-Gene
+.,I-Gene
+ , 
+The,O
+BRCA1,B-Gene
+and,O
+BRCA2,B-Gene
+genes,O
+are,O
+involved,O
+in,O
+breast,O
+and,O
+ovarian,O
+cancer,O
+susceptibility,O
+.,O
+ , 
+About,O
+2,O
+to,O
+4,O
+%,O
+of,O
+breast,O
+cancer,O
+patients,O
+with,O
+positive,O
+family,O
+history,O
+,,O
+negative,O
+for,O
+point,O
+mutations,O
+,,O
+can,O
+be,O
+expected,O
+to,O
+carry,O
+large,O
+rearrangements,O
+in,O
+one,O
+of,O
+these,O
+two,O
+genes,O
+.,O
+ , 
+We,O
+developed,O
+a,O
+novel,O
+diagnostic,O
+genetic,O
+test,O
+for,O
+the,O
+physical,O
+mapping,O
+of,O
+large,O
+rearrangements,O
+,,O
+based,O
+on,O
+molecular,O
+combing,O
+(,O
+MC,O
+),O
+,,O
+a,O
+FISH,O
+-,O
+based,O
+technique,O
+for,O
+direct,O
+visualization,O
+of,O
+single,O
+DNA,O
+molecules,O
+at,O
+high,O
+resolution,O
+.,O
+ , 
+We,O
+designed,O
+specific,O
+Genomic,O
+Morse,O
+Codes,O
+(,O
+GMCs,O
+),O
+,,O
+covering,O
+the,O
+exons,O
+,,O
+the,O
+noncoding,O
+regions,O
+,,O
+and,O
+large,O
+genomic,O
+portions,O
+flanking,O
+both,O
+genes,O
+.,O
+ , 
+We,O
+validated,O
+our,O
+approach,O
+by,O
+testing,O
+10,O
+index,O
+cases,O
+with,O
+positive,O
+family,O
+history,O
+of,O
+breast,O
+cancer,O
+and,O
+50,O
+negative,O
+controls,O
+.,O
+ , 
+Large,O
+rearrangements,O
+,,O
+corresponding,O
+to,O
+deletions,O
+and,O
+duplications,O
+with,O
+sizes,O
+ranging,O
+from,O
+3,O
+to,O
+40,O
+kb,O
+,,O
+were,O
+detected,O
+and,O
+characterized,O
+on,O
+both,O
+genes,O
+,,O
+including,O
+four,O
+novel,O
+mutations,O
+.,O
+ , 
+The,O
+nature,O
+of,O
+all,O
+the,O
+identified,O
+mutations,O
+was,O
+confirmed,O
+by,O
+high,O
+-,O
+resolution,O
+array,O
+comparative,O
+genomic,O
+hybridization,O
+(,O
+aCGH,O
+),O
+and,O
+breakpoints,O
+characterized,O
+by,O
+sequencing,O
+.,O
+ , 
+The,O
+developed,O
+GMCs,O
+allowed,O
+to,O
+localize,O
+several,O
+tandem,O
+repeat,O
+duplications,O
+on,O
+both,O
+genes,O
+.,O
+ , 
+We,O
+propose,O
+the,O
+developed,O
+genetic,O
+test,O
+as,O
+a,O
+valuable,O
+tool,O
+to,O
+screen,O
+large,O
+rearrangements,O
+in,O
+BRCA1,B-Gene
+and,O
+BRCA2,B-Gene
+to,O
+be,O
+combined,O
+in,O
+clinical,O
+settings,O
+with,O
+an,O
+assay,O
+capable,O
+of,O
+detecting,O
+small,O
+mutations,O
+.,O
+ , 
+#7726158
+Seven,O
+novel,O
+mutations,O
+in,O
+the,O
+methylenetetrahydrofolate,B-Gene
+reductase,I-Gene
+gene,O
+and,O
+genotype,O
+/,O
+phenotype,O
+correlations,O
+in,O
+severe,O
+methylenetetrahydrofolate,B-Gene
+reductase,I-Gene
+deficiency,O
+.,O
+ , 
+5,O
+-,O
+Methyltetrahydrofolate,O
+,,O
+the,O
+major,O
+form,O
+of,O
+folate,O
+in,O
+plasma,O
+,,O
+is,O
+a,O
+carbon,O
+donor,O
+for,O
+the,O
+remethylation,O
+of,O
+homocysteine,O
+to,O
+methionine,O
+.,O
+ , 
+This,O
+form,O
+of,O
+folate,O
+is,O
+generated,O
+from,O
+5,10,O
+-,O
+methylenetetrahydrofolate,O
+through,O
+the,O
+action,O
+of,O
+5,10,B-Gene
+-,I-Gene
+methylenetetrahydrofolate,I-Gene
+reductase,I-Gene
+(,B-Gene
+MTHFR,I-Gene
+),I-Gene
+,,O
+a,O
+cytosolic,O
+flavoprotein,O
+.,O
+ , 
+Patients,O
+with,O
+an,O
+autosomal,O
+recessive,O
+severe,O
+deficiency,O
+of,O
+MTHFR,B-Gene
+have,O
+homocystinuria,O
+and,O
+a,O
+wide,O
+range,O
+of,O
+neurological,O
+and,O
+vascular,O
+disturbances,O
+.,O
+ , 
+We,O
+have,O
+recently,O
+described,O
+the,O
+isolation,O
+of,O
+a,O
+cDNA,O
+for,O
+MTHFR,B-Gene
+and,O
+the,O
+identification,O
+of,O
+two,O
+mutations,O
+in,O
+patients,O
+with,O
+severe,O
+MTHFR,B-Gene
+deficiency,O
+.,O
+ , 
+We,O
+report,O
+here,O
+the,O
+characterization,O
+of,O
+seven,O
+novel,O
+mutations,O
+in,O
+this,O
+gene,O
+:,O
+six,O
+missense,O
+mutations,O
+and,O
+a,O
+5,O
+',O
+splice,O
+-,O
+site,O
+defect,O
+that,O
+activates,O
+a,O
+cryptic,O
+splice,O
+site,O
+in,O
+the,O
+coding,O
+sequence,O
+.,O
+ , 
+We,O
+also,O
+present,O
+a,O
+preliminary,O
+analysis,O
+of,O
+the,O
+relationship,O
+between,O
+genotype,O
+and,O
+phenotype,O
+for,O
+all,O
+nine,O
+mutations,O
+identified,O
+thus,O
+far,O
+in,O
+this,O
+gene,O
+.,O
+ , 
+A,O
+nonsense,O
+mutation,O
+and,O
+two,O
+missense,O
+mutations,O
+(,O
+proline,O
+to,O
+leucine,O
+and,O
+threonine,O
+to,O
+methionine,O
+),O
+in,O
+the,O
+homozygous,O
+state,O
+are,O
+associated,O
+with,O
+extremely,O
+low,O
+activity,O
+(,O
+0%-3,O
+%,O
+),O
+and,O
+onset,O
+of,O
+symptoms,O
+within,O
+the,O
+1st,O
+year,O
+of,O
+age,O
+.,O
+ , 
+Other,O
+missense,O
+mutations,O
+(,O
+arginine,O
+to,O
+cysteine,O
+and,O
+arginine,O
+to,O
+glutamine,O
+),O
+are,O
+associated,O
+with,O
+higher,O
+enzyme,O
+activity,O
+and,O
+later,O
+onset,O
+of,O
+symptoms,O
+.,O
+ , 
+#20691405
+Mutations,O
+in,O
+PVRL4,B-Gene
+,,I-Gene
+encoding,O
+cell,O
+adhesion,O
+molecule,O
+nectin-4,B-Gene
+,,I-Gene
+cause,O
+ectodermal,O
+dysplasia,O
+-,O
+syndactyly,O
+syndrome,O
+.,O
+ , 
+Ectodermal,O
+dysplasias,O
+form,O
+a,O
+large,O
+disease,O
+family,O
+with,O
+more,O
+than,O
+200,O
+members,O
+.,O
+ , 
+The,O
+combination,O
+of,O
+hair,O
+and,O
+tooth,O
+abnormalities,O
+,,O
+alopecia,O
+,,O
+and,O
+cutaneous,O
+syndactyly,O
+is,O
+characteristic,O
+of,O
+ectodermal,O
+dysplasia,O
+-,O
+syndactyly,O
+syndrome,O
+(,O
+EDSS,O
+),O
+.,O
+ , 
+We,O
+used,O
+a,O
+homozygosity,O
+mapping,O
+approach,O
+to,O
+map,O
+the,O
+EDSS,O
+locus,O
+to,O
+1q23,O
+in,O
+a,O
+consanguineous,O
+Algerian,O
+family,O
+.,O
+ , 
+By,O
+candidate,O
+gene,O
+analysis,O
+,,O
+we,O
+identified,O
+a,O
+homozygous,O
+mutation,O
+in,O
+the,O
+PVRL4,B-Gene
+gene,O
+that,O
+not,O
+only,O
+evoked,O
+an,O
+amino,O
+acid,O
+change,O
+but,O
+also,O
+led,O
+to,O
+exon,O
+skipping,O
+.,O
+ , 
+In,O
+an,O
+Italian,O
+family,O
+with,O
+two,O
+siblings,O
+affected,O
+by,O
+EDSS,O
+,,O
+we,O
+further,O
+detected,O
+a,O
+missense,O
+and,O
+a,O
+frameshift,O
+mutation,O
+.,O
+ , 
+PVRL4,B-Gene
+encodes,O
+for,O
+nectin-4,B-Gene
+,,I-Gene
+a,O
+cell,O
+adhesion,O
+molecule,O
+mainly,O
+implicated,O
+in,O
+the,O
+formation,O
+of,O
+cadherin,O
+-,O
+based,O
+adherens,O
+junctions,O
+.,O
+ , 
+We,O
+demonstrated,O
+high,O
+nectin-4,O
+expression,O
+in,O
+hair,O
+follicle,O
+structures,O
+,,O
+as,O
+well,O
+as,O
+in,O
+the,O
+separating,O
+digits,O
+of,O
+murine,O
+embryos,O
+,,O
+the,O
+tissues,O
+mainly,O
+affected,O
+by,O
+the,O
+EDSS,O
+phenotype,O
+.,O
+ , 
+In,O
+patient,O
+keratinocytes,O
+,,O
+mutated,O
+nectin-4,B-Gene
+lost,O
+its,O
+capability,O
+to,O
+bind,O
+nectin-1,B-Gene
+.,I-Gene
+ , 
+Additionally,O
+,,O
+in,O
+discrete,O
+structures,O
+of,O
+the,O
+hair,O
+follicle,O
+,,O
+we,O
+found,O
+alterations,O
+of,O
+the,O
+membrane,O
+localization,O
+of,O
+nectin,O
+-,O
+afadin,O
+and,O
+cadherin,O
+-,O
+catenin,O
+complexes,O
+,,O
+which,O
+are,O
+essential,O
+for,O
+adherens,O
+junction,O
+formation,O
+,,O
+and,O
+we,O
+found,O
+reorganization,O
+of,O
+actin,O
+cytoskeleton,O
+.,O
+ , 
+Together,O
+with,O
+cleft,O
+lip,O
+and/or,O
+palate,O
+ectodermal,O
+dysplasia,O
+(,O
+CLPED1,O
+,,O
+or,O
+Zlotogora,O
+-,O
+Ogur,O
+syndrome,O
+),O
+due,O
+to,O
+an,O
+impaired,O
+function,O
+of,O
+nectin-1,B-Gene
+,,I-Gene
+EDSS,O
+is,O
+the,O
+second,O
+known,O
+",O
+nectinopathy,O
+",O
+caused,O
+by,O
+mutations,O
+in,O
+a,O
+nectin,O
+adhesion,O
+molecule,O
+.,O
+ , 
+#1642234
+Mode,O
+of,O
+inheritance,O
+of,O
+nonsyndromic,O
+cleft,O
+lip,O
+with,O
+or,O
+without,O
+cleft,O
+palate,O
+:,O
+a,O
+reanalysis,O
+.,O
+ , 
+Nonsyndromic,O
+cleft,O
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+or,O
+without,O
+cleft,O
+palate,O
+(,O
+CL,O
++,O
+/-,O
+ , 
+P,O
+),O
+is,O
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+recognized,O
+as,O
+a,O
+multifactorial,O
+threshold,O
+trait,O
+(,O
+MFT,O
+),O
+.,O
+ , 
+Recently,O
+,,O
+however,O
+,,O
+evidence,O
+for,O
+the,O
+involvement,O
+of,O
+a,O
+major,O
+gene,O
+in,O
+the,O
+etiology,O
+of,O
+CL,O
++,O
+/-,O
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+P,O
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+been,O
+reported,O
+.,O
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+To,O
+assess,O
+the,O
+potential,O
+for,O
+major,O
+-,O
+gene,O
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+in,O
+the,O
+etiology,O
+of,O
+this,O
+trait,O
+,,O
+familial,O
+recurrence,O
+patterns,O
+from,O
+several,O
+family,O
+studies,O
+of,O
+CL,O
++,O
+/-,O
+ , 
+P,O
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+reanalyzed,O
+.,O
+ , 
+The,O
+recurrence,O
+patterns,O
+in,O
+first,O
+-,O
+degree,O
+relatives,O
+of,O
+CL,O
++,O
+/-,O
+ , 
+P,O
+probands,O
+were,O
+found,O
+to,O
+be,O
+compatible,O
+with,O
+the,O
+expectations,O
+for,O
+either,O
+an,O
+MFT,O
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+a,O
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+single,O
+-,O
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+-,O
+locus,O
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+gSML,O
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+trait,O
+.,O
+ , 
+The,O
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+proband,O
+sex,O
+,,O
+defect,O
+bilaterality,O
+,,O
+or,O
+palatal,O
+involvement,O
+did,O
+not,O
+help,O
+to,O
+discriminate,O
+between,O
+these,O
+models,O
+.,O
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+However,O
+,,O
+the,O
+pattern,O
+of,O
+recurrence,O
+among,O
+MZ,O
+twins,O
+and,O
+more,O
+remote,O
+relatives,O
+of,O
+CL,O
++,O
+/-,O
+ , 
+P,O
+probands,O
+is,O
+not,O
+consistent,O
+with,O
+gSML,O
+inheritance,O
+but,O
+is,O
+compatible,O
+with,O
+either,O
+an,O
+MFT,O
+model,O
+or,O
+a,O
+model,O
+specifying,O
+multiple,O
+interacting,O
+loci,O
+.,O
+ , 
+For,O
+such,O
+a,O
+model,O
+,,O
+no,O
+single,O
+locus,O
+can,O
+account,O
+for,O
+more,O
+than,O
+a,O
+sixfold,O
+increase,O
+in,O
+risk,O
+to,O
+first,O
+-,O
+degree,O
+relatives,O
+.,O
+ , 
+These,O
+findings,O
+have,O
+important,O
+implications,O
+with,O
+regard,O
+to,O
+the,O
+feasibility,O
+of,O
+detecting,O
+linkage,O
+to,O
+loci,O
+conferring,O
+susceptibility,O
+to,O
+CL,O
++,O
+/-,O
+ , 
+P.,O
+ , 
+#21412953
+Breakage,O
+-,O
+fusion,O
+-,O
+bridge,O
+cycles,O
+leading,O
+to,O
+inv,O
+dup,O
+del,O
+occur,O
+in,O
+human,O
+cleavage,O
+stage,O
+embryos,O
+.,O
+ , 
+Recently,O
+,,O
+a,O
+high,O
+incidence,O
+of,O
+chromosome,O
+instability,O
+(,O
+CIN,O
+),O
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+in,O
+human,O
+cleavage,O
+stage,O
+embryos,O
+.,O
+ , 
+Based,O
+on,O
+the,O
+copy,O
+number,O
+changes,O
+that,O
+were,O
+observed,O
+in,O
+the,O
+blastomeres,O
+it,O
+was,O
+hypothesized,O
+that,O
+chromosome,O
+breakages,O
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+fusions,O
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+cleavage,O
+stage,O
+human,O
+embryos,O
+and,O
+instigate,O
+subsequent,O
+breakage,O
+-,O
+fusion,O
+-,O
+bridge,O
+cycles,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+it,O
+was,O
+hypothesized,O
+that,O
+the,O
+DNA,O
+breaks,O
+present,O
+in,O
+spermatozoa,O
+could,O
+trigger,O
+this,O
+CIN,O
+.,O
+ , 
+To,O
+test,O
+these,O
+hypotheses,O
+,,O
+we,O
+genotyped,O
+both,O
+parents,O
+as,O
+well,O
+as,O
+93,O
+blastomeres,O
+from,O
+24,O
+IVF,O
+embryos,O
+and,O
+developed,O
+a,O
+novel,O
+single,O
+nucleotide,O
+polymorphism,O
+(,O
+SNP,O
+),O
+array,O
+-,O
+based,O
+algorithm,O
+to,O
+determine,O
+the,O
+parental,O
+origin,O
+of,O
+(,O
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+),O
+loci,O
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+single,O
+cells,O
+.,O
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+Paternal,O
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+as,O
+maternal,O
+alleles,O
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+commonly,O
+rearranged,O
+in,O
+the,O
+blastomeres,O
+indicating,O
+that,O
+sperm,O
+-,O
+specific,O
+DNA,O
+breaks,O
+do,O
+not,O
+explain,O
+the,O
+majority,O
+of,O
+these,O
+structural,O
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+.,O
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+The,O
+parent,O
+-,O
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+-,O
+origin,O
+analyses,O
+together,O
+with,O
+microarray,O
+-,O
+guided,O
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+analyses,O
+demonstrate,O
+the,O
+presence,O
+of,O
+inv,O
+dup,O
+del,O
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+as,O
+more,O
+complex,O
+rearrangements,O
+.,O
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+These,O
+data,O
+provide,O
+unequivocal,O
+evidence,O
+for,O
+breakage,O
+-,O
+fusion,O
+-,O
+bridge,O
+cycles,O
+in,O
+those,O
+embryos,O
+and,O
+suggest,O
+that,O
+the,O
+human,O
+cleavage,O
+stage,O
+embryo,O
+is,O
+a,O
+major,O
+source,O
+of,O
+chromosomal,O
+disorders,O
+.,O
+ , 
+#8755932
+mtDNA,O
+sequence,O
+diversity,O
+in,O
+Africa,O
+.,O
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+mtDNA,O
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+were,O
+determined,O
+from,O
+241,O
+individuals,O
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+nine,O
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+groups,O
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+Africa,O
+.,O
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+When,O
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+were,O
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+with,O
+published,O
+data,O
+from,O
+other,O
+groups,O
+,,O
+it,O
+was,O
+found,O
+that,O
+the,O
+!,O
+Kung,O
+,,O
+Mbuti,O
+,,O
+and,O
+Biaka,O
+show,O
+on,O
+the,O
+order,O
+of,O
+10,O
+times,O
+more,O
+sequence,O
+differences,O
+between,O
+the,O
+three,O
+groups,O
+,,O
+as,O
+well,O
+as,O
+between,O
+those,O
+and,O
+the,O
+other,O
+groups,O
+(,O
+the,O
+Fulbe,O
+,,O
+Hausa,O
+,,O
+Tuareg,O
+,,O
+Songhai,O
+,,O
+Kanuri,O
+,,O
+Yoruba,O
+,,O
+Mandenka,O
+,,O
+Somali,O
+,,O
+Tukana,O
+,,O
+and,O
+Kikuyu,O
+),O
+,,O
+than,O
+these,O
+other,O
+groups,O
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+between,O
+one,O
+other,O
+.,O
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+Furthermore,O
+,,O
+the,O
+pairwise,O
+sequence,O
+distributions,O
+,,O
+patterns,O
+of,O
+coalescence,O
+events,O
+,,O
+and,O
+numbers,O
+of,O
+variable,O
+positions,O
+relative,O
+to,O
+the,O
+mean,O
+sequence,O
+difference,O
+indicate,O
+that,O
+the,O
+former,O
+three,O
+groups,O
+have,O
+been,O
+of,O
+constant,O
+size,O
+over,O
+time,O
+,,O
+whereas,O
+the,O
+latter,O
+have,O
+expanded,O
+in,O
+size,O
+.,O
+ , 
+We,O
+suggest,O
+that,O
+this,O
+reflects,O
+subsistence,O
+patterns,O
+in,O
+that,O
+the,O
+populations,O
+that,O
+have,O
+expanded,O
+in,O
+size,O
+are,O
+food,O
+producers,O
+whereas,O
+those,O
+that,O
+have,O
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+and,O
+gatherers,O
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+#10486315
+Tissue,O
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+muscular,O
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+dependent,O
+on,O
+CAG,O
+-,O
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+length,O
+and,O
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+The,O
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+somatic,O
+mosaicism,O
+in,O
+CAG,O
+-,O
+repeat,O
+diseases,O
+have,O
+not,O
+yet,O
+been,O
+fully,O
+resolved,O
+.,O
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+We,O
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+a,O
+detailed,O
+analysis,O
+of,O
+the,O
+degree,O
+of,O
+somatic,O
+mosaicism,O
+in,O
+various,O
+tissues,O
+from,O
+20,O
+patients,O
+with,O
+spinal,O
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+bulbar,O
+muscular,O
+atrophy,O
+(,O
+SBMA,O
+),O
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+4,O
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+.,O
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+The,O
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+outstanding,O
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+prominent,O
+somatic,O
+mosaicism,O
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+in,O
+the,O
+cardiac,O
+and,O
+skeletal,O
+muscles,O
+,,O
+composed,O
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+of,O
+postmitotic,O
+cells,O
+,,O
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+in,O
+the,O
+skin,O
+,,O
+prostate,O
+,,O
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+testis,O
+.,O
+ , 
+The,O
+CNS,O
+tissues,O
+,,O
+liver,O
+,,O
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+spleen,O
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+the,O
+least,O
+mosaicism,O
+.,O
+ , 
+The,O
+tissue,O
+distribution,O
+of,O
+somatic,O
+mosaicism,O
+in,O
+patients,O
+with,O
+SBMA,O
+was,O
+markedly,O
+different,O
+from,O
+that,O
+in,O
+patients,O
+with,O
+Huntington,O
+disease,O
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+HD,O
+),O
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+that,O
+in,O
+patients,O
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+dentatorubral,O
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+with,O
+the,O
+CAG,O
+-,O
+repeat,O
+number,O
+but,O
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+with,O
+age,O
+at,O
+examination,O
+.,O
+ , 
+Furthermore,O
+,,O
+tissues,O
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+a,O
+higher,O
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+well,O
+to,O
+those,O
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+a,O
+higher,O
+expression,O
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+androgen,O
+receptor,O
+protein,O
+.,O
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+The,O
+tissue,O
+-,O
+specific,O
+pattern,O
+of,O
+somatic,O
+mosaicism,O
+related,O
+not,O
+only,O
+to,O
+cell,O
+composition,O
+with,O
+different,O
+cell,O
+turnover,O
+rates,O
+but,O
+to,O
+repeat,O
+size,O
+and,O
+gene,O
+expression,O
+levels,O
+,,O
+and,O
+postnatal,O
+cell,O
+division,O
+is,O
+unlikely,O
+to,O
+be,O
+a,O
+major,O
+cause,O
+of,O
+somatic,O
+mosaicism,O
+probably,O
+because,O
+of,O
+the,O
+relative,O
+stability,O
+of,O
+CAG,O
+repeat,O
+in,O
+SBMA,O
+.,O
+ , 
+#8651280
+Autosomal,O
+recessive,O
+Wolfram,O
+syndrome,O
+associated,O
+with,O
+an,O
+8.5,O
+-,O
+kb,O
+mtDNA,O
+single,O
+deletion,O
+.,O
+ , 
+Wolfram,O
+syndrome,O
+(,O
+MIM,O
+222300,O
+),O
+is,O
+characterized,O
+by,O
+optic,O
+atrophy,O
+,,O
+diabetes,O
+mellitus,O
+,,O
+diabetes,O
+insipidus,O
+,,O
+neurosensory,O
+hearing,O
+loss,O
+,,O
+urinary,O
+tract,O
+abnormalities,O
+,,O
+and,O
+neurological,O
+dysfunction,O
+.,O
+ , 
+The,O
+association,O
+of,O
+clinical,O
+manifestations,O
+in,O
+tissues,O
+and,O
+organs,O
+unrelated,O
+functionally,O
+or,O
+embryologically,O
+suggested,O
+the,O
+possibility,O
+of,O
+a,O
+mitochondrial,O
+implication,O
+in,O
+the,O
+disease,O
+,,O
+which,O
+has,O
+been,O
+demonstrated,O
+in,O
+two,O
+sporadic,O
+cases,O
+.,O
+ , 
+Nonetheless,O
+,,O
+familial,O
+studies,O
+suggested,O
+an,O
+autosomal,O
+recessive,O
+mode,O
+of,O
+transmission,O
+,,O
+and,O
+recent,O
+data,O
+demonstrated,O
+linkage,O
+with,O
+markers,O
+on,O
+the,O
+short,O
+arm,O
+of,O
+human,O
+chromosome,O
+4,O
+.,O
+ , 
+The,O
+patient,O
+reported,O
+here,O
+,,O
+as,O
+well,O
+as,O
+her,O
+parents,O
+and,O
+unaffected,O
+sister,O
+,,O
+carried,O
+a,O
+heteroplasmic,O
+8.5,O
+-,O
+kb,O
+deletion,O
+in,O
+mtDNA,O
+.,O
+ , 
+The,O
+deletion,O
+accounted,O
+for,O
+23,O
+%,O
+of,O
+mitochondrial,O
+genomes,O
+in,O
+lymphocytes,O
+from,O
+the,O
+patient,O
+and,O
+approximately,O
+5,O
+%,O
+in,O
+the,O
+tissues,O
+studied,O
+from,O
+members,O
+of,O
+her,O
+family,O
+.,O
+ , 
+The,O
+presence,O
+of,O
+the,O
+deletion,O
+in,O
+the,O
+patient,O
+in,O
+a,O
+proportion,O
+higher,O
+than,O
+in,O
+her,O
+unaffected,O
+parents,O
+suggests,O
+a,O
+putative,O
+defect,O
+in,O
+a,O
+nuclear,O
+gene,O
+that,O
+acts,O
+at,O
+the,O
+mitochondrial,O
+level,O
+.,O
+ , 
+#19084217
+Variants,O
+in,O
+TF,B-Gene
+and,O
+HFE,B-Gene
+explain,O
+approximately,O
+40,O
+%,O
+of,O
+genetic,O
+variation,O
+in,O
+serum,O
+-,O
+transferrin,O
+levels,O
+.,O
+ , 
+Only,O
+a,O
+small,O
+proportion,O
+of,O
+genetic,O
+variation,O
+in,O
+complex,O
+traits,O
+has,O
+been,O
+explained,O
+by,O
+SNPs,O
+from,O
+genome,O
+-,O
+wide,O
+association,O
+studies,O
+(,O
+GWASs,O
+),O
+.,O
+ , 
+We,O
+report,O
+the,O
+results,O
+from,O
+two,O
+GWASs,O
+for,O
+serum,O
+markers,O
+of,O
+iron,O
+status,O
+(,O
+serum,O
+iron,O
+,,O
+serum,O
+transferrin,O
+,,O
+transferrin,O
+saturation,O
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+iron,O
+,,O
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+serum,O
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+),O
+,,O
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+important,O
+in,O
+iron,O
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+(,O
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+,,O
+hemochromatosis,O
+),O
+and,O
+deficiency,O
+(,O
+e.g.,O
+,,O
+anemia,O
+),O
+conditions,O
+.,O
+ , 
+We,O
+performed,O
+two,O
+GWASs,O
+on,O
+samples,O
+of,O
+Australians,O
+of,O
+European,O
+descent,O
+.,O
+ , 
+In,O
+the,O
+first,O
+GWAS,O
+,,O
+411,O
+adolescent,O
+twins,O
+and,O
+their,O
+siblings,O
+were,O
+genotyped,O
+with,O
+100,O
+K,O
+SNPs,O
+.,O
+ , 
+rs1830084,O
+,,O
+10.8,O
+kb,O
+3,O
+',O
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+serum,O
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+(,O
+p,O
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+test,O
+=,O
+1.0,O
+x,O
+10(-9,O
+),O
+;,O
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+within,O
+-,O
+family,O
+test,O
+=,O
+2.2,O
+x,O
+10(-5,O
+),O
+),O
+.,O
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+In,O
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+second,O
+GWAS,O
+on,O
+an,O
+independent,O
+sample,O
+of,O
+459,O
+female,O
+monozygotic,O
+(,O
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+),O
+twin,O
+pairs,O
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+300,O
+K,O
+SNPs,O
+,,O
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+found,O
+rs3811647,O
+(,O
+within,O
+intron,O
+11,O
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+TF,B-Gene
+,,I-Gene
+HapMap,O
+CEU,O
+r(2,O
+),O
+with,O
+rs1830084,O
+=,O
+0.86,O
+),O
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+associated,O
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+serum,O
+transferrin,O
+(,O
+p,O
+=,O
+3.0,O
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+10(-15,O
+),O
+),O
+.,O
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+In,O
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+second,O
+GWAS,O
+,,O
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+found,O
+two,O
+additional,O
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+TF,B-Gene
+(,O
+rs1799852,O
+and,O
+rs2280673,O
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+and,O
+confirmed,O
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+known,O
+C282Y,B-SNP
+mutation,O
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+HFE,B-Gene
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+be,O
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+serum,O
+transferrin,O
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+ , 
+The,O
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+TF,B-Gene
+(,O
+rs3811647,O
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+rs1799852,O
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+rs2280673,O
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+HFE,B-Gene
+C282Y,B-SNP
+mutation,O
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+approximately,O
+40,O
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+serum,O
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+(,O
+p,O
+=,O
+7.8,O
+x,O
+10(-25,O
+),O
+),O
+.,O
+ , 
+These,O
+findings,O
+are,O
+potentially,O
+important,O
+for,O
+our,O
+understanding,O
+of,O
+iron,O
+metabolism,O
+and,O
+of,O
+regulation,O
+of,O
+hepatic,O
+protein,O
+secretion,O
+,,O
+and,O
+also,O
+strongly,O
+support,O
+the,O
+hypothesis,O
+that,O
+the,O
+genetic,O
+architecture,O
+of,O
+some,O
+endophenotypes,O
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+be,O
+simpler,O
+than,O
+that,O
+of,O
+disease,O
+.,O
+ , 
+#10094554
+A,O
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+FRAXA,O
+,,O
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+FRAXF,O
+PCR,O
+assay,O
+convenient,O
+for,O
+wide,O
+screening,O
+programs,O
+.,O
+ , 
+FRAXA,O
+,,O
+FRAXE,O
+,,O
+and,O
+FRAXF,O
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+folate,O
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+fragile,O
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+discovered,O
+in,O
+patients,O
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+X,O
+-,O
+linked,O
+mental,O
+retardation,O
+.,O
+ , 
+The,O
+FMR1,B-Gene
+gene,O
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+exon,O
+includes,O
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+FRAXA,O
+site,O
+on,O
+Xq27.3,O
+,,O
+accounts,O
+for,O
+15,O
+-,O
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+Loss,O
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+FMR2,B-Gene
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+FRAXE,O
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+Xq28,O
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+FRAXE,O
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+mild,O
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+patients,O
+.,O
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+FRAXF,O
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+a,O
+fragile,O
+site,O
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+expression,O
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+any,O
+pathological,O
+phenotype,O
+.,O
+ , 
+The,O
+fragility,O
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+caused,O
+by,O
+expansions,O
+of,O
+CGG,O
+repeats,O
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+to,O
+hypermethylated,O
+CpG,O
+islands,O
+.,O
+ , 
+The,O
+prevalence,O
+of,O
+FRAXA,O
+,,O
+FRAXE,O
+,,O
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+FRAXF,O
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+uncertain,O
+because,O
+of,O
+the,O
+lack,O
+of,O
+a,O
+simple,O
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+cost,O
+-,O
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+FRAXF,O
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+.,O
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+We,O
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+developed,O
+a,O
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+multiplex,O
+polymerase,O
+chain,O
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+(,O
+PCR,O
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+FRAXA,O
+,,O
+FRAXE,O
+,,O
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+FRAXF,O
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+displayed,O
+.,O
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+The,O
+test,O
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+very,O
+simple,O
+and,O
+cost,O
+-,O
+effective,O
+,,O
+requires,O
+only,O
+30,O
+microl,O
+of,O
+peripheral,O
+blood,O
+,,O
+and,O
+can,O
+be,O
+used,O
+for,O
+performing,O
+diagnoses,O
+,,O
+postnatal,O
+and,O
+prenatal,O
+,,O
+and,O
+for,O
+screening,O
+large,O
+groups,O
+of,O
+control,O
+and,O
+mentally,O
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+boys,O
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+#7887433
+Prenatal,O
+genetic,O
+counseling,O
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+hemoglobinopathy,O
+carriers,O
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+a,O
+comparison,O
+of,O
+primary,O
+providers,O
+of,O
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+care,O
+and,O
+professional,O
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+counselors,O
+.,O
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+Health,O
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+insufficient,O
+to,O
+meet,O
+the,O
+demand,O
+for,O
+genetic,O
+services,O
+.,O
+ , 
+Methods,O
+must,O
+be,O
+found,O
+to,O
+enable,O
+primary,O
+care,O
+providers,O
+to,O
+offer,O
+commonly,O
+needed,O
+genetic,O
+services,O
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+.,O
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+In,O
+our,O
+recently,O
+reported,O
+community,O
+-,O
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+,,O
+36,O
+%,O
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+a,O
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+a,O
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+center,O
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+counseling,O
+and,O
+thus,O
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+To,O
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+program,O
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+if,O
+counseling,O
+were,O
+provided,O
+by,O
+the,O
+prenatal,O
+care,O
+provider,O
+(,O
+obstetrician,O
+or,O
+family,O
+practitioner,O
+),O
+,,O
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+a,O
+pilot,O
+training,O
+program,O
+on,O
+the,O
+basis,O
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+experience,O
+in,O
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+such,O
+services,O
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+enlisted,O
+68,O
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+The,O
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+of,O
+patients,O
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+Knowledge,O
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+regard,O
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+#9399882
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+We,O
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+Multiple,O
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+In,O
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+14,O
+families,O
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+parent,O
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+Comparative,O
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+15q,O
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+a,O
+smaller,O
+group,O
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+a,O
+maternally,O
+derived,O
+PWACR,O
+duplication,O
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+consistently,O
+associated,O
+with,O
+developmental,O
+delay,O
+and,O
+speech,O
+difficulties,O
+but,O
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+overt,O
+features,O
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+either,O
+Prader,O
+-,O
+Willi,O
+syndrome,O
+or,O
+Angelman,O
+syndrome,O
+.,O
+ , 
+#17311297
+Extensive,O
+in,O
+silico,O
+analysis,O
+of,O
+NF1,B-Gene
+splicing,O
+defects,O
+uncovers,O
+determinants,O
+for,O
+splicing,O
+outcome,O
+upon,O
+5,O
+',O
+splice,O
+-,O
+site,O
+disruption,O
+.,O
+ , 
+We,O
+describe,O
+94,O
+pathogenic,O
+NF1,B-Gene
+gene,O
+alterations,O
+in,O
+a,O
+cohort,O
+of,O
+97,O
+Austrian,O
+neurofibromatosis,O
+type,O
+1,O
+patients,O
+meeting,O
+the,O
+NIH,O
+criteria,O
+.,O
+ , 
+All,O
+mutations,O
+were,O
+fully,O
+characterized,O
+at,O
+the,O
+genomic,O
+and,O
+mRNA,O
+levels,O
+.,O
+ , 
+Over,O
+half,O
+of,O
+the,O
+patients,O
+carried,O
+novel,O
+mutations,O
+,,O
+and,O
+only,O
+a,O
+quarter,O
+carried,O
+recurrent,O
+minor,O
+-,O
+lesion,O
+mutations,O
+at,O
+16,O
+mutational,O
+warm,O
+spots,O
+.,O
+ , 
+The,O
+remaining,O
+patients,O
+carried,O
+NF1,O
+microdeletions,O
+(,O
+7,O
+%,O
+),O
+and,O
+rare,O
+recurring,O
+mutations,O
+.,O
+ , 
+Thirty,O
+-,O
+six,O
+of,O
+the,O
+mutations,O
+(,O
+38,O
+%,O
+),O
+altered,O
+pre,O
+-,O
+mRNA,O
+splicing,O
+,,O
+and,O
+fall,O
+into,O
+five,O
+groups,O
+:,O
+exon,O
+skipping,O
+resulting,O
+from,O
+mutations,O
+at,O
+authentic,O
+splice,O
+sites,O
+(,O
+type,O
+I,O
+),O
+,,O
+cryptic,O
+exon,O
+inclusion,O
+caused,O
+by,O
+deep,O
+intronic,O
+mutations,O
+(,O
+type,O
+II,O
+),O
+,,O
+creation,O
+of,O
+de,O
+novo,O
+splice,O
+sites,O
+causing,O
+loss,O
+of,O
+exonic,O
+sequences,O
+(,O
+type,O
+III,O
+),O
+,,O
+activation,O
+of,O
+cryptic,O
+splice,O
+sites,O
+upon,O
+authentic,O
+splice,O
+-,O
+site,O
+disruption,O
+(,O
+type,O
+IV,O
+),O
+,,O
+and,O
+exonic,O
+sequence,O
+alterations,O
+causing,O
+exon,O
+skipping,O
+(,O
+type,O
+V,O
+),O
+.,O
+ , 
+Extensive,O
+in,O
+silico,O
+analyses,O
+of,O
+37,O
+NF1,O
+exons,O
+and,O
+surrounding,O
+intronic,O
+sequences,O
+suggested,O
+that,O
+the,O
+availability,O
+of,O
+a,O
+cryptic,O
+splice,O
+site,O
+combined,O
+with,O
+a,O
+strong,O
+natural,O
+upstream,O
+3,O
+',O
+splice,O
+site,O
+(,O
+3'ss)is,O
+the,O
+main,O
+determinant,O
+of,O
+cryptic,O
+splice,O
+-,O
+site,O
+activation,O
+upon,O
+5,O
+',O
+splice,O
+-,O
+site,O
+disruption,O
+.,O
+ , 
+Furthermore,O
+,,O
+the,O
+exonic,O
+sequences,O
+downstream,O
+of,O
+exonic,O
+cryptic,O
+5,O
+',O
+splice,O
+sites,O
+(,O
+5'ss,O
+),O
+resemble,O
+intronic,O
+more,O
+than,O
+exonic,O
+sequences,O
+with,O
+respect,O
+to,O
+exonic,O
+splicing,O
+enhancer,O
+and,O
+silencer,O
+density,O
+,,O
+helping,O
+to,O
+distinguish,O
+between,O
+exonic,O
+cryptic,O
+and,O
+pseudo,O
+5'ss,O
+.,O
+ , 
+This,O
+study,O
+provides,O
+valuable,O
+predictors,O
+for,O
+the,O
+splicing,O
+pathway,O
+used,O
+upon,O
+5'ss,O
+mutation,O
+,,O
+and,O
+underscores,O
+the,O
+importance,O
+of,O
+using,O
+RNA,O
+-,O
+based,O
+techniques,O
+,,O
+together,O
+with,O
+methods,O
+to,O
+identify,O
+microdeletions,O
+and,O
+intragenic,O
+copy,O
+-,O
+number,O
+changes,O
+,,O
+for,O
+effective,O
+and,O
+reliable,O
+NF1,B-Gene
+mutation,O
+detection,O
+.,O
+ , 
+#21636067
+X,O
+-,O
+linked,O
+congenital,O
+hypertrichosis,O
+syndrome,O
+is,O
+associated,O
+with,O
+interchromosomal,O
+insertions,O
+mediated,O
+by,O
+a,O
+human,O
+-,O
+specific,O
+palindrome,O
+near,O
+SOX3,B-Gene
+.,I-Gene
+ , 
+X,O
+-,O
+linked,O
+congenital,O
+generalized,O
+hypertrichosis,O
+(,O
+CGH,O
+),O
+,,O
+an,O
+extremely,O
+rare,O
+condition,O
+characterized,O
+by,O
+universal,O
+overgrowth,O
+of,O
+terminal,O
+hair,O
+,,O
+was,O
+first,O
+mapped,O
+to,O
+chromosome,O
+Xq24,O
+-,O
+q27.1,O
+in,O
+a,O
+Mexican,O
+family,O
+.,O
+ , 
+However,O
+,,O
+the,O
+underlying,O
+genetic,O
+defect,O
+remains,O
+unknown,O
+.,O
+ , 
+We,O
+ascertained,O
+a,O
+large,O
+Chinese,O
+family,O
+with,O
+an,O
+X,O
+-,O
+linked,O
+congenital,O
+hypertrichosis,O
+syndrome,O
+combining,O
+CGH,O
+,,O
+scoliosis,O
+,,O
+and,O
+spina,O
+bifida,O
+and,O
+mapped,O
+the,O
+disease,O
+locus,O
+to,O
+a,O
+5.6,O
+Mb,O
+critical,O
+region,O
+within,O
+the,O
+interval,O
+defined,O
+by,O
+the,O
+previously,O
+reported,O
+Mexican,O
+family,O
+.,O
+ , 
+Through,O
+the,O
+combination,O
+of,O
+a,O
+high,O
+-,O
+resolution,O
+copy,O
+-,O
+number,O
+variation,O
+(,O
+CNV,O
+),O
+scan,O
+and,O
+targeted,O
+genomic,O
+sequencing,O
+,,O
+we,O
+identified,O
+an,O
+interchromosomal,O
+insertion,O
+at,O
+Xq27.1,O
+of,O
+a,O
+125,577,O
+ ,O
+bp,O
+intragenic,O
+fragment,O
+of,O
+COL23A1,B-Gene
+on,O
+5q35.3,O
+,,O
+with,O
+one,O
+X,O
+breakpoint,O
+within,O
+and,O
+the,O
+other,O
+very,O
+close,O
+to,O
+a,O
+human,O
+-,O
+specific,O
+short,O
+palindromic,O
+sequence,O
+located,O
+82,O
+kb,O
+downstream,O
+of,O
+SOX3,B-Gene
+.,I-Gene
+ , 
+In,O
+the,O
+Mexican,O
+family,O
+,,O
+we,O
+found,O
+an,O
+interchromosomal,O
+insertion,O
+at,O
+the,O
+same,O
+Xq27.1,O
+site,O
+of,O
+a,O
+300,036,O
+ ,O
+bp,O
+genomic,O
+fragment,O
+on,O
+4q31.2,O
+,,O
+encompassing,O
+PRMT10,B-Gene
+and,O
+TMEM184C,B-Gene
+and,O
+involving,O
+parts,O
+of,O
+ARHGAP10,B-Gene
+and,O
+EDNRA,B-Gene
+.,I-Gene
+ , 
+Notably,O
+,,O
+both,O
+of,O
+the,O
+two,O
+X,O
+breakpoints,O
+were,O
+within,O
+the,O
+short,O
+palindrome,O
+.,O
+ , 
+The,O
+two,O
+palindrome,O
+-,O
+mediated,O
+insertions,O
+fully,O
+segregate,O
+with,O
+the,O
+CGH,O
+phenotype,O
+in,O
+each,O
+of,O
+the,O
+families,O
+,,O
+and,O
+the,O
+CNV,O
+gains,O
+of,O
+the,O
+respective,O
+autosomal,O
+genomic,O
+segments,O
+are,O
+not,O
+present,O
+in,O
+the,O
+public,O
+database,O
+and,O
+were,O
+not,O
+found,O
+in,O
+1274,O
+control,O
+individuals,O
+.,O
+ , 
+Analysis,O
+of,O
+control,O
+individuals,O
+revealed,O
+deletions,O
+ranging,O
+from,O
+173,O
+ ,O
+bp,O
+to,O
+9104,O
+ ,O
+bp,O
+at,O
+the,O
+site,O
+of,O
+the,O
+insertions,O
+with,O
+no,O
+phenotypic,O
+consequence,O
+.,O
+ , 
+Taken,O
+together,O
+,,O
+our,O
+results,O
+strongly,O
+support,O
+the,O
+pathogenicity,O
+of,O
+the,O
+identified,O
+insertions,O
+and,O
+establish,O
+X,O
+-,O
+linked,O
+congenital,O
+hypertrichosis,O
+syndrome,O
+as,O
+a,O
+genomic,O
+disorder,O
+.,O
+ , 
+#21898660
+Dilated,O
+cardiomyopathy,O
+-,O
+associated,O
+BAG3,B-Gene
+mutations,O
+impair,O
+Z,O
+-,O
+disc,O
+assembly,O
+and,O
+enhance,O
+sensitivity,O
+to,O
+apoptosis,O
+in,O
+cardiomyocytes,O
+.,O
+ , 
+Dilated,O
+cardiomyopathy,O
+(,O
+DCM,O
+),O
+is,O
+characterized,O
+by,O
+dilation,O
+of,O
+left,O
+ventricular,O
+cavity,O
+with,O
+systolic,O
+dysfunction,O
+.,O
+ , 
+Clinical,O
+symptom,O
+of,O
+DCM,O
+is,O
+heart,O
+failure,O
+,,O
+often,O
+associated,O
+with,O
+cardiac,O
+sudden,O
+death,O
+.,O
+ , 
+About,O
+20,O
+-,O
+35,O
+%,O
+of,O
+DCM,O
+patients,O
+have,O
+apparent,O
+family,O
+histories,O
+and,O
+it,O
+has,O
+been,O
+revealed,O
+that,O
+mutations,O
+in,O
+genes,O
+for,O
+sarcomere,O
+proteins,O
+cause,O
+DCM,O
+.,O
+ , 
+However,O
+,,O
+the,O
+disease,O
+-,O
+causing,O
+mutations,O
+can,O
+be,O
+found,O
+only,O
+in,O
+about,O
+17,O
+%,O
+of,O
+Japanese,O
+patients,O
+with,O
+familial,O
+DCM,O
+.,O
+ , 
+Bcl-2,B-Gene
+-,I-Gene
+associated,O
+athanogene,B-Gene
+3,I-Gene
+(,B-Gene
+BAG3,I-Gene
+),I-Gene
+is,O
+a,O
+co,O
+-,O
+chaperone,O
+protein,O
+with,O
+antiapoptotic,O
+function,O
+,,O
+which,O
+localizes,O
+at,O
+Z,O
+-,O
+disc,O
+in,O
+the,O
+striated,O
+muscles,O
+.,O
+ , 
+Recently,O
+,,O
+BAG3,B-Gene
+gene,O
+mutations,O
+in,O
+DCM,O
+patients,O
+were,O
+reported,O
+,,O
+but,O
+the,O
+functional,O
+abnormalities,O
+caused,O
+by,O
+the,O
+mutations,O
+are,O
+not,O
+fully,O
+unraveled,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+analyzed,O
+72,O
+Japanese,O
+familial,O
+DCM,O
+patients,O
+for,O
+mutations,O
+in,O
+BAG3,B-Gene
+and,O
+found,O
+two,O
+mutations,O
+,,O
+p.,B-SNP
+Arg218Trp,I-SNP
+and,O
+p.,B-SNP
+Leu462Pro,I-SNP
+,,I-SNP
+in,O
+two,O
+cases,O
+of,O
+adult,O
+-,O
+onset,O
+DCM,O
+without,O
+skeletal,O
+myopathy,O
+,,O
+which,O
+were,O
+absent,O
+from,O
+400,O
+control,O
+subjects,O
+.,O
+ , 
+Functional,O
+studies,O
+at,O
+the,O
+cellular,O
+level,O
+revealed,O
+that,O
+the,O
+DCM,O
+-,O
+associated,O
+BAG3,B-Gene
+mutations,O
+impaired,O
+the,O
+Z,O
+-,O
+disc,O
+assembly,O
+and,O
+increased,O
+the,O
+sensitivities,O
+to,O
+stress,O
+-,O
+induced,O
+apoptosis,O
+.,O
+ , 
+These,O
+observations,O
+suggested,O
+that,O
+BAG3,B-Gene
+mutations,O
+present,O
+in,O
+2.8,O
+%,O
+of,O
+Japanese,O
+familial,O
+DCM,O
+patients,O
+caused,O
+DCM,O
+possibly,O
+by,O
+interfering,O
+with,O
+Z,O
+-,O
+disc,O
+assembly,O
+and,O
+inducing,O
+apoptotic,O
+cell,O
+death,O
+under,O
+the,O
+metabolic,O
+stress,O
+.,O
+ , 
+#10677305
+A,O
+new,O
+locus,O
+for,O
+autosomal,O
+recessive,O
+hypercholesterolemia,O
+maps,O
+to,O
+human,O
+chromosome,O
+15q25,O
+-,O
+q26,O
+.,O
+ , 
+High,O
+serum,O
+cholesterol,O
+is,O
+an,O
+established,O
+risk,O
+factor,O
+for,O
+cardiovascular,O
+disease,O
+and,O
+is,O
+the,O
+prime,O
+target,O
+for,O
+therapeutic,O
+intervention,O
+in,O
+large,O
+groups,O
+of,O
+patients,O
+.,O
+ , 
+The,O
+development,O
+of,O
+modern,O
+treatments,O
+for,O
+this,O
+major,O
+risk,O
+factor,O
+was,O
+propelled,O
+by,O
+the,O
+early,O
+realization,O
+that,O
+forms,O
+of,O
+severe,O
+hypercholesterolemia,O
+could,O
+be,O
+caused,O
+by,O
+dominantly,O
+inherited,O
+defects,O
+in,O
+the,O
+LDL,O
+receptor,O
+or,O
+in,O
+the,O
+APOB,B-Gene
+gene,O
+.,O
+ , 
+Further,O
+understanding,O
+of,O
+the,O
+mechanisms,O
+contributing,O
+to,O
+early,O
+atherosclerosis,O
+will,O
+allow,O
+for,O
+new,O
+targets,O
+for,O
+therapy,O
+.,O
+ , 
+We,O
+therefore,O
+identified,O
+and,O
+investigated,O
+the,O
+genetics,O
+of,O
+families,O
+from,O
+Sardinia,O
+that,O
+have,O
+recessive,O
+inheritance,O
+of,O
+precocious,O
+hypercholesterolemia,O
+.,O
+ , 
+We,O
+used,O
+five,O
+families,O
+in,O
+an,O
+analysis,O
+of,O
+linkage,O
+of,O
+the,O
+autosomal,O
+recessive,O
+hypercholesterolemia,O
+locus,O
+,,O
+termed,O
+",B-Gene
+ARH1,I-Gene
+,,I-Gene
+",O
+to,O
+chromosome,O
+15q25,O
+-,O
+q26,O
+.,O
+ , 
+A,O
+genomewide,O
+search,O
+mapped,O
+the,O
+disease,O
+-,O
+causing,O
+gene,O
+with,O
+a,O
+LOD,O
+score,O
+of,O
+3.3,O
+and,O
+excluded,O
+major,O
+contributions,O
+to,O
+the,O
+phenotype,O
+of,O
+other,O
+genes,O
+.,O
+ , 
+A,O
+candidate,O
+gene,O
+present,O
+in,O
+the,O
+mapped,O
+chromosome,O
+region,O
+-,O
+the,O
+ligand,O
+-,O
+activated,O
+liver,O
+-,O
+transcription,O
+-,O
+factor,O
+gene,O
+ARP1,B-Gene
+(,O
+apolipoprotein,O
+regulatory,O
+-,O
+protein,O
+gene)-has,O
+been,O
+excluded,O
+after,O
+DNA,O
+sequencing,O
+.,O
+ , 
+The,O
+close,O
+-,O
+bred,O
+nature,O
+of,O
+the,O
+Sardinian,O
+population,O
+offers,O
+unique,O
+opportunities,O
+for,O
+isolation,O
+of,O
+this,O
+hypercholesterolemia,O
+-,O
+causing,O
+gene,O
+.,O
+ , 
+#8651275
+Guanidinoacetate,O
+methyltransferase,O
+deficiency,O
+:,O
+the,O
+first,O
+inborn,O
+error,O
+of,O
+creatine,O
+metabolism,O
+in,O
+man,O
+.,O
+ , 
+In,O
+two,O
+children,O
+with,O
+an,O
+accumulation,O
+of,O
+guanidinoacetate,O
+in,O
+brain,O
+and,O
+a,O
+deficiency,O
+of,O
+creatine,O
+in,O
+blood,O
+,,O
+a,O
+severe,O
+deficiency,O
+of,O
+guanidinoacetate,B-Gene
+methyltransferase,I-Gene
+(,B-Gene
+GAMT,I-Gene
+),I-Gene
+activity,O
+was,O
+detected,O
+in,O
+the,O
+liver,O
+.,O
+ , 
+Two,O
+mutant,O
+GAMT,B-Gene
+alleles,O
+were,O
+identified,O
+that,O
+carried,O
+a,O
+single,O
+base,O
+substitution,O
+within,O
+a,O
+5,O
+',O
+splice,O
+site,O
+or,O
+a,O
+13,O
+-,O
+nt,O
+insertion,O
+and,O
+gave,O
+rise,O
+to,O
+four,O
+mutant,O
+transcripts,O
+.,O
+ , 
+Three,O
+of,O
+the,O
+transcripts,O
+encode,O
+truncated,O
+polypeptides,O
+that,O
+lack,O
+a,O
+residue,O
+known,O
+to,O
+be,O
+critical,O
+for,O
+catalytic,O
+activity,O
+of,O
+GAMT,B-Gene
+.,I-Gene
+ , 
+Deficiency,O
+of,O
+GAMT,B-Gene
+is,O
+the,O
+first,O
+inborn,O
+error,O
+of,O
+creatine,O
+metabolism,O
+.,O
+ , 
+It,O
+causes,O
+a,O
+severe,O
+developmental,O
+delay,O
+and,O
+extrapyramidal,O
+symptoms,O
+in,O
+early,O
+infancy,O
+and,O
+is,O
+treatable,O
+by,O
+oral,O
+substitution,O
+with,O
+creatine,O
+.,O
+ , 
+#7825583
+Mapping,O
+of,O
+the,O
+gene,O
+for,O
+Machado,O
+-,O
+Joseph,O
+disease,O
+within,O
+a,O
+3.6,O
+-,O
+cM,O
+interval,O
+flanked,O
+by,O
+D14S291,O
+/,O
+D14S280,O
+and,O
+D14S81,O
+,,O
+on,O
+the,O
+basis,O
+of,O
+studies,O
+of,O
+linkage,O
+and,O
+linkage,O
+disequilibrium,O
+in,O
+24,O
+Japanese,O
+families,O
+.,O
+ , 
+The,O
+gene,O
+locus,O
+of,O
+Machado,O
+-,O
+Joseph,O
+disease,O
+(,O
+MJD,O
+),O
+has,O
+recently,O
+been,O
+mapped,O
+within,O
+a,O
+29,O
+-,O
+cM,O
+subregion,O
+of,O
+14q,O
+chromosome,O
+.,O
+ , 
+We,O
+did,O
+a,O
+linkage,O
+study,O
+of,O
+24,O
+multigenerational,O
+MJD,O
+Japanese,O
+pedigrees,O
+,,O
+in,O
+an,O
+attempt,O
+to,O
+narrow,O
+the,O
+candidate,O
+region,O
+of,O
+this,O
+gene,O
+.,O
+ , 
+Pairwise,O
+and,O
+multipoint,O
+linkage,O
+analysis,O
+,,O
+together,O
+with,O
+haplotype,O
+segregation,O
+analysis,O
+,,O
+led,O
+to,O
+the,O
+conclusion,O
+that,O
+the,O
+MJD,B-Gene
+gene,O
+is,O
+located,O
+at,O
+the,O
+6.8,O
+-,O
+cM,O
+interval,O
+between,O
+D14S256,O
+and,O
+D14S81,O
+(,O
+Zmax,O
+=,O
+24.78,O
+,,O
+multipoint,O
+linkage,O
+analysis,O
+),O
+.,O
+ , 
+D14S291,O
+and,O
+D14S280,O
+,,O
+located,O
+at,O
+the,O
+center,O
+of,O
+this,O
+interval,O
+,,O
+showed,O
+no,O
+obligate,O
+recombination,O
+with,O
+the,O
+MJD,B-Gene
+gene,O
+(,O
+Zmax,O
+=,O
+5.93,O
+for,O
+D14S291,O
+and,O
+9.99,O
+for,O
+D14S280,O
+),O
+.,O
+ , 
+A,O
+weak,O
+,,O
+but,O
+significant,O
+,,O
+linkage,O
+disequilibrium,O
+of,O
+MJD,B-Gene
+gene,O
+was,O
+noted,O
+with,O
+D14S81,O
+(,O
+P,O
+<,O
+.05,O
+),O
+but,O
+not,O
+with,O
+D14S291,O
+or,O
+D14S280,O
+.,O
+ , 
+These,O
+results,O
+suggest,O
+that,O
+a,O
+3.6,O
+-,O
+cM,O
+interval,O
+flanked,O
+by,O
+D14S291,O
+/,O
+D14S280,O
+and,O
+D14S81,O
+is,O
+the,O
+most,O
+likely,O
+location,O
+of,O
+the,O
+MJD,B-Gene
+gene,O
+and,O
+that,O
+it,O
+is,O
+closest,O
+to,O
+D14S81,O
+.,O
+ , 
+#10053017
+Ancestral,O
+Asian,O
+source(s,O
+),O
+of,O
+new,O
+world,O
+Y,O
+-,O
+chromosome,O
+founder,O
+haplotypes,O
+.,O
+ , 
+Haplotypes,O
+constructed,O
+from,O
+Y,O
+-,O
+chromosome,O
+markers,O
+were,O
+used,O
+to,O
+trace,O
+the,O
+origins,O
+of,O
+Native,O
+Americans,O
+.,O
+ , 
+Our,O
+sample,O
+consisted,O
+of,O
+2,198,O
+males,O
+from,O
+60,O
+global,O
+populations,O
+,,O
+including,O
+19,O
+Native,O
+American,O
+and,O
+15,O
+indigenous,O
+North,O
+Asian,O
+groups,O
+.,O
+ , 
+A,O
+set,O
+of,O
+12,O
+biallelic,O
+polymorphisms,O
+gave,O
+rise,O
+to,O
+14,O
+unique,O
+Y,O
+-,O
+chromosome,O
+haplotypes,O
+that,O
+were,O
+unevenly,O
+distributed,O
+among,O
+the,O
+populations,O
+.,O
+ , 
+Combining,O
+multiallelic,O
+variation,O
+at,O
+two,O
+Y,O
+-,O
+linked,O
+microsatellites,O
+(,O
+DYS19,O
+and,O
+DXYS156Y,O
+),O
+with,O
+the,O
+unique,O
+haplotypes,O
+results,O
+in,O
+a,O
+total,O
+of,O
+95,O
+combination,O
+haplotypes,O
+.,O
+ , 
+Contra,O
+previous,O
+findings,O
+based,O
+on,O
+Y-,O
+chromosome,O
+data,O
+,,O
+our,O
+new,O
+results,O
+suggest,O
+the,O
+possibility,O
+of,O
+more,O
+than,O
+one,O
+Native,O
+American,O
+paternal,O
+founder,O
+haplotype,O
+.,O
+ , 
+We,O
+postulate,O
+that,O
+,,O
+of,O
+the,O
+nine,O
+unique,O
+haplotypes,O
+found,O
+in,O
+Native,O
+Americans,O
+,,O
+haplotypes,O
+1C,O
+and,O
+1F,O
+are,O
+the,O
+best,O
+candidates,O
+for,O
+major,O
+New,O
+World,O
+founder,O
+haplotypes,O
+,,O
+whereas,O
+haplotypes,O
+1B,O
+,,O
+1I,O
+,,O
+and,O
+1U,O
+may,O
+either,O
+be,O
+founder,O
+haplotypes,O
+and/or,O
+have,O
+arrived,O
+in,O
+the,O
+New,O
+World,O
+via,O
+recent,O
+admixture,O
+.,O
+ , 
+Two,O
+of,O
+the,O
+other,O
+four,O
+haplotypes,O
+(,B-Gene
+YAP+,I-Gene
+haplotypes,O
+4,O
+and,O
+5,O
+),O
+are,O
+probably,O
+present,O
+because,O
+of,O
+post,O
+-,O
+Columbian,O
+admixture,O
+,,O
+whereas,O
+haplotype,O
+1,O
+G,O
+may,O
+have,O
+originated,O
+in,O
+the,O
+New,O
+World,O
+,,O
+and,O
+the,O
+Old,O
+World,O
+source,O
+of,O
+the,O
+final,O
+New,O
+World,O
+haplotype,O
+(,O
+1D,O
+),O
+remains,O
+unresolved,O
+.,O
+ , 
+The,O
+contrasting,O
+distribution,O
+patterns,O
+of,O
+the,O
+two,O
+major,O
+candidate,O
+founder,O
+haplotypes,O
+in,O
+Asia,O
+and,O
+the,O
+New,O
+World,O
+,,O
+as,O
+well,O
+as,O
+the,O
+results,O
+of,O
+a,O
+nested,O
+cladistic,O
+analysis,O
+,,O
+suggest,O
+the,O
+possibility,O
+of,O
+more,O
+than,O
+one,O
+paternal,O
+migration,O
+from,O
+the,O
+general,O
+region,O
+of,O
+Lake,O
+Baikal,O
+to,O
+the,O
+Americas,O
+.,O
+ , 
+#15208783
+Genomewide,O
+linkage,O
+scan,O
+for,O
+bipolar,O
+-,O
+disorder,O
+susceptibility,O
+loci,O
+among,O
+Ashkenazi,O
+Jewish,O
+families,O
+.,O
+ , 
+The,O
+relatively,O
+short,O
+history,O
+of,O
+linkage,O
+studies,O
+in,O
+bipolar,O
+disorders,O
+(,O
+BPs,O
+),O
+has,O
+produced,O
+inconsistent,O
+findings,O
+.,O
+ , 
+Implicated,O
+regions,O
+have,O
+been,O
+large,O
+,,O
+with,O
+reduced,O
+levels,O
+of,O
+significance,O
+and,O
+modest,O
+effect,O
+sizes,O
+.,O
+ , 
+Both,O
+phenotypic,O
+and,O
+genetic,O
+heterogeneity,O
+may,O
+have,O
+contributed,O
+to,O
+the,O
+failure,O
+to,O
+define,O
+risk,O
+loci,O
+.,O
+ , 
+BP,O
+is,O
+part,O
+of,O
+a,O
+spectrum,O
+of,O
+apparently,O
+familial,O
+affective,O
+disorders,O
+,,O
+which,O
+have,O
+been,O
+organized,O
+by,O
+severity,O
+.,O
+ , 
+Heterogeneity,O
+may,O
+arise,O
+because,O
+of,O
+insufficient,O
+data,O
+to,O
+define,O
+the,O
+spectrum,O
+boundaries,O
+,,O
+and,O
+,,O
+in,O
+general,O
+,,O
+the,O
+less,O
+-,O
+severe,O
+disorders,O
+are,O
+more,O
+difficult,O
+to,O
+diagnose,O
+reliably,O
+.,O
+ , 
+To,O
+address,O
+the,O
+inherent,O
+complexities,O
+in,O
+detecting,O
+BP,O
+susceptibility,O
+loci,O
+,,O
+we,O
+have,O
+used,O
+restricted,O
+diagnostic,O
+classifications,O
+and,O
+a,O
+genetically,O
+more,O
+homogeneous,O
+(,O
+Ashkenazi,O
+Jewish,O
+),O
+family,O
+collection,O
+to,O
+perform,O
+a,O
+9,O
+-,O
+cM,O
+autosomal,O
+genomewide,O
+linkage,O
+scan,O
+.,O
+ , 
+Although,O
+they,O
+are,O
+genetically,O
+more,O
+homogeneous,O
+,,O
+there,O
+are,O
+no,O
+data,O
+to,O
+suggest,O
+that,O
+the,O
+rate,O
+of,O
+illness,O
+in,O
+the,O
+Ashkenazim,O
+differs,O
+from,O
+that,O
+in,O
+other,O
+populations,O
+.,O
+ , 
+In,O
+a,O
+genome,O
+scan,O
+of,O
+41,O
+Ashkenazi,O
+pedigrees,O
+with,O
+a,O
+proband,O
+affected,O
+with,O
+bipolar,O
+I,O
+disorder,O
+(,O
+BPI,O
+),O
+and,O
+at,O
+least,O
+one,O
+other,O
+member,O
+affected,O
+with,O
+BPI,O
+or,O
+bipolar,O
+II,O
+disorder,O
+(,O
+BPII,O
+),O
+,,O
+we,O
+identified,O
+four,O
+regions,O
+suggestive,O
+of,O
+linkage,O
+on,O
+chromosomes,O
+1,O
+,,O
+3,O
+,,O
+11,O
+,,O
+and,O
+18,O
+.,O
+ , 
+Follow,O
+-,O
+up,O
+genotyping,O
+showed,O
+that,O
+the,O
+regions,O
+on,O
+chromosomes,O
+1,O
+,,O
+3,O
+,,O
+and,O
+18,O
+are,O
+also,O
+suggestive,O
+of,O
+linkage,O
+in,O
+a,O
+subset,O
+of,O
+pedigrees,O
+limited,O
+to,O
+relative,O
+pairs,O
+affected,O
+with,O
+BPI,O
+.,O
+ , 
+Furthermore,O
+,,O
+our,O
+chromosome,O
+18q22,O
+signal,O
+(,O
+D18S541,O
+and,O
+D18S477,O
+),O
+overlaps,O
+with,O
+previous,O
+BP,O
+findings,O
+.,O
+ , 
+This,O
+research,O
+is,O
+being,O
+conducted,O
+in,O
+parallel,O
+with,O
+our,O
+companion,O
+study,O
+of,O
+schizophrenia,O
+,,O
+in,O
+which,O
+,,O
+by,O
+use,O
+of,O
+an,O
+identical,O
+approach,O
+,,O
+we,O
+recently,O
+reported,O
+significant,O
+evidence,O
+for,O
+a,O
+schizophrenia,O
+susceptibility,O
+locus,O
+in,O
+the,O
+Ashkenazim,O
+on,O
+chromosome,O
+10q22,O
+.,O
+ , 
+#10090909
+A,O
+mutation,O
+(,B-SNP
+2314delG,I-SNP
+),I-SNP
+in,O
+the,O
+Usher,B-Gene
+syndrome,I-Gene
+type,I-Gene
+IIA,I-Gene
+gene,I-Gene
+:,I-Gene
+high,O
+prevalence,O
+and,O
+phenotypic,O
+variation,O
+.,O
+ , 
+#9452051
+The,O
+molecular,O
+basis,O
+of,O
+hypoxanthine,O
+-,O
+guanine,O
+phosphoribosyltransferase,O
+deficiency,O
+in,O
+French,O
+families,O
+;,O
+report,O
+of,O
+two,O
+novel,O
+mutations,O
+.,O
+ , 
+#23122590
+Linkage,O
+-,O
+disequilibrium,O
+-,O
+based,O
+binning,O
+misleads,O
+the,O
+interpretation,O
+of,O
+genome,O
+-,O
+wide,O
+association,O
+studies,O
+.,O
+ , 
+#9245996
+The,O
+seventh,O
+form,O
+of,O
+autosomal,O
+recessive,O
+limb,O
+-,O
+girdle,O
+muscular,O
+dystrophy,O
+is,O
+mapped,O
+to,O
+17q11,O
+-,O
+12,O
+.,O
+ , 
+The,O
+group,O
+of,O
+autosomal,O
+recessive,O
+(,O
+AR,O
+),O
+muscular,O
+dystrophies,O
+includes,O
+,,O
+among,O
+others,O
+,,O
+two,O
+main,O
+clinical,O
+entities,O
+,,O
+the,O
+limb,O
+-,O
+girdle,O
+muscular,O
+dystrophies,O
+(,O
+LGMDs,O
+),O
+and,O
+the,O
+distal,O
+muscular,O
+dystrophies,O
+.,O
+ , 
+The,O
+former,O
+are,O
+characterized,O
+mainly,O
+by,O
+muscle,O
+wasting,O
+of,O
+the,O
+upper,O
+and,O
+lower,O
+limbs,O
+,,O
+with,O
+a,O
+wide,O
+range,O
+of,O
+clinical,O
+severity,O
+.,O
+ , 
+This,O
+clinical,O
+heterogeneity,O
+has,O
+been,O
+demonstrated,O
+at,O
+the,O
+molecular,O
+level,O
+,,O
+since,O
+the,O
+genes,O
+for,O
+six,O
+AR,O
+forms,O
+have,O
+been,O
+cloned,O
+and/or,O
+have,O
+been,O
+mapped,O
+to,O
+15q15.1,O
+(,B-Gene
+LGMD2A,I-Gene
+),I-Gene
+,,I-Gene
+2p12,O
+-,O
+16,O
+(,B-Gene
+LGMD2B,I-Gene
+),I-Gene
+,,I-Gene
+13q12,O
+(,B-Gene
+LGMD2C,I-Gene
+),I-Gene
+,,I-Gene
+17q12,O
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+q21.33,O
+(,B-Gene
+LGMD2D),4q12,I-Gene
+(,B-Gene
+LGMD2E,I-Gene
+),I-Gene
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+34,O
+(,B-Gene
+LGMD2F,I-Gene
+),I-Gene
+.,I-Gene
+ , 
+The,O
+AR,O
+distal,O
+muscular,O
+dystrophies,O
+originally,O
+included,O
+two,O
+subgroups,O
+,,O
+Miyoshi,O
+myopathy,O
+,,O
+characterized,O
+mainly,O
+by,O
+extremely,O
+elevated,O
+serum,O
+creatine,O
+kinase,O
+(,O
+CK,O
+),O
+activity,O
+and,O
+by,O
+a,O
+dystrophic,O
+muscle,O
+pattern,O
+,,O
+and,O
+Nonaka,O
+myopathy,O
+,,O
+which,O
+is,O
+distinct,O
+from,O
+the,O
+others,O
+because,O
+of,O
+the,O
+normal,O
+to,O
+slightly,O
+elevated,O
+serum,O
+CK,O
+levels,O
+and,O
+a,O
+myopathic,O
+muscle,O
+pattern,O
+with,O
+rimmed,O
+vacuoles,O
+.,O
+ , 
+With,O
+regard,O
+to,O
+our,O
+unclassified,O
+AR,O
+LGMD,O
+families,O
+,,O
+analysis,O
+of,O
+the,O
+affected,O
+sibs,O
+from,O
+one,O
+of,O
+them,O
+(,O
+family,O
+LG61,O
+),O
+revealed,O
+some,O
+clinical,O
+and,O
+laboratory,O
+findings,O
+(,O
+early,O
+involvement,O
+of,O
+the,O
+distal,O
+muscles,O
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+mildly,O
+elevated,O
+serum,O
+CK,O
+levels,O
+,,O
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+rimmed,O
+vacuoles,O
+in,O
+muscle,O
+biopsies,O
+),O
+that,O
+usually,O
+are,O
+not,O
+observed,O
+in,O
+the,O
+analysis,O
+of,O
+patients,O
+with,O
+LGMD2A,O
+-,O
+LGMD2F.,O
+In,O
+the,O
+present,O
+investigation,O
+,,O
+through,O
+a,O
+genomewide,O
+search,O
+in,O
+family,O
+LG61,O
+,,O
+we,O
+demonstrated,O
+linkage,O
+of,O
+the,O
+allele,O
+causing,O
+this,O
+form,O
+of,O
+muscular,O
+dystrophy,O
+to,O
+a,O
+3,O
+-,O
+cM,O
+region,O
+on,O
+17q11,O
+-,O
+12,O
+.,O
+ , 
+We,O
+suggest,O
+that,O
+this,O
+form,O
+,,O
+which,O
+,,O
+interestingly,O
+,,O
+clinically,O
+resembles,O
+AR,O
+Kugelberg,O
+-,O
+Welander,O
+disease,O
+,,O
+should,O
+be,O
+classified,O
+as,O
+LGMD2G.,B-Gene
+ , 
+In,O
+addition,O
+,,O
+our,O
+results,O
+indicate,O
+the,O
+existence,O
+of,O
+still,O
+another,O
+locus,O
+causing,O
+severe,O
+LGMD,O
+.,O
+ , 
+#22100073
+Blood,O
+pressure,O
+loci,O
+identified,O
+with,O
+a,O
+gene,O
+-,O
+centric,O
+array,O
+.,O
+ , 
+Raised,O
+blood,O
+pressure,O
+(,O
+BP,O
+),O
+is,O
+a,O
+major,O
+risk,O
+factor,O
+for,O
+cardiovascular,O
+disease,O
+.,O
+ , 
+Previous,O
+studies,O
+have,O
+identified,O
+47,O
+distinct,O
+genetic,O
+variants,O
+robustly,O
+associated,O
+with,O
+BP,O
+,,O
+but,O
+collectively,O
+these,O
+explain,O
+only,O
+a,O
+few,O
+percent,O
+of,O
+the,O
+heritability,O
+for,O
+BP,O
+phenotypes,O
+.,O
+ , 
+To,O
+find,O
+additional,O
+BP,O
+loci,O
+,,O
+we,O
+used,O
+a,O
+bespoke,O
+gene,O
+-,O
+centric,O
+array,O
+to,O
+genotype,O
+an,O
+independent,O
+discovery,O
+sample,O
+of,O
+25,118,O
+individuals,O
+that,O
+combined,O
+hypertensive,O
+case,O
+-,O
+control,O
+and,O
+general,O
+population,O
+samples,O
+.,O
+ , 
+We,O
+followed,O
+up,O
+four,O
+SNPs,O
+associated,O
+with,O
+BP,O
+at,O
+our,O
+p,O
+<,O
+8.56,O
+ ,O
+×,O
+10(-7,O
+),O
+study,O
+-,O
+specific,O
+significance,O
+threshold,O
+and,O
+six,O
+suggestively,O
+associated,O
+SNPs,O
+in,O
+a,O
+further,O
+59,349,O
+individuals,O
+.,O
+ , 
+We,O
+identified,O
+and,O
+replicated,O
+a,O
+SNP,O
+at,O
+LSP1,B-Gene
+/,B-Gene
+TNNT3,I-Gene
+,,I-Gene
+a,O
+SNP,O
+at,O
+MTHFR,B-Gene
+-,I-Gene
+NPPB,I-Gene
+independent,O
+(,O
+r(2,O
+),O
+=,O
+0.33,O
+),O
+of,O
+previous,O
+reports,O
+,,O
+and,O
+replicated,O
+SNPs,O
+at,O
+AGT,B-Gene
+and,O
+ATP2B1,B-Gene
+reported,O
+previously,O
+.,O
+ , 
+An,O
+analysis,O
+of,O
+combined,O
+discovery,O
+and,O
+follow,O
+-,O
+up,O
+data,O
+identified,O
+SNPs,O
+significantly,O
+associated,O
+with,O
+BP,O
+at,O
+p,O
+<,O
+8.56,O
+ ,O
+×,O
+10(-7,O
+),O
+at,O
+four,O
+further,O
+loci,O
+(,B-Gene
+NPR3,I-Gene
+,,I-Gene
+HFE,B-Gene
+,,I-Gene
+NOS3,B-Gene
+,,I-Gene
+and,O
+SOX6,B-Gene
+),I-Gene
+.,O
+ , 
+The,O
+high,O
+number,O
+of,O
+discoveries,O
+made,O
+with,O
+modest,O
+genotyping,O
+effort,O
+can,O
+be,O
+attributed,O
+to,O
+using,O
+a,O
+large,O
+-,O
+scale,O
+yet,O
+targeted,O
+genotyping,O
+array,O
+and,O
+to,O
+the,O
+development,O
+of,O
+a,O
+weighting,O
+scheme,O
+that,O
+maximized,O
+power,O
+when,O
+meta,O
+-,O
+analyzing,O
+results,O
+from,O
+samples,O
+ascertained,O
+with,O
+extreme,O
+phenotypes,O
+,,O
+in,O
+combination,O
+with,O
+results,O
+from,O
+nonascertained,O
+or,O
+population,O
+samples,O
+.,O
+ , 
+Chromatin,O
+immunoprecipitation,O
+and,O
+transcript,O
+expression,O
+data,O
+highlight,O
+potential,O
+gene,O
+regulatory,O
+mechanisms,O
+at,O
+the,O
+MTHFR,B-Gene
+and,O
+NOS3,B-Gene
+loci,O
+.,O
+ , 
+These,O
+results,O
+provide,O
+candidates,O
+for,O
+further,O
+study,O
+to,O
+help,O
+dissect,O
+mechanisms,O
+affecting,O
+BP,O
+and,O
+highlight,O
+the,O
+utility,O
+of,O
+studying,O
+SNPs,O
+and,O
+samples,O
+that,O
+are,O
+independent,O
+of,O
+those,O
+studied,O
+previously,O
+even,O
+when,O
+the,O
+sample,O
+size,O
+is,O
+smaller,O
+than,O
+that,O
+in,O
+previous,O
+studies,O
+.,O
+ , 
+#11536080
+Genomewide,O
+-,O
+linkage,O
+and,O
+haplotype,O
+-,O
+association,O
+studies,O
+map,O
+intracranial,O
+aneurysm,O
+to,O
+chromosome,O
+7q11,O
+.,O
+ , 
+Rupture,O
+of,O
+intracranial,O
+aneurysms,O
+(,O
+IAs,O
+),O
+causes,O
+subarachnoid,O
+hemorrhage,O
+,,O
+a,O
+devastating,O
+condition,O
+with,O
+high,O
+morbidity,O
+and,O
+mortality,O
+.,O
+ , 
+Angiographic,O
+and,O
+autopsy,O
+studies,O
+show,O
+that,O
+IA,O
+is,O
+a,O
+common,O
+disorder,O
+,,O
+with,O
+a,O
+prevalence,O
+of,O
+3%-6,O
+%,O
+.,O
+ , 
+Although,O
+IA,O
+has,O
+a,O
+substantial,O
+genetic,O
+component,O
+,,O
+little,O
+attention,O
+has,O
+been,O
+given,O
+to,O
+the,O
+genetic,O
+determinants,O
+.,O
+ , 
+We,O
+report,O
+here,O
+a,O
+genomewide,O
+linkage,O
+study,O
+of,O
+IA,O
+in,O
+104,O
+Japanese,O
+affected,O
+sib,O
+pairs,O
+in,O
+which,O
+positive,O
+evidence,O
+of,O
+linkage,O
+on,O
+chromosomes,O
+5q22,O
+-,O
+31,O
+(,O
+maximum,O
+LOD,O
+score,O
+[,O
+MLS,O
+],O
+2.24,O
+),O
+,,O
+7q11,O
+(,O
+MLS,O
+3.22,O
+),O
+,,O
+and,O
+14q22,O
+(,O
+MLS,O
+2.31,O
+),O
+were,O
+found,O
+.,O
+ , 
+The,O
+best,O
+evidence,O
+of,O
+linkage,O
+is,O
+detected,O
+at,O
+D7S2472,B-SNP
+,,I-SNP
+in,O
+the,O
+vicinity,O
+of,O
+the,O
+elastin,B-Gene
+gene,O
+(,B-Gene
+ELN,I-Gene
+),I-Gene
+,,O
+a,O
+candidate,O
+gene,O
+for,O
+IA,O
+.,O
+ , 
+Fourteen,O
+distinct,O
+single,O
+-,O
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+(,O
+SNPs,O
+),O
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+in,O
+ELN,B-Gene
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+obvious,O
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+between,O
+IA,O
+and,O
+each,O
+SNP,O
+was,O
+observed,O
+.,O
+ , 
+The,O
+haplotype,O
+between,O
+the,O
+intron-20,O
+/,O
+intron-23,O
+polymorphism,O
+of,O
+ELN,B-Gene
+is,O
+strongly,O
+associated,O
+with,O
+IA,O
+(,O
+P=3.81x10,O
+-,O
+6,O
+),O
+,,O
+and,O
+homozygous,O
+patients,O
+are,O
+at,O
+high,O
+risk,O
+(,O
+P=.002,O
+),O
+,,O
+with,O
+an,O
+odds,O
+ratio,O
+of,O
+4.39,O
+.,O
+ , 
+These,O
+findings,O
+suggest,O
+that,O
+a,O
+genetic,O
+locus,O
+for,O
+IA,O
+lies,O
+within,O
+or,O
+close,O
+to,O
+the,O
+ELN,B-Gene
+locus,O
+on,O
+chromosome,O
+7,O
+.,O
+ , 
+#18752264
+Ethnically,O
+diverse,O
+causes,O
+of,O
+Walker,O
+-,O
+Warburg,O
+syndrome,O
+(,O
+WWS,O
+):,O
+FCMD,O
+mutations,O
+are,O
+a,O
+more,O
+common,O
+cause,O
+of,O
+WWS,O
+outside,O
+of,O
+the,O
+Middle,O
+East,O
+.,O
+ , 
+Walker,O
+-,O
+Warburg,O
+syndrome,O
+(,O
+WWS,O
+),O
+is,O
+a,O
+genetically,O
+heterogeneous,O
+autosomal,O
+recessive,O
+disease,O
+characterized,O
+by,O
+congenital,O
+muscular,O
+dystrophy,O
+,,O
+cobblestone,O
+lissencephaly,O
+,,O
+and,O
+ocular,O
+malformations,O
+.,O
+ , 
+Mutations,O
+in,O
+six,O
+genes,O
+involved,O
+in,O
+the,O
+glycosylation,O
+of,O
+á,O
+-,O
+dystroglycan,O
+(,B-Gene
+POMT1,I-Gene
+,,I-Gene
+POMT2,B-Gene
+,,I-Gene
+POMGNT1,B-Gene
+,,I-Gene
+FCMD,B-Gene
+,,I-Gene
+FKRP,B-Gene
+and,O
+LARGE,B-Gene
+),I-Gene
+have,O
+been,O
+identified,O
+in,O
+WWS,O
+patients,O
+,,O
+but,O
+account,O
+for,O
+only,O
+a,O
+portion,O
+of,O
+WWS,O
+cases,O
+.,O
+ , 
+To,O
+better,O
+understand,O
+the,O
+genetics,O
+of,O
+WWS,O
+and,O
+establish,O
+the,O
+frequency,O
+and,O
+distribution,O
+of,O
+mutations,O
+across,O
+WWS,O
+genes,O
+,,O
+we,O
+genotyped,O
+all,O
+known,O
+loci,O
+in,O
+a,O
+cohort,O
+of,O
+43,O
+WWS,O
+patients,O
+of,O
+varying,O
+geographical,O
+and,O
+ethnic,O
+origin,O
+.,O
+ , 
+Surprisingly,O
+,,O
+we,O
+reached,O
+a,O
+molecular,O
+diagnosis,O
+for,O
+40,O
+%,O
+of,O
+our,O
+patients,O
+and,O
+found,O
+mutations,O
+in,O
+POMT1,B-Gene
+,,I-Gene
+POMT2,B-Gene
+,,I-Gene
+FCMD,B-Gene
+and,O
+FKRP,B-Gene
+,,I-Gene
+many,O
+of,O
+which,O
+were,O
+novel,O
+alleles,O
+,,O
+but,O
+no,O
+mutations,O
+in,O
+POMGNT1,B-Gene
+or,O
+LARGE,B-Gene
+.,I-Gene
+ , 
+Notably,O
+,,O
+the,O
+FCMD,B-Gene
+gene,O
+was,O
+a,O
+more,O
+common,O
+cause,O
+of,O
+WWS,O
+than,O
+previously,O
+expected,O
+in,O
+the,O
+European,O
+/,O
+American,O
+subset,O
+of,O
+our,O
+cohort,O
+,,O
+including,O
+all,O
+Ashkenazi,O
+Jewish,O
+cases,O
+,,O
+who,O
+carried,O
+the,O
+same,O
+founder,O
+mutation,O
+.,O
+ , 
+#12655559
+Gene,O
+structure,O
+of,O
+human,O
+carbamylphosphate,O
+synthetase,O
+1,O
+and,O
+novel,O
+mutations,O
+in,O
+patients,O
+with,O
+neonatal,O
+onset,O
+.,O
+ , 
+Carbamylphosphate,O
+synthetase,O
+1,O
+(,O
+E.C.,O
+6.3.4.16,O
+),O
+deficiency,O
+is,O
+a,O
+rare,O
+autosomal,O
+recessive,O
+disorder,O
+of,O
+the,O
+urea,O
+cycle,O
+that,O
+can,O
+result,O
+in,O
+severe,O
+neonatal,O
+hyperammonemia,O
+.,O
+ , 
+Since,O
+the,O
+genomic,O
+structure,O
+of,O
+the,O
+CPS1,B-Gene
+gene,O
+was,O
+not,O
+yet,O
+elucidated,O
+,,O
+mutation,O
+detection,O
+was,O
+performed,O
+by,O
+analysis,O
+of,O
+transcripts,O
+in,O
+the,O
+past,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+present,O
+the,O
+entire,O
+DNA,O
+sequence,O
+of,O
+the,O
+human,O
+CPS1,B-Gene
+gene,O
+including,O
+all,O
+exon,O
+-,O
+intron,O
+boundaries,O
+.,O
+ , 
+Moreover,O
+,,O
+mutation,O
+analysis,O
+was,O
+performed,O
+in,O
+six,O
+patients,O
+leading,O
+to,O
+the,O
+detection,O
+of,O
+9,O
+novel,O
+mutations,O
+including,O
+the,O
+missense,O
+mutations,O
+c.2528T,B-SNP
+>,I-SNP
+C,I-SNP
+and,O
+c.2623A,B-SNP
+>,I-SNP
+G,I-SNP
+,,I-SNP
+the,O
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+mutations,O
+c.712C,B-SNP
+>,I-SNP
+T,I-SNP
+and,O
+c.2115ins35bp,B-SNP
+,,I-SNP
+the,O
+splice,O
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+c.1263,B-SNP
++,I-SNP
+5G,I-SNP
+>,I-SNP
+C,I-SNP
+,,I-SNP
+c.3558,B-SNP
++,I-SNP
+1G,I-SNP
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+C,I-SNP
+and,O
+c.4101,B-SNP
++,I-SNP
+2T,I-SNP
+>,I-SNP
+C,I-SNP
+,,I-SNP
+and,O
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+small,O
+deletion,O
+c.3036_3038delGGT,B-SNP
+.,I-SNP
+ , 
+The,O
+mutations,O
+c.2528T,B-SNP
+>,I-SNP
+C,I-SNP
+and,O
+c.2623A,B-SNP
+>,I-SNP
+G,I-SNP
+were,O
+identified,O
+on,O
+a,O
+double,O
+mutated,O
+allele,O
+.,O
+ , 
+New,O
+data,O
+on,O
+the,O
+genomic,O
+structure,O
+of,O
+the,O
+CPS1,B-Gene
+gene,O
+provided,O
+in,O
+this,O
+study,O
+are,O
+useful,O
+to,O
+characterize,O
+the,O
+heterogenous,O
+molecular,O
+basis,O
+of,O
+the,O
+disease,O
+in,O
+patients,O
+deficient,O
+for,O
+carbamylphosphate,O
+1,O
+deficiency,O
+.,O
+ , 
+#16673358
+The,O
+spectrum,O
+of,O
+WRN,O
+mutations,O
+in,O
+Werner,O
+syndrome,O
+patients,O
+.,O
+ , 
+The,O
+International,O
+Registry,O
+of,O
+Werner,O
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+www.wernersyndrome.org,O
+),O
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+been,O
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+the,O
+Werner,O
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+(,O
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+),O
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+past,O
+decade,O
+.,O
+ , 
+The,O
+present,O
+communication,O
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+,,O
+from,O
+among,O
+99,O
+WS,O
+subjects,O
+,,O
+the,O
+spectrum,O
+of,O
+50,O
+distinct,O
+mutations,O
+discovered,O
+by,O
+our,O
+group,O
+and,O
+by,O
+others,O
+since,O
+the,O
+WRN,B-Gene
+gene,O
+(,O
+also,O
+called,O
+RECQL2,B-Gene
+or,O
+REQ3,B-Gene
+),I-Gene
+was,O
+first,O
+cloned,O
+in,O
+1996,O
+;,O
+25,O
+of,O
+these,O
+have,O
+not,O
+previously,O
+been,O
+published,O
+.,O
+ , 
+All,O
+WRN,B-Gene
+mutations,O
+reported,O
+thus,O
+far,O
+have,O
+resulted,O
+in,O
+the,O
+elimination,O
+of,O
+the,O
+nuclear,O
+localization,O
+signal,O
+at,O
+the,O
+C,O
+-,O
+terminus,O
+of,O
+the,O
+protein,O
+,,O
+precluding,O
+functional,O
+interactions,O
+in,O
+the,O
+nucleus,O
+;,O
+thus,O
+,,O
+all,O
+could,O
+be,O
+classified,O
+as,O
+null,O
+mutations,O
+.,O
+ , 
+We,O
+now,O
+report,O
+two,O
+new,O
+mutations,O
+in,O
+the,O
+N,O
+-,O
+terminus,O
+that,O
+result,O
+in,O
+instability,O
+of,O
+the,O
+WRN,B-Gene
+protein,O
+.,O
+ , 
+Clinical,O
+data,O
+confirm,O
+that,O
+the,O
+most,O
+penetrant,O
+phenotype,O
+is,O
+bilateral,O
+ocular,O
+cataracts,O
+.,O
+ , 
+Other,O
+cardinal,O
+signs,O
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+seen,O
+in,O
+more,O
+than,O
+95,O
+%,O
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+the,O
+cases,O
+.,O
+ , 
+The,O
+median,O
+age,O
+of,O
+death,O
+,,O
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+reported,O
+to,O
+be,O
+in,O
+the,O
+range,O
+of,O
+46,O
+-,O
+48,O
+years,O
+,,O
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+54,O
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+.,O
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+Lymphoblastoid,O
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+lines,O
+(,O
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+),O
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+been,O
+cryopreserved,O
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+the,O
+majority,O
+of,O
+our,O
+index,O
+cases,O
+,,O
+including,O
+material,O
+from,O
+nuclear,O
+pedigrees,O
+.,O
+ , 
+These,O
+,,O
+as,O
+well,O
+as,O
+inducible,O
+and,O
+complemented,O
+hTERT,O
+(,O
+catalytic,O
+subunit,O
+of,O
+human,O
+telomerase,O
+),O
+immortalized,O
+skin,O
+fibroblast,O
+cell,O
+lines,O
+are,O
+available,O
+to,O
+qualified,O
+investigators,O
+.,O
+ , 
+#9090528
+Mutations,O
+and,O
+DNA,O
+diagnoses,O
+of,O
+classical,O
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+Classical,O
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+is,O
+an,O
+autosomal,O
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+disease,O
+caused,O
+by,O
+a,O
+genetic,O
+deficiency,O
+of,O
+argininosuccinate,O
+synthetase,O
+(,O
+ASS,O
+),O
+.,O
+ , 
+We,O
+have,O
+previously,O
+identified,O
+20,O
+mutations,O
+in,O
+ASS,B-Gene
+mRNA,O
+of,O
+human,O
+classical,O
+citrullinemia,O
+and,O
+already,O
+established,O
+the,O
+DNA,O
+diagnosis,O
+of,O
+seven,O
+mutations,O
+as,O
+follows,O
+.,O
+ , 
+By,O
+Southern,O
+blot,O
+analysis,O
+,,O
+each,O
+of,O
+the,O
+alleles,O
+with,O
+exon,O
+5,O
+or,O
+6,O
+deletion,O
+in,O
+mRNA,O
+appears,O
+to,O
+involve,O
+deletion,O
+of,O
+genomic,O
+DNA,O
+from,O
+this,O
+region,O
+.,O
+ , 
+Five,O
+mutations,O
+involving,O
+R304W,B-SNP
+,,I-SNP
+G324S,B-SNP
+,,I-SNP
+IVS-6(-2,B-SNP
+),I-SNP
+(,O
+delta,O
+Ex7,O
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+,,O
+IVS-13(+5,B-SNP
+),I-SNP
+(,O
+delta,O
+Ex13,O
+),O
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+delta,O
+13,B-SNP
+bp,I-SNP
+/,I-SNP
+Ex15&IVS-15,I-SNP
+(,B-SNP
+ins37,I-SNP
+b,I-SNP
+/,I-SNP
+Ex15&16,I-SNP
+),I-SNP
+are,O
+diagnosed,O
+by,O
+a,O
+combination,O
+of,O
+PCR,O
+(,O
+or,O
+modified,O
+PCR,O
+),O
+and,O
+restriction,O
+enzyme,O
+digestion,O
+.,O
+ , 
+It,O
+is,O
+important,O
+to,O
+identify,O
+the,O
+mutation,O
+in,O
+genomic,O
+DNA,O
+for,O
+prenatal,O
+diagnosis,O
+and,O
+carrier,O
+detection,O
+.,O
+ , 
+In,O
+the,O
+present,O
+study,O
+,,O
+we,O
+report,O
+a,O
+novel,O
+missense,O
+mutation,O
+(,B-SNP
+R279Q,I-SNP
+),I-SNP
+and,O
+a,O
+new,O
+abnormality,O
+in,O
+the,O
+ASS,O
+gene,O
+(,B-SNP
+delta,I-SNP
+11,I-SNP
+bp,I-SNP
+/,I-SNP
+IVS-15,I-SNP
+),I-SNP
+.,O
+ , 
+As,O
+three,O
+missense,O
+mutations,O
+(,B-SNP
+R272C,I-SNP
+,,I-SNP
+R279Q,B-SNP
+,,I-SNP
+and,O
+G280R,B-SNP
+),I-SNP
+were,O
+found,O
+in,O
+exon,O
+12,O
+,,O
+we,O
+isolated,O
+and,O
+sequenced,O
+the,O
+intron,O
+regions,O
+surrounding,O
+exon,O
+12,O
+to,O
+establish,O
+a,O
+DNA,O
+diagnostic,O
+test,O
+.,O
+ , 
+Although,O
+a,O
+mutation,O
+with,O
+a,O
+deletion,B-SNP
+of,I-SNP
+the,I-SNP
+first,I-SNP
+seven,I-SNP
+bases,I-SNP
+in,I-SNP
+exon,I-SNP
+16,I-SNP
+of,O
+mRNA,O
+(,B-SNP
+delta,I-SNP
+7,I-SNP
+b,I-SNP
+/,I-SNP
+Ex16,I-SNP
+),I-SNP
+was,O
+found,O
+in,O
+both,O
+Japanese,O
+and,O
+American,O
+patients,O
+,,O
+the,O
+abnormality,O
+on,O
+the,O
+ASS,B-Gene
+gene,O
+was,O
+different,O
+between,O
+the,O
+Japanese,O
+allele,O
+(,B-SNP
+delta,I-SNP
+11,I-SNP
+bp,I-SNP
+/,I-SNP
+IVS-15,I-SNP
+),I-SNP
+and,O
+American,O
+allele,O
+(,B-SNP
+IVS-15(-1,I-SNP
+),I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+DNA,O
+diagnosis,O
+of,O
+47,O
+Japanese,O
+alleles,O
+with,O
+classical,O
+citrullinemia,O
+showed,O
+that,O
+the,O
+IVS-6(-2,O
+),O
+and,O
+R304W,B-SNP
+mutations,O
+were,O
+found,O
+in,O
+49,O
+%,O
+and,O
+17,O
+%,O
+of,O
+the,O
+mutated,O
+alleles,O
+,,O
+respectively,O
+.,O
+ , 
+We,O
+now,O
+have,O
+DNA,O
+diagnosis,O
+systems,O
+to,O
+detect,O
+14,O
+out,O
+of,O
+22,O
+mutations,O
+and,O
+are,O
+performing,O
+prenatal,O
+diagnosis,O
+and,O
+carrier,O
+detection,O
+using,O
+genomic,O
+DNA,O
+on,O
+classical,O
+citrullinemia,O
+.,O
+ , 
+#9837829
+Evidence,O
+for,O
+a,O
+Turner,O
+syndrome,O
+locus,O
+or,O
+loci,O
+at,O
+Xp11.2,O
+-,O
+p22.1,O
+.,O
+ , 
+Turner,O
+syndrome,O
+is,O
+the,O
+complex,O
+human,O
+phenotype,O
+associated,O
+with,O
+complete,O
+or,O
+partial,O
+monosomy,O
+X.,O
+Principle,O
+features,O
+of,O
+Turner,O
+syndrome,O
+include,O
+short,O
+stature,O
+,,O
+ovarian,O
+failure,O
+,,O
+and,O
+a,O
+variety,O
+of,O
+other,O
+anatomic,O
+and,O
+physiological,O
+abnormalities,O
+,,O
+such,O
+as,O
+webbed,O
+neck,O
+,,O
+lymphedema,O
+,,O
+cardiovascular,O
+and,O
+renal,O
+anomalies,O
+,,O
+hypertension,O
+,,O
+and,O
+autoimmune,O
+thyroid,O
+disease,O
+.,O
+ , 
+We,O
+studied,O
+28,O
+apparently,O
+nonmosaic,O
+subjects,O
+with,O
+partial,O
+deletions,O
+of,O
+Xp,O
+,,O
+in,O
+order,O
+to,O
+map,O
+loci,O
+responsible,O
+for,O
+various,O
+components,O
+of,O
+the,O
+Turner,O
+syndrome,O
+phenotype,O
+.,O
+ , 
+Subjects,O
+were,O
+carefully,O
+evaluated,O
+for,O
+the,O
+presence,O
+or,O
+absence,O
+of,O
+Turner,O
+syndrome,O
+features,O
+,,O
+and,O
+their,O
+deletions,O
+were,O
+mapped,O
+by,O
+FISH,O
+with,O
+a,O
+panel,O
+of,O
+Xp,O
+markers,O
+.,O
+ , 
+Using,O
+a,O
+statistical,O
+method,O
+to,O
+examine,O
+genotype,O
+/,O
+phenotype,O
+correlations,O
+,,O
+we,O
+mapped,O
+one,O
+or,O
+more,O
+Turner,O
+syndrome,O
+traits,O
+to,O
+a,O
+critical,O
+region,O
+in,O
+Xp11.2,O
+-,O
+p22.1,O
+.,O
+ , 
+These,O
+traits,O
+included,O
+short,O
+stature,O
+,,O
+ovarian,O
+failure,O
+,,O
+high,O
+-,O
+arched,O
+palate,O
+,,O
+and,O
+autoimmune,O
+thyroid,O
+disease,O
+.,O
+ , 
+The,O
+results,O
+are,O
+useful,O
+for,O
+genetic,O
+counseling,O
+of,O
+individuals,O
+with,O
+partial,O
+monosomy,O
+X.,O
+Study,O
+of,O
+additional,O
+subjects,O
+should,O
+refine,O
+the,O
+localization,O
+of,O
+Turner,O
+syndrome,O
+loci,O
+and,O
+provide,O
+a,O
+rational,O
+basis,O
+for,O
+exploration,O
+of,O
+candidate,O
+genes,O
+.,O
+ , 
+#21782149
+Mutations,O
+in,O
+ANKRD11,B-Gene
+cause,O
+KBG,O
+syndrome,O
+,,O
+characterized,O
+by,O
+intellectual,O
+disability,O
+,,O
+skeletal,O
+malformations,O
+,,O
+and,O
+macrodontia,O
+.,O
+ , 
+KBG,O
+syndrome,O
+is,O
+characterized,O
+by,O
+intellectual,O
+disability,O
+associated,O
+with,O
+macrodontia,O
+of,O
+the,O
+upper,O
+central,O
+incisors,O
+as,O
+well,O
+as,O
+distinct,O
+craniofacial,O
+findings,O
+,,O
+short,O
+stature,O
+,,O
+and,O
+skeletal,O
+anomalies,O
+.,O
+ , 
+Although,O
+believed,O
+to,O
+be,O
+genetic,O
+in,O
+origin,O
+,,O
+the,O
+specific,O
+underlying,O
+defect,O
+is,O
+unknown,O
+.,O
+ , 
+Through,O
+whole,O
+-,O
+exome,O
+sequencing,O
+,,O
+we,O
+identified,O
+deleterious,O
+heterozygous,O
+mutations,O
+in,O
+ANKRD11,B-Gene
+encoding,O
+ankyrin,B-Gene
+repeat,I-Gene
+domain,I-Gene
+11,I-Gene
+,,I-Gene
+also,O
+known,O
+as,O
+ankyrin,B-Gene
+repeat,I-Gene
+-,I-Gene
+containing,I-Gene
+cofactor,I-Gene
+1,I-Gene
+.,I-Gene
+ , 
+A,O
+splice,O
+-,O
+site,O
+mutation,O
+,,O
+c.7570,B-SNP
+-,I-SNP
+1G,I-SNP
+>,I-SNP
+C,I-SNP
+(,B-SNP
+p.,I-SNP
+Glu2524_Lys2525del,I-SNP
+),I-SNP
+,,O
+cosegregated,O
+with,O
+the,O
+disease,O
+in,O
+a,O
+family,O
+with,O
+three,O
+affected,O
+members,O
+,,O
+whereas,O
+in,O
+a,O
+simplex,O
+case,O
+a,O
+de,O
+novo,O
+truncating,O
+mutation,O
+,,O
+c.2305delT,B-SNP
+(,B-SNP
+p.,I-SNP
+Ser769GlnfsX8,I-SNP
+),I-SNP
+,,O
+was,O
+detected,O
+.,O
+ , 
+Sanger,O
+sequencing,O
+revealed,O
+additional,O
+de,O
+novo,O
+truncating,O
+ANKRD11,B-Gene
+mutations,O
+in,O
+three,O
+other,O
+simplex,O
+cases,O
+.,O
+ , 
+ANKRD11,B-Gene
+is,O
+known,O
+to,O
+interact,O
+with,O
+nuclear,O
+receptor,O
+complexes,O
+to,O
+modify,O
+transcriptional,O
+activation,O
+.,O
+ , 
+We,O
+demonstrated,O
+that,O
+ANKRD11,B-Gene
+localizes,O
+mainly,O
+to,O
+the,O
+nuclei,O
+of,O
+neurons,O
+and,O
+accumulates,O
+in,O
+discrete,O
+inclusions,O
+when,O
+neurons,O
+are,O
+depolarized,O
+,,O
+suggesting,O
+that,O
+it,O
+plays,O
+a,O
+role,O
+in,O
+neural,O
+plasticity,O
+.,O
+ , 
+Our,O
+results,O
+demonstrate,O
+that,O
+mutations,O
+in,O
+ANKRD11,B-Gene
+cause,O
+KBG,O
+syndrome,O
+and,O
+outline,O
+a,O
+fundamental,O
+role,O
+of,O
+ANKRD11,B-Gene
+in,O
+craniofacial,O
+,,O
+dental,O
+,,O
+skeletal,O
+,,O
+and,O
+central,O
+nervous,O
+system,O
+development,O
+and,O
+function,O
+.,O
+ , 
+#8364588
+Paternal,O
+mosaicism,O
+for,O
+a,O
+COL1A1,B-Gene
+dominant,O
+mutation,O
+(,B-SNP
+alpha,I-SNP
+1,I-SNP
+Ser-415,I-SNP
+),I-SNP
+causes,O
+recurrent,O
+osteogenesis,O
+imperfecta,O
+.,O
+ , 
+We,O
+describe,O
+a,O
+dominant,O
+point,O
+mutation,O
+in,O
+the,O
+COL1A1,B-Gene
+gene,O
+causing,O
+extremely,O
+severe,O
+osteogenesis,O
+imperfecta,O
+(,O
+OI,O
+type,O
+II,O
+/,O
+III,O
+),O
+which,O
+was,O
+detected,O
+in,O
+the,O
+dermal,O
+fibroblasts,O
+of,O
+a,O
+proband,O
+,,O
+diagnosed,O
+by,O
+ultrasonography,O
+at,O
+24,O
+weeks,O
+of,O
+gestation,O
+.,O
+ , 
+Type,B-Gene
+I,I-Gene
+collagen,I-Gene
+secretion,O
+was,O
+reduced,O
+and,O
+pro,O
+alpha,O
+1(I,O
+),O
+chains,O
+were,O
+overmodified,O
+.,O
+ , 
+The,O
+mutation,O
+was,O
+localised,O
+in,O
+one,O
+COL1A1,B-Gene
+allele,O
+by,O
+chemical,O
+cleavage,O
+of,O
+mismatched,O
+bases,O
+in,O
+normal,O
+cDNA,O
+/,O
+proband,O
+'s,O
+mRNA,O
+heteroduplexes,O
+,,O
+and,O
+identified,O
+by,O
+cloning,O
+and,O
+sequencing,O
+.,O
+ , 
+A,O
+G,O
+-,O
+to,O
+-,O
+A,O
+transition,O
+which,O
+causes,O
+the,O
+substitution,O
+of,O
+Gly-415,B-SNP
+with,I-SNP
+serine,I-SNP
+in,O
+the,O
+alpha,O
+1(I,O
+),O
+triple,O
+helical,O
+domain,O
+was,O
+found,O
+.,O
+ , 
+The,O
+same,O
+mutation,O
+was,O
+detected,O
+in,O
+the,O
+father,O
+'s,O
+spermatozoa,O
+and,O
+lymphocytes,O
+.,O
+ , 
+Mosaicism,O
+in,O
+the,O
+father,O
+'s,O
+germline,O
+explains,O
+the,O
+occurrence,O
+in,O
+the,O
+family,O
+of,O
+two,O
+additional,O
+OI,O
+pregnancies,O
+,,O
+which,O
+were,O
+documented,O
+by,O
+X,O
+-,O
+ray,O
+and,O
+ultrasound,O
+investigations,O
+.,O
+ , 
+#10649495
+Glucocerebrosidase,B-Gene
+gene,O
+mutations,O
+in,O
+patients,O
+with,O
+type,O
+2,O
+Gaucher,O
+disease,O
+.,O
+ , 
+Gaucher,O
+disease,O
+,,O
+the,O
+most,O
+common,O
+lysosomal,O
+storage,O
+disorder,O
+,,O
+results,O
+from,O
+the,O
+inherited,O
+deficiency,O
+of,O
+the,O
+enzyme,O
+glucocerebrosidase,O
+.,O
+ , 
+Three,O
+clinical,O
+types,O
+are,O
+recognized,O
+:,O
+type,O
+1,O
+,,O
+non,O
+-,O
+neuronopathic,O
+;,O
+type,O
+2,O
+,,O
+acute,O
+neuronopathic,O
+;,O
+and,O
+type,O
+3,O
+,,O
+subacute,O
+neuronopathic,O
+.,O
+ , 
+Type,O
+2,O
+Gaucher,O
+disease,O
+,,O
+the,O
+rarest,O
+type,O
+,,O
+is,O
+progressive,O
+and,O
+fatal,O
+.,O
+ , 
+We,O
+have,O
+performed,O
+molecular,O
+analyses,O
+of,O
+a,O
+cohort,O
+of,O
+31,O
+patients,O
+with,O
+type,O
+2,O
+Gaucher,O
+disease,O
+.,O
+ , 
+The,O
+cases,O
+studied,O
+included,O
+fetuses,O
+presenting,O
+prenatally,O
+with,O
+hydrops,O
+fetalis,O
+,,O
+infants,O
+with,O
+the,O
+collodion,O
+baby,O
+phenotype,O
+,,O
+and,O
+infants,O
+diagnosed,O
+after,O
+several,O
+months,O
+of,O
+life,O
+.,O
+ , 
+All,O
+62,O
+mutant,O
+glucocerebrosidase,B-Gene
+(,B-Gene
+GBA,I-Gene
+),I-Gene
+alleles,O
+were,O
+identified,O
+.,O
+ , 
+Thirty,O
+-,O
+three,O
+different,O
+mutant,O
+alleles,O
+were,O
+found,O
+,,O
+including,O
+point,O
+mutations,O
+,,O
+splice,O
+junction,O
+mutations,O
+,,O
+deletions,O
+,,O
+fusion,O
+alleles,O
+and,O
+recombinant,O
+alleles,O
+.,O
+ , 
+Eleven,O
+novel,O
+mutations,O
+were,O
+identified,O
+in,O
+these,O
+patients,O
+:,O
+R131L,B-SNP
+,,I-SNP
+H255Q,B-SNP
+,,I-SNP
+R285H,B-SNP
+,,I-SNP
+S196P,B-SNP
+,,I-SNP
+H311R,B-SNP
+,,I-SNP
+c.330delA,B-SNP
+,,I-SNP
+V398F,B-SNP
+,,I-SNP
+F259L,B-SNP
+,,I-SNP
+c.533delC,B-SNP
+,,I-SNP
+Y304C,B-SNP
+and,O
+A190E.,B-SNP
+Mutation,O
+L444P,B-SNP
+was,O
+found,O
+on,O
+25,O
+patient,O
+alleles,O
+.,O
+ , 
+Southern,O
+blots,O
+and,O
+direct,O
+sequencing,O
+demonstrated,O
+that,O
+mutation,O
+L444P,B-SNP
+occurred,O
+alone,O
+on,O
+9,O
+alleles,O
+,,O
+with,O
+E326,B-SNP
+K,I-SNP
+on,O
+one,O
+allele,O
+and,O
+as,O
+part,O
+of,O
+a,O
+recombinant,O
+allele,O
+on,O
+15,O
+alleles,O
+.,O
+ , 
+There,O
+were,O
+no,O
+homozygotes,O
+for,O
+point,O
+mutation,O
+L444P.,B-SNP
+The,O
+recombinant,O
+alleles,O
+that,O
+included,O
+L444P,B-SNP
+resulted,O
+from,O
+either,O
+reciprocal,O
+recombination,O
+or,O
+gene,O
+conversion,O
+with,O
+the,O
+nearby,O
+glucocerebrosidase,O
+pseudogene,O
+,,O
+and,O
+seven,O
+different,O
+sites,O
+of,O
+recombination,O
+were,O
+identified,O
+.,O
+ , 
+Homozygosity,O
+for,O
+a,O
+recombinant,O
+allele,O
+was,O
+associated,O
+with,O
+early,O
+lethality,O
+.,O
+ , 
+We,O
+have,O
+also,O
+summarized,O
+the,O
+literature,O
+describing,O
+mutations,O
+associated,O
+with,O
+type,O
+2,O
+disease,O
+,,O
+and,O
+list,O
+50,O
+different,O
+mutations,O
+.,O
+ , 
+This,O
+report,O
+constitutes,O
+the,O
+most,O
+comprehensive,O
+molecular,O
+study,O
+to,O
+date,O
+of,O
+type,O
+2,O
+Gaucher,O
+disease,O
+,,O
+and,O
+it,O
+demonstrates,O
+that,O
+there,O
+is,O
+significant,O
+phenotypic,O
+and,O
+genotypic,O
+heterogeneity,O
+among,O
+patients,O
+with,O
+type,O
+2,O
+Gaucher,O
+disease,O
+.,O
+ , 
+Hum,O
+Mutat,O
+15:181,O
+-,O
+188,O
+,,O
+2000,O
+.,O
+ , 
+Published,O
+2000,O
+Wiley,O
+-,O
+Liss,O
+,,O
+Inc.,O
+ , 
+#9792882
+Prevalence,O
+of,O
+mutations,O
+in,O
+TIGR,B-Gene
+/,I-Gene
+Myocilin,I-Gene
+in,O
+patients,O
+with,O
+adult,O
+and,O
+juvenile,O
+primary,O
+open,O
+-,O
+angle,O
+glaucoma,O
+.,O
+ , 
+#11968082
+GeneTests,O
+-,O
+GeneClinics,O
+:,O
+genetic,O
+testing,O
+information,O
+for,O
+a,O
+growing,O
+audience,O
+.,O
+ , 
+The,O
+development,O
+and,O
+usage,O
+of,O
+two,O
+companion,O
+NIH,O
+-,O
+funded,O
+genetic,O
+testing,O
+information,O
+databases,O
+,,O
+GeneTests,O
+(,O
+www.genetests.org,O
+),O
+and,O
+GeneClinics,O
+(,O
+www.geneclinics.org,O
+),O
+,,O
+now,O
+merged,O
+into,O
+one,O
+web,O
+site,O
+,,O
+reflect,O
+the,O
+steadily,O
+increasing,O
+use,O
+of,O
+genetic,O
+testing,O
+and,O
+the,O
+expanding,O
+audience,O
+for,O
+genetic,O
+testing,O
+information,O
+.,O
+ , 
+Established,O
+in,O
+1993,O
+as,O
+Helix,O
+,,O
+a,O
+genetics,O
+laboratory,O
+directory,O
+of,O
+approximately,O
+110,O
+listings,O
+,,O
+GeneTests,O
+has,O
+grown,O
+into,O
+a,O
+database,O
+of,O
+over,O
+900,O
+tests,O
+for,O
+inherited,O
+diseases,O
+,,O
+a,O
+directory,O
+of,O
+over,O
+500,O
+international,O
+laboratories,O
+,,O
+a,O
+directory,O
+of,O
+over,O
+1,000,O
+U.S.,O
+and,O
+international,O
+genetics,O
+clinics,O
+,,O
+and,O
+a,O
+resource,O
+for,O
+educational,O
+/,O
+teaching,O
+materials,O
+and,O
+reports,O
+of,O
+summary,O
+genetic,O
+test,O
+data,O
+.,O
+ , 
+GeneClinics,O
+,,O
+founded,O
+in,O
+1997,O
+as,O
+an,O
+expert,O
+-,O
+authored,O
+,,O
+peer,O
+-,O
+reviewed,O
+,,O
+disease,O
+-,O
+specific,O
+knowledge,O
+base,O
+relating,O
+genetic,O
+testing,O
+to,O
+patient,O
+care,O
+,,O
+has,O
+grown,O
+steadily,O
+,,O
+now,O
+containing,O
+over,O
+130,O
+expert,O
+-,O
+authored,O
+,,O
+peer,O
+-,O
+reviewed,O
+full,O
+-,O
+text,O
+entries,O
+relating,O
+genetic,O
+testing,O
+information,O
+to,O
+diagnosis,O
+,,O
+management,O
+,,O
+and,O
+genetic,O
+counseling,O
+of,O
+specific,O
+inherited,O
+diseases,O
+.,O
+ , 
+In,O
+spring,O
+2001,O
+the,O
+two,O
+databases,O
+were,O
+merged,O
+and,O
+in,O
+October,O
+2001,O
+the,O
+two,O
+web,O
+sites,O
+were,O
+merged,O
+for,O
+the,O
+purpose,O
+of,O
+seamless,O
+navigation,O
+into,O
+the,O
+GeneTests,O
+-,O
+GeneClinics,O
+site,O
+(,O
+www.genetests.org,O
+or,O
+www.geneclinics.org,O
+),O
+;,O
+the,O
+GeneClinics,O
+knowledge,O
+base,O
+was,O
+renamed,O
+",O
+GeneReviews,O
+",O
+to,O
+avoid,O
+confusion,O
+with,O
+the,O
+U.S.,O
+and,O
+international,O
+clinic,O
+directories,O
+.,O
+ , 
+As,O
+genetic,O
+testing,O
+has,O
+moved,O
+steadily,O
+out,O
+of,O
+research,O
+venues,O
+and,O
+into,O
+routine,O
+medical,O
+practice,O
+,,O
+the,O
+user,O
+audience,O
+for,O
+these,O
+databases,O
+has,O
+become,O
+international,O
+and,O
+expansive,O
+and,O
+includes,O
+healthcare,O
+providers,O
+,,O
+patients,O
+,,O
+educators,O
+,,O
+policy,O
+makers,O
+,,O
+and,O
+the,O
+media,O
+.,O
+ , 
+The,O
+use,O
+of,O
+these,O
+combined,O
+resources,O
+has,O
+grown,O
+to,O
+approximately,O
+3,200,O
+visits,O
+/,O
+day,O
+.,O
+ , 
+#17999356
+Genetic,O
+basis,O
+for,O
+correction,O
+of,O
+very,O
+-,O
+long,O
+-,O
+chain,O
+acyl,O
+-,O
+coenzyme,O
+A,O
+dehydrogenase,O
+deficiency,O
+by,O
+bezafibrate,O
+in,O
+patient,O
+fibroblasts,O
+:,O
+toward,O
+a,O
+genotype,O
+-,O
+based,O
+therapy,O
+.,O
+ , 
+Very,B-Gene
+-,I-Gene
+long,I-Gene
+-,I-Gene
+chain,I-Gene
+acyl,I-Gene
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+coenzyme,I-Gene
+A,I-Gene
+dehydrogenase,I-Gene
+(,B-Gene
+VLCAD,I-Gene
+),I-Gene
+deficiency,O
+is,O
+an,O
+inborn,O
+mitochondrial,O
+fatty,O
+-,O
+acid,O
+beta,O
+-,O
+oxidation,O
+(,O
+FAO,O
+),O
+defect,O
+associated,O
+with,O
+a,O
+broad,O
+mutational,O
+spectrum,O
+,,O
+with,O
+phenotypes,O
+ranging,O
+from,O
+fatal,O
+cardiopathy,O
+in,O
+infancy,O
+to,O
+adolescent,O
+-,O
+onset,O
+myopathy,O
+,,O
+and,O
+for,O
+which,O
+there,O
+is,O
+no,O
+established,O
+treatment,O
+.,O
+ , 
+Recent,O
+data,O
+suggest,O
+that,O
+bezafibrate,O
+could,O
+improve,O
+the,O
+FAO,O
+capacities,O
+in,O
+beta,O
+-,O
+oxidation,O
+-,O
+deficient,O
+cells,O
+,,O
+by,O
+enhancing,O
+the,O
+residual,O
+level,O
+of,O
+mutant,O
+enzyme,O
+activity,O
+via,O
+gene,O
+-,O
+expression,O
+stimulation,O
+.,O
+ , 
+Since,O
+VLCAD,O
+-,O
+deficient,O
+patients,O
+frequently,O
+harbor,O
+missense,O
+mutations,O
+with,O
+unpredictable,O
+effects,O
+on,O
+enzyme,O
+activity,O
+,,O
+we,O
+investigated,O
+the,O
+response,O
+to,O
+bezafibrate,O
+as,O
+a,O
+function,O
+of,O
+genotype,O
+in,O
+33,O
+VLCAD,O
+-,O
+deficient,O
+fibroblasts,O
+representing,O
+45,O
+different,O
+mutations,O
+.,O
+ , 
+Treatment,O
+with,O
+bezafibrate,O
+(,O
+400,O
+microM,O
+for,O
+48,O
+h,O
+),O
+resulted,O
+in,O
+a,O
+marked,O
+increase,O
+in,O
+FAO,O
+capacities,O
+,,O
+often,O
+leading,O
+to,O
+restoration,O
+of,O
+normal,O
+values,O
+,,O
+for,O
+21,O
+genotypes,O
+that,O
+mainly,O
+corresponded,O
+to,O
+patients,O
+with,O
+the,O
+myopathic,O
+phenotype,O
+.,O
+ , 
+In,O
+contrast,O
+,,O
+bezafibrate,O
+induced,O
+no,O
+changes,O
+in,O
+FAO,O
+for,O
+11,O
+genotypes,O
+corresponding,O
+to,O
+severe,O
+neonatal,O
+or,O
+infantile,O
+phenotypes,O
+.,O
+ , 
+This,O
+pattern,O
+of,O
+response,O
+was,O
+not,O
+due,O
+to,O
+differential,O
+inductions,O
+of,O
+VLCAD,B-Gene
+messenger,O
+RNA,O
+,,O
+as,O
+shown,O
+by,O
+quantitative,O
+real,O
+-,O
+time,O
+polymerase,O
+chain,O
+reaction,O
+,,O
+but,O
+reflected,O
+variable,O
+increases,O
+in,O
+measured,O
+VLCAD,B-Gene
+residual,O
+enzyme,O
+activity,O
+in,O
+response,O
+to,O
+bezafibrate,O
+.,O
+ , 
+Genotype,O
+cross,O
+-,O
+analysis,O
+allowed,O
+the,O
+identification,O
+of,O
+alleles,O
+carrying,O
+missense,O
+mutations,O
+,,O
+which,O
+could,O
+account,O
+for,O
+these,O
+different,O
+pharmacological,O
+profiles,O
+and,O
+,,O
+on,O
+this,O
+basis,O
+,,O
+led,O
+to,O
+the,O
+characterization,O
+of,O
+9,O
+mild,O
+and,O
+11,O
+severe,O
+missense,O
+mutations,O
+.,O
+ , 
+Altogether,O
+,,O
+the,O
+responses,O
+to,O
+bezafibrate,O
+reflected,O
+the,O
+severity,O
+of,O
+the,O
+metabolic,O
+blockage,O
+in,O
+various,O
+genotypes,O
+,,O
+which,O
+appeared,O
+to,O
+be,O
+correlated,O
+with,O
+the,O
+phenotype,O
+,,O
+thus,O
+providing,O
+a,O
+new,O
+approach,O
+for,O
+analysis,O
+of,O
+genetic,O
+heterogeneity,O
+.,O
+ , 
+Finally,O
+,,O
+this,O
+study,O
+emphasizes,O
+the,O
+potential,O
+of,O
+bezafibrate,O
+,,O
+a,O
+widely,O
+prescribed,O
+hypolipidemic,O
+drug,O
+,,O
+for,O
+the,O
+correction,O
+of,O
+VLCAD,B-Gene
+deficiency,O
+and,O
+exemplifies,O
+the,O
+integration,O
+of,O
+molecular,O
+information,O
+in,O
+a,O
+therapeutic,O
+strategy,O
+.,O
+ , 
+#9634522
+The,O
+8765delAG,B-SNP
+mutation,O
+in,O
+BRCA2,B-Gene
+is,O
+common,O
+among,O
+Jews,O
+of,O
+Yemenite,O
+extraction,O
+.,O
+ , 
+#11353403
+Evaluation,O
+of,O
+candidate,O
+genes,O
+in,O
+case,O
+-,O
+control,O
+studies,O
+:,O
+a,O
+statistical,O
+method,O
+to,O
+account,O
+for,O
+related,O
+subjects,O
+.,O
+ , 
+Traditional,O
+case,O
+-,O
+control,O
+studies,O
+provide,O
+a,O
+powerful,O
+and,O
+efficient,O
+method,O
+for,O
+evaluation,O
+of,O
+association,O
+between,O
+candidate,O
+genes,O
+and,O
+disease,O
+.,O
+ , 
+The,O
+sampling,O
+of,O
+cases,O
+from,O
+multiplex,O
+pedigrees,O
+,,O
+rather,O
+than,O
+from,O
+a,O
+catchment,O
+area,O
+,,O
+can,O
+increase,O
+the,O
+likelihood,O
+that,O
+genetic,O
+cases,O
+are,O
+selected,O
+.,O
+ , 
+However,O
+,,O
+use,O
+of,O
+all,O
+the,O
+related,O
+cases,O
+without,O
+accounting,O
+for,O
+their,O
+biological,O
+relationship,O
+can,O
+increase,O
+the,O
+type,O
+I,O
+error,O
+rate,O
+of,O
+the,O
+statistical,O
+test,O
+.,O
+ , 
+To,O
+overcome,O
+this,O
+problem,O
+,,O
+we,O
+present,O
+an,O
+analysis,O
+method,O
+that,O
+is,O
+used,O
+to,O
+compare,O
+genotype,O
+frequencies,O
+between,O
+cases,O
+and,O
+controls,O
+,,O
+according,O
+to,O
+a,O
+trend,O
+in,O
+proportions,O
+as,O
+the,O
+dosage,O
+of,O
+the,O
+risk,O
+allele,O
+increases,O
+.,O
+ , 
+This,O
+method,O
+uses,O
+the,O
+appropriate,O
+variance,O
+to,O
+account,O
+for,O
+the,O
+correlated,O
+family,O
+data,O
+,,O
+thus,O
+maintaining,O
+the,O
+correct,O
+type,O
+I,O
+error,O
+rate,O
+.,O
+ , 
+The,O
+magnitude,O
+of,O
+the,O
+association,O
+is,O
+estimated,O
+by,O
+the,O
+odds,O
+ratio,O
+,,O
+with,O
+the,O
+variance,O
+of,O
+the,O
+odds,O
+ratio,O
+also,O
+accounting,O
+for,O
+the,O
+correlated,O
+data,O
+.,O
+ , 
+Our,O
+method,O
+makes,O
+efficient,O
+use,O
+of,O
+data,O
+collected,O
+from,O
+multiplex,O
+families,O
+and,O
+should,O
+prove,O
+useful,O
+for,O
+the,O
+analysis,O
+of,O
+candidate,O
+genes,O
+among,O
+families,O
+sampled,O
+for,O
+linkage,O
+studies,O
+.,O
+ , 
+An,O
+application,O
+of,O
+our,O
+method,O
+,,O
+to,O
+family,O
+data,O
+from,O
+a,O
+prostate,O
+cancer,O
+study,O
+,,O
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+presented,O
+to,O
+illustrate,O
+the,O
+method,O
+'s,O
+utility,O
+.,O
+ , 
+#11951176
+Quantitative,O
+trait,O
+loci,O
+on,O
+chromosomes,O
+1,O
+,,O
+2,O
+,,O
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+,,O
+4,O
+,,O
+8,O
+,,O
+9,O
+,,O
+11,O
+,,O
+12,O
+,,O
+and,O
+18,O
+control,O
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+levels,O
+of,O
+T,O
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+B,O
+lymphocyte,O
+subpopulations,O
+.,O
+ , 
+Lymphocyte,O
+subpopulation,O
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+are,O
+used,O
+for,O
+prognosis,O
+and,O
+monitoring,O
+of,O
+a,O
+variety,O
+of,O
+human,O
+diseases,O
+,,O
+especially,O
+those,O
+with,O
+an,O
+infectious,O
+etiology,O
+.,O
+ , 
+As,O
+a,O
+primary,O
+step,O
+to,O
+defining,O
+the,O
+major,O
+gene,O
+variation,O
+underlying,O
+these,O
+phenotypes,O
+,,O
+we,O
+conducted,O
+the,O
+first,O
+whole,O
+-,O
+genome,O
+screen,O
+for,O
+quantitative,O
+variation,O
+in,O
+lymphocyte,O
+count,O
+,,O
+CD4,O
+T,O
+cell,O
+,,O
+CD8,O
+T,O
+cell,O
+,,O
+B,O
+cell,O
+,,O
+and,O
+natural,O
+killer,O
+cell,O
+numbers,O
+,,O
+as,O
+well,O
+as,O
+CD4,O
+:,O
+CD8,O
+ratio,O
+.,O
+ , 
+The,O
+screen,O
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+performed,O
+in,O
+15,O
+of,O
+the,O
+CEPH,O
+families,O
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+form,O
+the,O
+main,O
+human,O
+genome,O
+genetic,O
+project,O
+mapping,O
+resource,O
+.,O
+ , 
+Quantitative,O
+-,O
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+(,O
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+8,O
+,,O
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+11,O
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+12,O
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+The,O
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+CD4,O
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+chromosome,O
+8,O
+(,O
+empirical,O
+P=.00005,O
+),O
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+ , 
+Two,O
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+4,O
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+(,O
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+P=.00007,O
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+P=.003,O
+),O
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+A,O
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+the,O
+highly,O
+correlated,O
+measures,O
+of,O
+CD4,O
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+CD19,O
+levels,O
+colocalized,O
+at,O
+18q21,O
+(,O
+both,O
+P=.003,O
+),O
+.,O
+ , 
+Similarly,O
+,,O
+a,O
+shared,O
+region,O
+of,O
+chromosome,O
+1,O
+was,O
+linked,O
+to,O
+CD8,O
+and,O
+CD19,O
+levels,O
+(,O
+P=.0001,O
+and,O
+P=.002,O
+,,O
+respectively,O
+),O
+.,O
+ , 
+Several,O
+of,O
+the,O
+identified,O
+chromosome,O
+regions,O
+are,O
+likely,O
+to,O
+harbor,O
+polymorphic,O
+candidate,O
+genes,O
+responsible,O
+for,O
+these,O
+important,O
+human,O
+phenotypes,O
+.,O
+ , 
+Their,O
+discovery,O
+has,O
+important,O
+implications,O
+for,O
+understanding,O
+the,O
+generation,O
+of,O
+the,O
+immune,O
+repertoire,O
+and,O
+understanding,O
+immune,O
+-,O
+system,O
+homeostasis,O
+.,O
+ , 
+More,O
+generally,O
+,,O
+these,O
+data,O
+show,O
+the,O
+power,O
+of,O
+an,O
+integrated,O
+human,O
+gene,O
+-,O
+mapping,O
+approach,O
+for,O
+heritable,O
+molecular,O
+phenotypes,O
+,,O
+using,O
+large,O
+pedigrees,O
+that,O
+have,O
+been,O
+extensively,O
+genotyped,O
+.,O
+ , 
+#16358215
+Hereditary,O
+hypophosphatemic,O
+rickets,O
+with,O
+hypercalciuria,O
+is,O
+caused,O
+by,O
+mutations,O
+in,O
+the,O
+sodium,B-Gene
+-,I-Gene
+phosphate,I-Gene
+cotransporter,I-Gene
+gene,O
+SLC34A3,B-Gene
+.,I-Gene
+ , 
+Hypophosphatemia,O
+due,O
+to,O
+isolated,O
+renal,O
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+wasting,O
+results,O
+from,O
+a,O
+heterogeneous,O
+group,O
+of,O
+disorders,O
+.,O
+ , 
+Hereditary,O
+hypophosphatemic,O
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+with,O
+hypercalciuria,O
+(,O
+HHRH,O
+),O
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+autosomal,O
+recessive,O
+form,O
+that,O
+is,O
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+by,O
+reduced,O
+renal,O
+phosphate,O
+reabsorption,O
+,,O
+hypophosphatemia,O
+,,O
+and,O
+rickets,O
+.,O
+ , 
+It,O
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+be,O
+distinguished,O
+from,O
+other,O
+forms,O
+of,O
+hypophosphatemia,O
+by,O
+increased,O
+serum,O
+levels,O
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+1,25,O
+-,O
+dihydroxyvitamin,O
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+resulting,O
+in,O
+hypercalciuria,O
+.,O
+ , 
+Using,O
+SNP,O
+array,O
+genotyping,O
+,,O
+we,O
+mapped,O
+the,O
+disease,O
+locus,O
+in,O
+two,O
+consanguineous,O
+families,O
+to,O
+the,O
+end,O
+of,O
+the,O
+long,O
+arm,O
+of,O
+chromosome,O
+9,O
+.,O
+ , 
+The,O
+candidate,O
+region,O
+contained,O
+a,O
+sodium,O
+-,O
+phosphate,O
+cotransporter,O
+gene,O
+,,O
+SLC34A3,B-Gene
+,,I-Gene
+which,O
+has,O
+been,O
+shown,O
+to,O
+be,O
+expressed,O
+in,O
+proximal,O
+tubulus,O
+cells,O
+.,O
+ , 
+Sequencing,O
+of,O
+this,O
+gene,O
+revealed,O
+disease,O
+-,O
+associated,O
+mutations,O
+in,O
+five,O
+families,O
+,,O
+including,O
+two,O
+frameshift,O
+and,O
+one,O
+splice,O
+-,O
+site,O
+mutation,O
+.,O
+ , 
+Loss,O
+of,O
+function,O
+of,O
+the,O
+SLC34A3,B-Gene
+protein,O
+presumably,O
+results,O
+in,O
+a,O
+primary,O
+renal,O
+tubular,O
+defect,O
+and,O
+is,O
+compatible,O
+with,O
+the,O
+HHRH,O
+phenotype,O
+.,O
+ , 
+We,O
+also,O
+show,O
+that,O
+the,O
+phosphaturic,O
+factor,O
+FGF23,B-Gene
+(,B-Gene
+fibroblast,I-Gene
+growth,I-Gene
+factor,I-Gene
+23,I-Gene
+),I-Gene
+,,O
+which,O
+is,O
+increased,O
+in,O
+X,O
+-,O
+linked,O
+hypophosphatemic,O
+rickets,O
+and,O
+carries,O
+activating,O
+mutations,O
+in,O
+autosomal,O
+dominant,O
+hypophosphatemic,O
+rickets,O
+,,O
+is,O
+at,O
+normal,O
+or,O
+low,O
+-,O
+normal,O
+serum,O
+levels,O
+in,O
+the,O
+patients,O
+with,O
+HHRH,O
+,,O
+further,O
+supporting,O
+a,O
+primary,O
+renal,O
+defect,O
+.,O
+ , 
+Identification,O
+of,O
+the,O
+gene,O
+mutated,O
+in,O
+a,O
+further,O
+form,O
+of,O
+hypophosphatemia,O
+adds,O
+to,O
+the,O
+understanding,O
+of,O
+phosphate,O
+homeostasis,O
+and,O
+may,O
+help,O
+to,O
+elucidate,O
+the,O
+interaction,O
+of,O
+the,O
+proteins,O
+involved,O
+in,O
+this,O
+pathway,O
+.,O
+ , 
+#8651277
+Maternally,O
+inherited,O
+cardiomyopathy,O
+and,O
+hearing,O
+loss,O
+associated,O
+with,O
+a,O
+novel,O
+mutation,O
+in,O
+the,O
+mitochondrial,B-Gene
+tRNA(Lys,I-Gene
+),I-Gene
+gene,I-Gene
+(,B-SNP
+G8363A,I-SNP
+),I-SNP
+.,O
+ , 
+A,O
+novel,O
+G8363A,B-SNP
+mutation,O
+in,O
+the,O
+mtDNA,B-Gene
+tRNA(Lys,I-Gene
+),I-Gene
+gene,O
+was,O
+associated,O
+,,O
+in,O
+two,O
+unrelated,O
+families,O
+,,O
+with,O
+a,O
+syndrome,O
+consisting,O
+of,O
+encephalomyopathy,O
+,,O
+sensorineural,O
+hearing,O
+loss,O
+,,O
+and,O
+hypertrophic,O
+cardiomyopathy,O
+.,O
+ , 
+Muscle,O
+biopsies,O
+from,O
+the,O
+probands,O
+showed,O
+mitochondrial,O
+proliferation,O
+and,O
+partial,O
+defects,O
+of,O
+complexes,O
+I,O
+,,O
+III,O
+,,O
+and,O
+IV,O
+of,O
+the,O
+electron,O
+-,O
+transport,O
+chain,O
+.,O
+ , 
+The,O
+G8363A,B-SNP
+mutation,O
+was,O
+very,O
+abundant,O
+(,O
+>,O
+95,O
+%,O
+),O
+in,O
+muscle,O
+samples,O
+from,O
+the,O
+probands,O
+and,O
+was,O
+less,O
+copious,O
+in,O
+blood,O
+from,O
+18,O
+maternal,O
+relatives,O
+(,O
+mean,O
+81.3,O
+%,O
++,O
+/-,O
+8.5,O
+%,O
+),O
+.,O
+ , 
+Single,O
+-,O
+muscle,O
+-,O
+fiber,O
+analysis,O
+showed,O
+significantly,O
+higher,O
+levels,O
+of,O
+mutant,O
+genomes,O
+in,O
+cytochrome,O
+(,O
+c,O
+),O
+oxidase,O
+-,O
+negative,O
+fibers,O
+than,O
+in,O
+cytochrome,O
+(,O
+c,O
+),O
+oxidase,O
+-,O
+positive,O
+fibers,O
+.,O
+ , 
+The,O
+mutation,O
+was,O
+not,O
+found,O
+in,O
+>,O
+200,O
+individuals,O
+,,O
+including,O
+normal,O
+controls,O
+and,O
+patients,O
+with,O
+other,O
+mitochondrial,O
+encephalomyopathies,O
+,,O
+thus,O
+fulfilling,O
+accepted,O
+criteria,O
+for,O
+pathogenicity,O
+.,O
+ , 
+#17721928
+Identification,O
+of,O
+the,O
+first,O
+germline,O
+mutation,O
+in,O
+the,O
+extracellular,O
+domain,O
+of,O
+the,O
+follitropin,O
+receptor,O
+responsible,O
+for,O
+spontaneous,O
+ovarian,O
+hyperstimulation,O
+syndrome,O
+.,O
+ , 
+The,O
+receptors,O
+for,O
+follitropin,B-Gene
+(,B-Gene
+FSHR,I-Gene
+),I-Gene
+,,O
+thyrotropin,B-Gene
+(,B-Gene
+TSHR,I-Gene
+),I-Gene
+,,O
+and,O
+lutropin,B-Gene
+/,I-Gene
+chorionic,I-Gene
+gonadotropin,I-Gene
+(,B-Gene
+LHCGR,I-Gene
+),I-Gene
+are,O
+the,O
+members,O
+of,O
+the,O
+glycoprotein,B-Gene
+hormone,I-Gene
+(,B-Gene
+GPH,I-Gene
+),I-Gene
+receptors,O
+(,B-Gene
+GPHR,I-Gene
+),I-Gene
+family,O
+.,O
+ , 
+They,O
+present,O
+a,O
+bipartite,O
+structure,O
+with,O
+a,O
+large,O
+extracellular,O
+amino,O
+-,O
+terminal,O
+domain,O
+(,O
+ECD,O
+),O
+,,O
+responsible,O
+for,O
+high,O
+-,O
+affinity,O
+hormone,O
+binding,O
+,,O
+and,O
+a,O
+carboxyl,O
+-,O
+terminal,O
+serpentine,O
+region,O
+,,O
+implicated,O
+in,O
+transduction,O
+of,O
+the,O
+activation,O
+signal,O
+.,O
+ , 
+Spontaneous,O
+ovarian,O
+hyperstimulation,O
+syndrome,O
+(,O
+sOHSS,O
+),O
+is,O
+a,O
+rare,O
+genetic,O
+condition,O
+in,O
+which,O
+human,O
+chorionic,O
+gonadotropin,O
+(,O
+hCG,O
+),O
+promiscuously,O
+stimulates,O
+the,O
+FSHR,O
+during,O
+the,O
+first,O
+trimester,O
+of,O
+pregnancy,O
+.,O
+ , 
+Surprisingly,O
+,,O
+germline,O
+FSHR,B-Gene
+mutations,O
+responsible,O
+for,O
+the,O
+disease,O
+have,O
+so,O
+far,O
+been,O
+found,O
+only,O
+in,O
+the,O
+transmembrane,O
+helices,O
+of,O
+the,O
+serpentine,O
+region,O
+of,O
+the,O
+FSHR,B-Gene
+,,I-Gene
+outside,O
+the,O
+hormone,O
+binding,O
+domain,O
+.,O
+ , 
+When,O
+tested,O
+functionally,O
+,,O
+all,O
+mutants,O
+were,O
+abnormally,O
+sensitive,O
+to,O
+both,O
+hCG,O
+and,O
+thyrotropin,O
+(,O
+TSH,O
+),O
+while,O
+displaying,O
+constitutive,O
+activity,O
+.,O
+ , 
+This,O
+loss,O
+of,O
+ligand,O
+specificity,O
+was,O
+attributed,O
+to,O
+the,O
+lowering,O
+of,O
+an,O
+intramolecular,O
+barrier,O
+of,O
+activation,O
+rather,O
+than,O
+to,O
+an,O
+increase,O
+of,O
+binding,O
+affinity,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+the,O
+first,O
+germline,O
+mutation,O
+responsible,O
+for,O
+sOHSS,O
+(,B-SNP
+c.383C,I-SNP
+>,I-SNP
+A,I-SNP
+,,I-SNP
+p.,B-SNP
+Ser128Tyr,I-SNP
+),I-SNP
+,,O
+located,O
+in,O
+the,O
+ECD,O
+of,O
+the,O
+FSHR,B-Gene
+.,I-Gene
+ , 
+Contrary,O
+to,O
+the,O
+mutations,O
+described,O
+previously,O
+,,O
+the,O
+p.,B-SNP
+Ser128Tyr,I-SNP
+ , 
+FSHR,B-Gene
+mutant,O
+displayed,O
+increase,O
+in,O
+affinity,O
+and,O
+sensitivity,O
+toward,O
+hCG,O
+and,O
+did,O
+not,O
+show,O
+any,O
+constitutive,O
+activity,O
+,,O
+nor,O
+promiscuous,O
+activation,O
+by,O
+TSH,O
+.,O
+ , 
+Thus,O
+,,O
+sOHSS,O
+can,O
+be,O
+achieved,O
+from,O
+different,O
+molecular,O
+mechanisms,O
+involving,O
+each,O
+functional,O
+domains,O
+of,O
+the,O
+FSHR,B-Gene
+.,I-Gene
+ , 
+Based,O
+on,O
+the,O
+structure,O
+of,O
+the,O
+FSHR,B-Gene
+/,B-Gene
+FSH,I-Gene
+complex,O
+and,O
+site,O
+-,O
+directed,O
+mutagenesis,O
+studies,O
+,,O
+we,O
+provide,O
+robust,O
+molecular,O
+models,O
+for,O
+the,O
+GPH,B-Gene
+/,B-Gene
+GPHR,I-Gene
+complexes,O
+and,O
+we,O
+propose,O
+a,O
+molecular,O
+explanation,O
+to,O
+the,O
+binding,O
+characteristics,O
+of,O
+the,O
+p.,B-SNP
+Ser128Tyr,I-SNP
+mutant,O
+.,O
+ , 
+#20602914
+Whole,O
+exome,O
+sequencing,O
+and,O
+homozygosity,O
+mapping,O
+identify,O
+mutation,O
+in,O
+the,O
+cell,O
+polarity,O
+protein,O
+GPSM2,B-Gene
+as,O
+the,O
+cause,O
+of,O
+nonsyndromic,O
+hearing,O
+loss,O
+DFNB82,O
+.,O
+ , 
+Massively,O
+parallel,O
+sequencing,O
+of,O
+targeted,O
+regions,O
+,,O
+exomes,O
+,,O
+and,O
+complete,O
+genomes,O
+has,O
+begun,O
+to,O
+dramatically,O
+increase,O
+the,O
+pace,O
+of,O
+discovery,O
+of,O
+genes,O
+responsible,O
+for,O
+human,O
+disorders,O
+.,O
+ , 
+Here,O
+we,O
+describe,O
+how,O
+exome,O
+sequencing,O
+in,O
+conjunction,O
+with,O
+homozygosity,O
+mapping,O
+led,O
+to,O
+rapid,O
+identification,O
+of,O
+the,O
+causative,O
+allele,O
+for,O
+nonsyndromic,O
+hearing,O
+loss,O
+DFNB82,O
+in,O
+a,O
+consanguineous,O
+Palestinian,O
+family,O
+.,O
+ , 
+After,O
+filtering,O
+out,O
+worldwide,O
+and,O
+population,O
+-,O
+specific,O
+polymorphisms,O
+from,O
+the,O
+whole,O
+exome,O
+sequence,O
+,,O
+only,O
+a,O
+single,O
+deleterious,O
+mutation,O
+remained,O
+in,O
+the,O
+homozygous,O
+region,O
+linked,O
+to,O
+DFNB82,O
+.,O
+ , 
+The,O
+nonsense,O
+mutation,O
+leads,O
+to,O
+an,O
+early,O
+truncation,O
+of,O
+the,O
+G,B-Gene
+protein,I-Gene
+signaling,I-Gene
+modulator,I-Gene
+GPSM2,B-Gene
+,,I-Gene
+a,O
+protein,O
+that,O
+is,O
+essential,O
+for,O
+maintenance,O
+of,O
+cell,O
+polarity,O
+and,O
+spindle,O
+orientation,O
+.,O
+ , 
+In,O
+the,O
+mouse,O
+inner,O
+ear,O
+,,O
+GPSM2,B-Gene
+is,O
+localized,O
+to,O
+apical,O
+surfaces,O
+of,O
+hair,O
+cells,O
+and,O
+supporting,O
+cells,O
+and,O
+is,O
+most,O
+highly,O
+expressed,O
+during,O
+embryonic,O
+development,O
+.,O
+ , 
+Identification,O
+of,O
+GPSM2,B-Gene
+as,O
+essential,O
+to,O
+the,O
+development,O
+of,O
+normal,O
+hearing,O
+suggests,O
+dysregulation,O
+of,O
+cell,O
+polarity,O
+as,O
+a,O
+mechanism,O
+underlying,O
+hearing,O
+loss,O
+.,O
+ , 
+#12384858
+The,O
+fingerprint,O
+of,O
+phantom,O
+mutations,O
+in,O
+mitochondrial,O
+DNA,O
+data,O
+.,O
+ , 
+Phantom,O
+mutations,O
+are,O
+systematic,O
+artifacts,O
+generated,O
+in,O
+the,O
+course,O
+of,O
+the,O
+sequencing,O
+process,O
+itself,O
+.,O
+ , 
+In,O
+sequenced,O
+mitochondrial,O
+DNA,O
+(,O
+mtDNA,O
+),O
+,,O
+they,O
+generate,O
+a,O
+hotspot,O
+pattern,O
+quite,O
+different,O
+from,O
+that,O
+of,O
+natural,O
+mutations,O
+in,O
+the,O
+cell,O
+.,O
+ , 
+To,O
+identify,O
+the,O
+telltale,O
+patterns,O
+of,O
+a,O
+particular,O
+phantom,O
+mutation,O
+process,O
+,,O
+one,O
+first,O
+filters,O
+out,O
+the,O
+well,O
+-,O
+established,O
+frequent,O
+mutations,O
+(,O
+inferred,O
+from,O
+various,O
+data,O
+sets,O
+with,O
+additional,O
+coding,O
+region,O
+information,O
+),O
+.,O
+ , 
+The,O
+filtered,O
+data,O
+are,O
+represented,O
+by,O
+their,O
+full,O
+(,O
+quasi-)median,O
+network,O
+,,O
+to,O
+visualize,O
+the,O
+character,O
+conflicts,O
+,,O
+which,O
+can,O
+be,O
+expressed,O
+numerically,O
+by,O
+the,O
+cube,O
+spectrum,O
+.,O
+ , 
+Permutation,O
+tests,O
+are,O
+used,O
+to,O
+evaluate,O
+the,O
+overall,O
+phylogenetic,O
+content,O
+of,O
+the,O
+filtered,O
+data,O
+.,O
+ , 
+Comparison,O
+with,O
+benchmark,O
+data,O
+sets,O
+helps,O
+to,O
+sort,O
+out,O
+suspicious,O
+data,O
+and,O
+to,O
+infer,O
+features,O
+and,O
+potential,O
+causes,O
+for,O
+the,O
+phantom,O
+mutation,O
+process,O
+.,O
+ , 
+This,O
+approach,O
+,,O
+performed,O
+either,O
+in,O
+the,O
+lab,O
+or,O
+at,O
+the,O
+desk,O
+of,O
+a,O
+reviewer,O
+,,O
+will,O
+help,O
+to,O
+avoid,O
+errors,O
+that,O
+otherwise,O
+would,O
+go,O
+into,O
+print,O
+and,O
+could,O
+lead,O
+to,O
+erroneous,O
+evolutionary,O
+interpretations,O
+.,O
+ , 
+The,O
+filtering,O
+procedure,O
+is,O
+illustrated,O
+with,O
+two,O
+mtDNA,O
+data,O
+sets,O
+that,O
+were,O
+severely,O
+affected,O
+by,O
+phantom,O
+mutations,O
+.,O
+ , 
+#9829906
+Spectrum,O
+of,O
+mutations,O
+and,O
+sequence,O
+variants,O
+in,O
+the,O
+FALDH,B-Gene
+gene,O
+in,O
+patients,O
+with,O
+Sjögren,O
+-,O
+Larsson,O
+syndrome,O
+.,O
+ , 
+The,O
+gene,O
+encoding,O
+the,O
+human,O
+fatty,B-Gene
+aldehyde,I-Gene
+dehydrogenase,I-Gene
+(,B-Gene
+FALDH,I-Gene
+),I-Gene
+is,O
+located,O
+on,O
+17p11.2,O
+,,O
+causing,O
+Sjögren,O
+-,O
+Larsson,O
+syndrome,O
+(,O
+SLS,O
+),O
+when,O
+mutated,O
+.,O
+ , 
+SLS,O
+is,O
+an,O
+autosomal,O
+recessive,O
+disorder,O
+characterized,O
+by,O
+a,O
+combination,O
+of,O
+mental,O
+retardation,O
+,,O
+congenital,O
+ichthyosis,O
+,,O
+and,O
+spastic,O
+di-,O
+or,O
+tetraplegia,O
+.,O
+ , 
+We,O
+report,O
+here,O
+on,O
+studies,O
+of,O
+16,O
+SLS,O
+families,O
+from,O
+Europe,O
+and,O
+the,O
+Middle,O
+East,O
+,,O
+which,O
+resulted,O
+in,O
+identification,O
+of,O
+11,O
+different,O
+mutations,O
+.,O
+ , 
+The,O
+spectrum,O
+of,O
+mutations,O
+characterized,O
+in,O
+the,O
+present,O
+study,O
+are,O
+five,O
+nucleotide,O
+substitutions,O
+resulting,O
+in,O
+amino,O
+acid,O
+changes,O
+,,O
+five,O
+frameshift,O
+mutations,O
+introducing,O
+a,O
+stop,O
+codon,O
+,,O
+and,O
+one,O
+in,O
+-,O
+frame,O
+deletion,O
+with,O
+insertion,O
+at,O
+the,O
+same,O
+position,O
+.,O
+ , 
+We,O
+also,O
+observed,O
+silent,O
+sequence,O
+variants,O
+in,O
+the,O
+FALDH,B-Gene
+gene,O
+and,O
+a,O
+base,O
+pair,O
+substitution,O
+in,O
+exon,O
+5,O
+that,O
+alters,O
+aspartic,O
+acid,O
+to,O
+asparagine,O
+,,O
+all,O
+of,O
+which,O
+are,O
+considered,O
+polymorphisms,O
+.,O
+ , 
+#17503325
+Red,O
+-,O
+green,O
+color,O
+vision,O
+impairment,O
+in,O
+Duchenne,O
+muscular,O
+dystrophy,O
+.,O
+ , 
+The,O
+present,O
+study,O
+evaluated,O
+the,O
+color,O
+vision,O
+of,O
+44,O
+patients,O
+with,O
+Duchenne,O
+muscular,O
+dystrophy,O
+(,O
+DMD,O
+),O
+(,O
+mean,O
+age,O
+14.8,O
+years,O
+;,O
+SD,O
+4.9,O
+),O
+who,O
+were,O
+submitted,O
+to,O
+a,O
+battery,O
+of,O
+four,O
+different,O
+color,O
+tests,O
+:,O
+Cambridge,O
+Colour,O
+Test,O
+(,O
+CCT,O
+),O
+,,O
+Neitz,O
+Anomaloscope,O
+,,O
+Ishihara,O
+,,O
+and,O
+American,O
+Optical,O
+Hardy,O
+-,O
+Rand,O
+-,O
+Rittler,O
+(,O
+AO,O
+H,O
+-,O
+R,O
+-,O
+R,O
+),O
+.,O
+ , 
+Patients,O
+were,O
+divided,O
+into,O
+two,O
+groups,O
+according,O
+to,O
+the,O
+region,O
+of,O
+deletion,O
+in,O
+the,O
+dystrophin,B-Gene
+gene,O
+:,O
+upstream,O
+of,O
+exon,O
+30,O
+(,O
+n=12,O
+),O
+and,O
+downstream,O
+of,O
+exon,O
+30,O
+(,O
+n=32,O
+),O
+.,O
+ , 
+The,O
+control,O
+group,O
+was,O
+composed,O
+of,O
+70,O
+age,O
+-,O
+matched,O
+healthy,O
+male,O
+subjects,O
+with,O
+no,O
+ophthalmological,O
+complaints,O
+.,O
+ , 
+Of,O
+the,O
+patients,O
+with,O
+DMD,O
+,,O
+47,O
+%,O
+(,O
+21/44,O
+),O
+had,O
+a,O
+red,O
+-,O
+green,O
+color,O
+vision,O
+defect,O
+in,O
+the,O
+CCT,O
+,,O
+confirmed,O
+by,O
+the,O
+Neitz,O
+Anomaloscope,O
+with,O
+statistical,O
+agreement,O
+(,O
+P<.001,O
+),O
+.,O
+ , 
+The,O
+Ishihara,O
+and,O
+the,O
+AO,O
+H,O
+-,O
+R,O
+-,O
+R,O
+had,O
+a,O
+lower,O
+capacity,O
+to,O
+detect,O
+color,O
+defects--5,O
+%,O
+and,O
+7,O
+%,O
+,,O
+respectively,O
+,,O
+with,O
+no,O
+statistical,O
+similarity,O
+between,O
+the,O
+results,O
+of,O
+these,O
+two,O
+tests,O
+nor,O
+between,O
+CCT,O
+and,O
+Anomaloscope,O
+results,O
+(,O
+P>.05,O
+),O
+.,O
+ , 
+Of,O
+the,O
+patients,O
+with,O
+deletion,O
+downstream,O
+of,O
+exon,O
+30,O
+,,O
+66,O
+%,O
+had,O
+a,O
+red,O
+-,O
+green,O
+color,O
+defect,O
+.,O
+ , 
+No,O
+color,O
+defect,O
+was,O
+found,O
+in,O
+the,O
+patients,O
+with,O
+deletion,O
+upstream,O
+of,O
+exon,O
+30,O
+.,O
+ , 
+A,O
+negative,O
+correlation,O
+between,O
+the,O
+color,O
+thresholds,O
+and,O
+age,O
+was,O
+found,O
+for,O
+the,O
+controls,O
+and,O
+patients,O
+with,O
+DMD,O
+,,O
+suggesting,O
+a,O
+nonprogressive,O
+color,O
+defect,O
+.,O
+ , 
+The,O
+percentage,O
+(,O
+66,O
+%,O
+),O
+of,O
+patients,O
+with,O
+a,O
+red,O
+-,O
+green,O
+defect,O
+was,O
+significantly,O
+higher,O
+than,O
+the,O
+expected,O
+<,O
+10,O
+%,O
+for,O
+the,O
+normal,O
+male,O
+population,O
+(,O
+P<.001,O
+),O
+.,O
+ , 
+In,O
+contrast,O
+,,O
+patients,O
+with,O
+DMD,O
+with,O
+deletion,O
+upstream,O
+of,O
+exon,O
+30,O
+had,O
+normal,O
+color,O
+vision,O
+.,O
+ , 
+This,O
+color,O
+defect,O
+might,O
+be,O
+partially,O
+explained,O
+by,O
+a,O
+retina,O
+impairment,O
+related,O
+to,O
+dystrophin,B-Gene
+isoform,O
+Dp260,O
+.,O
+ , 
+#11180609
+Three,O
+novel,O
+mutations,O
+(,B-SNP
+P760L,I-SNP
+,,I-SNP
+L1305P,B-SNP
+,,I-SNP
+Q1351Stop,B-SNP
+),I-SNP
+causing,O
+Wilson,O
+disease,O
+.,O
+ , 
+#12058347
+Heterozygous,O
+submicroscopic,O
+inversions,O
+involving,O
+olfactory,O
+receptor,O
+-,O
+gene,O
+clusters,O
+mediate,O
+the,O
+recurrent,O
+t(4;8)(p16;p23,O
+),O
+translocation,O
+.,O
+ , 
+The,O
+t(4;8)(p16;p23,O
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+translocation,O
+,,O
+in,O
+either,O
+the,O
+balanced,O
+form,O
+or,O
+the,O
+unbalanced,O
+form,O
+,,O
+has,O
+been,O
+reported,O
+several,O
+times,O
+.,O
+ , 
+Taking,O
+into,O
+consideration,O
+the,O
+fact,O
+that,O
+this,O
+translocation,O
+may,O
+be,O
+undetected,O
+in,O
+routine,O
+cytogenetics,O
+,,O
+we,O
+find,O
+that,O
+it,O
+may,O
+be,O
+the,O
+most,O
+frequent,O
+translocation,O
+after,O
+t(11q;22q,O
+),O
+,,O
+which,O
+is,O
+the,O
+most,O
+common,O
+reciprocal,O
+translocation,O
+in,O
+humans,O
+.,O
+ , 
+Case,O
+subjects,O
+with,O
+der(4,O
+),O
+have,O
+the,O
+Wolf,O
+-,O
+Hirschhorn,O
+syndrome,O
+,,O
+whereas,O
+case,O
+subjects,O
+with,O
+der(8,O
+),O
+show,O
+a,O
+milder,O
+spectrum,O
+of,O
+dysmorphic,O
+features,O
+.,O
+ , 
+Two,O
+pairs,O
+of,O
+the,O
+many,O
+olfactory,O
+receptor,O
+(,O
+OR)-gene,O
+clusters,O
+are,O
+located,O
+close,O
+to,O
+each,O
+other,O
+,,O
+on,O
+both,O
+4p16,O
+and,O
+8p23,O
+.,O
+ , 
+Previously,O
+,,O
+we,O
+demonstrated,O
+that,O
+an,O
+inversion,O
+polymorphism,O
+of,O
+the,O
+OR,O
+region,O
+at,O
+8p23,O
+plays,O
+a,O
+crucial,O
+role,O
+in,O
+the,O
+generation,O
+of,O
+chromosomal,O
+imbalances,O
+through,O
+unusual,O
+meiotic,O
+exchanges,O
+.,O
+ , 
+These,O
+findings,O
+prompted,O
+us,O
+to,O
+investigate,O
+whether,O
+OR,O
+-,O
+related,O
+inversion,O
+polymorphisms,O
+at,O
+4p16,O
+and,O
+8p23,O
+might,O
+also,O
+be,O
+involved,O
+in,O
+the,O
+origin,O
+of,O
+the,O
+t(4;8)(p16;p23,O
+),O
+translocation,O
+.,O
+ , 
+In,O
+seven,O
+case,O
+subjects,O
+(,O
+five,O
+of,O
+whom,O
+both,O
+represented,O
+de,O
+novo,O
+cases,O
+and,O
+were,O
+of,O
+maternal,O
+origin,O
+),O
+,,O
+including,O
+individuals,O
+with,O
+unbalanced,O
+and,O
+balanced,O
+translocations,O
+,,O
+we,O
+demonstrated,O
+that,O
+the,O
+breakpoints,O
+fell,O
+within,O
+the,O
+4p,O
+and,O
+8p,O
+OR,O
+-,O
+gene,O
+clusters,O
+.,O
+ , 
+FISH,O
+experiments,O
+with,O
+appropriate,O
+bacterial,O
+-,O
+artificial,O
+-,O
+chromosome,O
+probes,O
+detected,O
+heterozygous,O
+submicroscopic,O
+inversions,O
+of,O
+both,O
+4p,O
+and,O
+8p,O
+regions,O
+in,O
+all,O
+the,O
+five,O
+mothers,O
+of,O
+the,O
+de,O
+novo,O
+case,O
+subjects,O
+.,O
+ , 
+Heterozygous,O
+inversions,O
+on,O
+4p16,O
+and,O
+8p23,O
+were,O
+detected,O
+in,O
+12.5,O
+%,O
+and,O
+26,O
+%,O
+of,O
+control,O
+subjects,O
+,,O
+respectively,O
+,,O
+whereas,O
+2.5,O
+%,O
+of,O
+them,O
+were,O
+scored,O
+as,O
+doubly,O
+heterozygous,O
+.,O
+ , 
+These,O
+novel,O
+data,O
+emphasize,O
+the,O
+importance,O
+of,O
+segmental,O
+duplications,O
+and,O
+large,O
+-,O
+scale,O
+genomic,O
+polymorphisms,O
+in,O
+the,O
+evolution,O
+and,O
+pathology,O
+of,O
+the,O
+human,O
+genome,O
+.,O
+ , 
+#18726931
+FOXL2,B-Gene
+mutations,O
+and,O
+genomic,O
+rearrangements,O
+in,O
+BPES,O
+.,O
+ , 
+The,O
+FOXL2,B-Gene
+gene,O
+is,O
+one,O
+of,O
+10,O
+forkhead,O
+genes,O
+,,O
+the,O
+mutations,O
+of,O
+which,O
+lead,O
+to,O
+human,O
+developmental,O
+disorders,O
+,,O
+often,O
+with,O
+ocular,O
+manifestations,O
+.,O
+ , 
+Mutations,O
+in,O
+FOXL2,O
+are,O
+known,O
+to,O
+cause,O
+blepharophimosis,O
+syndrome,O
+(,O
+BPES,O
+),O
+,,O
+an,O
+autosomal,O
+dominant,O
+eyelid,O
+malformation,O
+associated,O
+(,O
+type,O
+I,O
+),O
+or,O
+not,O
+(,O
+type,O
+II,O
+),O
+with,O
+ovarian,O
+dysfunction,O
+,,O
+leading,O
+to,O
+premature,O
+ovarian,O
+failure,O
+(,O
+POF,O
+),O
+.,O
+ , 
+In,O
+addition,O
+,,O
+a,O
+few,O
+mutations,O
+have,O
+been,O
+described,O
+in,O
+patients,O
+with,O
+isolated,O
+POF,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+review,O
+all,O
+currently,O
+described,O
+FOXL2,B-Gene
+sequence,O
+variations,O
+and,O
+genomic,O
+rearrangements,O
+in,O
+BPES,O
+and,O
+POF,O
+.,O
+ , 
+Using,O
+a,O
+combined,O
+mutation,O
+detection,O
+approach,O
+,,O
+it,O
+is,O
+possible,O
+to,O
+identify,O
+the,O
+underlying,O
+genetic,O
+defect,O
+in,O
+a,O
+major,O
+proportion,O
+(,O
+88,O
+%,O
+),O
+of,O
+typical,O
+BPES,O
+patients,O
+.,O
+ , 
+Of,O
+all,O
+genetic,O
+defects,O
+found,O
+in,O
+our,O
+BPES,O
+cohort,O
+,,O
+intragenic,O
+mutations,O
+represent,O
+81,O
+%,O
+.,O
+ , 
+They,O
+include,O
+missense,O
+changes,O
+,,O
+frameshift,O
+and,O
+nonsense,O
+mutations,O
+,,O
+in,O
+-,O
+frame,O
+deletions,O
+,,O
+and,O
+duplications,O
+,,O
+that,O
+are,O
+distributed,O
+along,O
+the,O
+single,O
+-,O
+exon,O
+gene,O
+.,O
+ , 
+Genomic,O
+rearrangements,O
+comprising,O
+both,O
+deletions,O
+encompassing,O
+FOXL2,B-Gene
+and,O
+deletions,O
+located,O
+outside,O
+its,O
+transcription,O
+unit,O
+,,O
+represent,O
+12,O
+%,O
+and,O
+5,O
+%,O
+of,O
+all,O
+genetic,O
+defects,O
+in,O
+our,O
+BPES,O
+cohort,O
+,,O
+respectively,O
+.,O
+ , 
+One,O
+of,O
+the,O
+challenges,O
+of,O
+genetic,O
+testing,O
+in,O
+BPES,O
+is,O
+the,O
+establishment,O
+of,O
+genotype,O
+-,O
+phenotype,O
+correlations,O
+,,O
+mainly,O
+with,O
+respect,O
+to,O
+the,O
+ovarian,O
+phenotype,O
+.,O
+ , 
+Genetic,O
+testing,O
+should,O
+be,O
+performed,O
+in,O
+the,O
+context,O
+of,O
+genetic,O
+counseling,O
+,,O
+however,O
+,,O
+and,O
+should,O
+be,O
+systematically,O
+complemented,O
+by,O
+a,O
+multidisciplinary,O
+clinical,O
+follow,O
+-,O
+up,O
+.,O
+ , 
+Another,O
+challenge,O
+for,O
+health,O
+care,O
+professionals,O
+involved,O
+in,O
+BPES,O
+is,O
+the,O
+treatment,O
+of,O
+the,O
+eyelid,O
+phenotype,O
+and,O
+the,O
+prevention,O
+or,O
+treatment,O
+of,O
+POF,O
+.,O
+ , 
+#9497255
+Autosomal,O
+genomic,O
+scan,O
+for,O
+loci,O
+linked,O
+to,O
+obesity,O
+and,O
+energy,O
+metabolism,O
+in,O
+Pima,O
+Indians,O
+.,O
+ , 
+An,O
+autosomal,O
+genomic,O
+scan,O
+to,O
+search,O
+for,O
+linkage,O
+to,O
+obesity,O
+and,O
+energy,O
+metabolism,O
+was,O
+completed,O
+in,O
+Pima,O
+Indians,O
+,,O
+a,O
+population,O
+prone,O
+to,O
+obesity,O
+.,O
+ , 
+Obesity,O
+was,O
+assessed,O
+by,O
+percent,O
+body,O
+fat,O
+(,O
+by,O
+hydrodensitometry,O
+),O
+and,O
+fat,O
+distribution,O
+(,O
+the,O
+ratio,O
+of,O
+waist,O
+circumference,O
+to,O
+thigh,O
+circumference,O
+),O
+.,O
+ , 
+Energy,O
+metabolism,O
+was,O
+measured,O
+in,O
+a,O
+respiratory,O
+chamber,O
+as,O
+24,O
+-,O
+h,O
+metabolic,O
+rate,O
+,,O
+sleeping,O
+metabolic,O
+rate,O
+,,O
+and,O
+24,O
+-,O
+h,O
+respiratory,O
+quotient,O
+(,O
+24RQ,O
+),O
+,,O
+an,O
+indicator,O
+of,O
+the,O
+ratio,O
+of,O
+carbohydrate,O
+oxidation,O
+to,O
+fat,O
+oxidation,O
+.,O
+ , 
+Five,O
+hundred,O
+sixteen,O
+microsatellite,O
+markers,O
+with,O
+a,O
+median,O
+spacing,O
+of,O
+6.4,O
+cM,O
+were,O
+analyzed,O
+,,O
+in,O
+362,O
+siblings,O
+who,O
+had,O
+measurements,O
+of,O
+body,O
+composition,O
+and,O
+in,O
+220,O
+siblings,O
+who,O
+had,O
+measurements,O
+of,O
+energy,O
+metabolism,O
+.,O
+ , 
+These,O
+comprised,O
+451,O
+sib,O
+pairs,O
+in,O
+127,O
+nuclear,O
+families,O
+,,O
+for,O
+linkage,O
+analysis,O
+to,O
+obesity,O
+,,O
+and,O
+236,O
+sib,O
+pairs,O
+in,O
+82,O
+nuclear,O
+families,O
+,,O
+for,O
+linkage,O
+analysis,O
+to,O
+energy,O
+metabolism,O
+.,O
+ , 
+Pointwise,O
+and,O
+multipoint,O
+methods,O
+for,O
+regression,O
+of,O
+sib,O
+-,O
+pair,O
+differences,O
+in,O
+identity,O
+by,O
+descent,O
+,,O
+as,O
+well,O
+as,O
+a,O
+sibling,O
+-,O
+based,O
+variance,O
+-,O
+components,O
+method,O
+,,O
+were,O
+used,O
+to,O
+detect,O
+linkage,O
+.,O
+ , 
+LOD,O
+scores,O
+>,O
+=,O
+2,O
+were,O
+found,O
+at,O
+11q21,O
+-,O
+q22,O
+,,O
+for,O
+percent,O
+body,O
+fat,O
+(,O
+LOD=2.1,O
+;,O
+P=.001,O
+),O
+,,O
+at,O
+11q23,O
+-,O
+q24,O
+,,O
+for,O
+24,O
+-,O
+h,O
+energy,O
+expenditure,O
+(,O
+LOD=2.0,O
+;,O
+P=.001,O
+),O
+,,O
+and,O
+at,O
+1p31,O
+-,O
+p21,O
+(,O
+LOD=2.0,O
+),O
+and,O
+20q11.2,O
+(,O
+LOD=3.0,O
+;,O
+P=.0001,O
+),O
+,,O
+for,O
+24RQ,O
+,,O
+by,O
+pointwise,O
+and,O
+multipoint,O
+analyses,O
+.,O
+ , 
+With,O
+the,O
+variance,O
+-,O
+components,O
+method,O
+,,O
+the,O
+highest,O
+LOD,O
+score,O
+(,O
+LOD=2.3,O
+P=.0006,O
+),O
+was,O
+found,O
+at,O
+18q21,O
+,,O
+for,O
+percent,O
+body,O
+fat,O
+,,O
+and,O
+at,O
+1p31,O
+-,O
+p21,O
+(,O
+LOD=2.8,O
+;,O
+P=.0003,O
+),O
+,,O
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+24RQ,O
+.,O
+ , 
+Possible,O
+candidate,O
+genes,O
+include,O
+LEPR,B-Gene
+(,B-Gene
+leptin,I-Gene
+receptor,I-Gene
+),I-Gene
+,,I-Gene
+at,O
+1p31,O
+,,O
+and,O
+ASIP,B-Gene
+(,B-Gene
+agouti,I-Gene
+-,I-Gene
+signaling,I-Gene
+protein,I-Gene
+),I-Gene
+,,I-Gene
+at,O
+20q11.2,O
+.,O
+ , 
+#9758627
+A,O
+missense,O
+mutation,O
+in,O
+the,O
+zinc,O
+-,O
+finger,O
+domain,O
+of,O
+the,O
+human,O
+hairless,O
+gene,O
+underlies,O
+congenital,O
+atrichia,O
+in,O
+a,O
+family,O
+of,O
+Irish,O
+travellers,O
+.,O
+ , 
+Congenital,O
+atrichia,O
+is,O
+a,O
+rare,O
+,,O
+recessively,O
+inherited,O
+form,O
+of,O
+hair,O
+loss,O
+affecting,O
+both,O
+males,O
+and,O
+females,O
+and,O
+is,O
+characterized,O
+by,O
+a,O
+complete,O
+absence,O
+of,O
+hair,O
+follicles,O
+.,O
+ , 
+Recently,O
+,,O
+a,O
+mutation,O
+in,O
+the,O
+human,O
+hairless,O
+gene,O
+was,O
+implicated,O
+in,O
+the,O
+pathogenesis,O
+of,O
+congenital,O
+atrichia,O
+.,O
+ , 
+The,O
+human,O
+hairless,O
+gene,O
+encodes,O
+a,O
+putative,O
+single,O
+zinc,O
+-,O
+finger,O
+transcription,O
+-,O
+factor,O
+protein,O
+with,O
+restricted,O
+expression,O
+in,O
+brain,O
+and,O
+skin,O
+,,O
+which,O
+is,O
+believed,O
+to,O
+regulate,O
+catagen,O
+remodeling,O
+in,O
+the,O
+hair,O
+cycle,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+report,O
+the,O
+identification,O
+of,O
+a,O
+missense,O
+mutation,O
+in,O
+the,O
+zinc,O
+-,O
+finger,O
+domain,O
+of,O
+the,O
+hairless,O
+gene,O
+in,O
+a,O
+large,O
+inbred,O
+family,O
+of,O
+Irish,O
+Travellers,O
+with,O
+congenital,O
+atrichia,O
+.,O
+ , 
+The,O
+mutated,O
+arginine,O
+residue,O
+is,O
+conserved,O
+among,O
+human,O
+,,O
+mouse,O
+,,O
+and,O
+rat,O
+,,O
+suggesting,O
+that,O
+it,O
+is,O
+of,O
+significant,O
+importance,O
+to,O
+the,O
+function,O
+of,O
+the,O
+zinc,O
+-,O
+finger,O
+domain,O
+.,O
+ , 
+#9792853
+Development,O
+and,O
+maintenance,O
+of,O
+ear,O
+innervation,O
+and,O
+function,O
+:,O
+lessons,O
+from,O
+mutations,O
+in,O
+mouse,O
+and,O
+man,O
+.,O
+ , 
+#17160901
+An,O
+absence,O
+of,O
+cutaneous,O
+neurofibromas,O
+associated,O
+with,O
+a,O
+3,O
+-,O
+bp,O
+inframe,O
+deletion,O
+in,O
+exon,O
+17,O
+of,O
+the,O
+NF1,B-Gene
+gene,O
+(,B-SNP
+c.2970,I-SNP
+-,I-SNP
+2972,I-SNP
+delAAT,I-SNP
+):,I-SNP
+evidence,O
+of,O
+a,O
+clinically,O
+significant,O
+NF1,B-Gene
+genotype,O
+-,O
+phenotype,O
+correlation,O
+.,O
+ , 
+Neurofibromatosis,O
+type,O
+1,O
+(,B-Gene
+NF1,I-Gene
+),I-Gene
+is,O
+characterized,O
+by,O
+cafe,O
+-,O
+au,O
+-,O
+lait,O
+spots,O
+,,O
+skinfold,O
+freckling,O
+,,O
+and,O
+cutaneous,O
+neurofibromas,O
+.,O
+ , 
+No,O
+obvious,O
+relationships,O
+between,O
+small,O
+mutations,O
+(,O
+<,O
+20,O
+bp,O
+),O
+of,O
+the,O
+NF1,B-Gene
+gene,O
+and,O
+a,O
+specific,O
+phenotype,O
+have,O
+previously,O
+been,O
+demonstrated,O
+,,O
+which,O
+suggests,O
+that,O
+interaction,O
+with,O
+either,O
+unlinked,O
+modifying,O
+genes,O
+and/or,O
+the,O
+normal,O
+NF1,B-Gene
+allele,O
+may,O
+be,O
+involved,O
+in,O
+the,O
+development,O
+of,O
+the,O
+particular,O
+clinical,O
+features,O
+associated,O
+with,O
+NF1,B-Gene
+.,I-Gene
+ , 
+We,O
+identified,O
+21,O
+unrelated,O
+probands,O
+with,O
+NF1,B-Gene
+(,O
+14,O
+familial,O
+and,O
+7,O
+sporadic,O
+cases,O
+),O
+who,O
+were,O
+all,O
+found,O
+to,O
+have,O
+the,O
+same,O
+c.2970,B-SNP
+-,I-SNP
+2972,I-SNP
+delAAT,I-SNP
+(,B-SNP
+p.990delM,I-SNP
+),I-SNP
+mutation,O
+but,O
+no,O
+cutaneous,O
+neurofibromas,O
+or,O
+clinically,O
+obvious,O
+plexiform,O
+neurofibromas,O
+.,O
+ , 
+Molecular,O
+analysis,O
+identified,O
+the,O
+same,O
+3,O
+-,O
+bp,O
+inframe,O
+deletion,O
+(,B-SNP
+c.2970,I-SNP
+-,I-SNP
+2972,I-SNP
+delAAT,I-SNP
+),I-SNP
+in,O
+exon,O
+17,O
+of,O
+the,O
+NF1,B-Gene
+gene,O
+in,O
+all,O
+affected,O
+subjects,O
+.,O
+ , 
+The,O
+Delta,O
+AAT,O
+mutation,O
+is,O
+predicted,O
+to,O
+result,O
+in,O
+the,O
+loss,O
+of,O
+one,O
+of,O
+two,O
+adjacent,O
+methionines,O
+(,O
+codon,O
+991,O
+or,O
+992,O
+),O
+(,O
+Delta,O
+Met991,O
+),O
+,,O
+in,O
+conjunction,O
+with,O
+silent,O
+ACA-->ACG,B-SNP
+change,I-SNP
+of,I-SNP
+codon,I-SNP
+990,I-SNP
+.,I-SNP
+ , 
+These,O
+two,O
+methionine,O
+residues,O
+are,O
+located,O
+in,O
+a,O
+highly,O
+conserved,O
+region,O
+of,O
+neurofibromin,O
+and,O
+are,O
+expected,O
+,,O
+therefore,O
+,,O
+to,O
+have,O
+a,O
+functional,O
+role,O
+in,O
+the,O
+protein,O
+.,O
+ , 
+Our,O
+data,O
+represent,O
+results,O
+from,O
+the,O
+first,O
+study,O
+to,O
+correlate,O
+a,O
+specific,O
+small,O
+mutation,O
+of,O
+the,O
+NF1,B-Gene
+gene,O
+to,O
+the,O
+expression,O
+of,O
+a,O
+particular,O
+clinical,O
+phenotype,O
+.,O
+ , 
+The,O
+biological,O
+mechanism,O
+that,O
+relates,O
+this,O
+specific,O
+mutation,O
+to,O
+the,O
+suppression,O
+of,O
+cutaneous,O
+neurofibroma,O
+development,O
+is,O
+unknown,O
+.,O
+ , 
+#8956059
+Three,O
+novel,O
+APC,B-Gene
+gene,O
+mutations,O
+in,O
+Portuguese,O
+FAP,O
+kindreds,O
+.,O
+ , 
+#1301957
+Molecular,O
+analysis,O
+of,O
+neurofibromatosis,B-Gene
+type,I-Gene
+1,I-Gene
+mutations,O
+.,O
+ , 
+We,O
+have,O
+examined,O
+a,O
+panel,O
+of,O
+115,O
+unrelated,O
+NF1,B-Gene
+individuals,O
+for,O
+mutation,O
+in,O
+the,O
+3,O
+',O
+region,O
+of,O
+the,O
+NF1,B-Gene
+gene,O
+,,O
+using,O
+Southern,O
+blotting,O
+and,O
+polymerase,O
+chain,O
+reaction,O
+amplification,O
+of,O
+exons,O
+followed,O
+by,O
+single,O
+-,O
+strand,O
+conformation,O
+polymorphism,O
+(,O
+SSCP,O
+),O
+analysis,O
+.,O
+ , 
+We,O
+found,O
+only,O
+2,O
+unequivocal,O
+mutations,O
+:,O
+a,O
+571,O
+bp,O
+deletion,O
+which,O
+removed,O
+exon,O
+6,O
+and,O
+resulted,O
+in,O
+a,O
+frameshift,O
+in,O
+exon,O
+7,O
+,,O
+and,O
+a,O
+2,O
+bp,O
+deletion,O
+in,O
+exon,O
+1,O
+.,O
+ , 
+A,O
+third,O
+sequence,O
+variation,O
+detected,O
+by,O
+SSCP,O
+was,O
+predicted,O
+to,O
+cause,O
+a,O
+lysine,O
+-,O
+arginine,O
+substitution,O
+in,O
+exon,O
+6,O
+.,O
+ , 
+This,O
+is,O
+a,O
+conservative,O
+change,O
+,,O
+and,O
+since,O
+the,O
+affected,O
+individual,O
+is,O
+a,O
+new,O
+mutation,O
+whose,O
+parents,O
+are,O
+not,O
+available,O
+,,O
+we,O
+can,O
+not,O
+be,O
+sure,O
+of,O
+its,O
+biological,O
+significance,O
+.,O
+ , 
+We,O
+detected,O
+mutations,O
+in,O
+at,O
+most,O
+3,O
+%,O
+of,O
+individuals,O
+,,O
+from,O
+an,O
+analysis,O
+which,O
+covered,O
+17,O
+%,O
+of,O
+the,O
+coding,O
+sequence,O
+by,O
+SSCP,O
+and,O
+a,O
+larger,O
+region,O
+by,O
+Southern,O
+blotting,O
+.,O
+ , 
+This,O
+relative,O
+failure,O
+to,O
+detect,O
+mutations,O
+accords,O
+with,O
+the,O
+experience,O
+of,O
+others,O
+.,O
+ , 
+Even,O
+allowing,O
+for,O
+the,O
+incomplete,O
+sensitivity,O
+of,O
+the,O
+methods,O
+used,O
+,,O
+the,O
+results,O
+suggest,O
+that,O
+the,O
+majority,O
+of,O
+NF1,B-Gene
+mutations,O
+lie,O
+elsewhere,O
+in,O
+the,O
+coding,O
+sequence,O
+or,O
+outside,O
+it,O
+.,O
+ , 
+#8554048
+Fine,O
+mapping,O
+of,O
+the,O
+EDA,B-Gene
+gene,O
+:,O
+a,O
+translocation,O
+breakpoint,O
+is,O
+associated,O
+with,O
+a,O
+CpG,O
+island,O
+that,O
+is,O
+transcribed,O
+.,O
+ , 
+In,O
+order,O
+to,O
+identify,O
+the,O
+gene,O
+for,O
+human,O
+X,O
+-,O
+linked,O
+anhidrotic,O
+ectodermal,O
+dysplasia,O
+(,O
+EDA,O
+),O
+,,O
+a,O
+translocation,O
+breakpoint,O
+in,O
+a,O
+female,O
+with,O
+t(X;1)(q13.1;p36.3,O
+),O
+and,O
+EDA,B-Gene
+(,O
+patient,O
+AK,O
+),O
+was,O
+finely,O
+mapped,O
+.,O
+ , 
+The,O
+EDA,B-Gene
+region,O
+contains,O
+five,O
+groups,O
+of,O
+rare,O
+-,O
+cutter,O
+restriction,O
+sites,O
+that,O
+define,O
+CpG,O
+islands,O
+.,O
+ , 
+The,O
+two,O
+more,O
+centromeric,O
+of,O
+these,O
+islands,O
+are,O
+associated,O
+with,O
+transcripts,O
+of,O
+3.5,O
+kb,O
+and,O
+1.8,O
+kb,O
+.,O
+ , 
+The,O
+third,O
+CpG,O
+island,O
+maps,O
+within,O
+<,O
+1,O
+kb,O
+of,O
+the,O
+translocation,O
+breakpoint,O
+in,O
+patient,O
+AK,O
+,,O
+as,O
+indicated,O
+by,O
+a,O
+genomic,O
+rearrangement,O
+,,O
+and,O
+approximately,O
+100,O
+kb,O
+centromeric,O
+from,O
+another,O
+previously,O
+mapped,O
+translocation,O
+breakpoint,O
+(,O
+patient,O
+AnLy,O
+),O
+.,O
+ , 
+Northern,O
+analysis,O
+with,O
+a,O
+probe,O
+from,O
+this,O
+CpG,O
+island,O
+detected,O
+an,O
+approximately,O
+6,O
+-,O
+kb,O
+mRNA,O
+in,O
+several,O
+fetal,O
+tissues,O
+tested,O
+.,O
+ , 
+An,O
+extended,O
+YAC,O
+contig,O
+of,O
+1,200,O
+kb,O
+with,O
+an,O
+average,O
+of,O
+fivefold,O
+coverage,O
+was,O
+constructed,O
+.,O
+ , 
+The,O
+two,O
+most,O
+telomeric,O
+CpG,O
+islands,O
+map,O
+350,O
+kb,O
+telomeric,O
+of,O
+the,O
+two,O
+translocations,O
+.,O
+ , 
+Taken,O
+together,O
+,,O
+the,O
+results,O
+suggest,O
+that,O
+the,O
+CpG,O
+island,O
+just,O
+proximal,O
+of,O
+the,O
+AK,O
+translocation,O
+breakpoint,O
+lies,O
+at,O
+the,O
+5,O
+',O
+end,O
+of,O
+a,O
+candidate,O
+gene,O
+for,O
+EDA,B-Gene
+.,I-Gene
+ , 
+#22243968
+A,O
+restricted,O
+spectrum,O
+of,O
+mutations,O
+in,O
+the,O
+SMAD4,B-Gene
+tumor,O
+-,O
+suppressor,O
+gene,O
+underlies,O
+Myhre,O
+syndrome,O
+.,O
+ , 
+Myhre,O
+syndrome,O
+is,O
+a,O
+developmental,O
+disorder,O
+characterized,O
+by,O
+reduced,O
+growth,O
+,,O
+generalized,O
+muscular,O
+hypertrophy,O
+,,O
+facial,O
+dysmorphism,O
+,,O
+deafness,O
+,,O
+cognitive,O
+deficits,O
+,,O
+joint,O
+stiffness,O
+,,O
+and,O
+skeletal,O
+anomalies,O
+.,O
+ , 
+Here,O
+,,O
+by,O
+performing,O
+exome,O
+sequencing,O
+of,O
+a,O
+single,O
+affected,O
+individual,O
+and,O
+coupling,O
+the,O
+results,O
+to,O
+a,O
+hypothesis,O
+-,O
+driven,O
+filtering,O
+strategy,O
+,,O
+we,O
+establish,O
+that,O
+heterozygous,O
+mutations,O
+in,O
+SMAD4,B-Gene
+,,I-Gene
+which,O
+encodes,O
+for,O
+a,O
+transducer,B-Gene
+mediating,I-Gene
+transforming,I-Gene
+growth,I-Gene
+factor,I-Gene
+β,I-Gene
+and,O
+bone,O
+morphogenetic,O
+protein,O
+signaling,O
+branches,O
+,,O
+underlie,O
+this,O
+rare,O
+Mendelian,O
+trait,O
+.,O
+ , 
+Two,O
+recurrent,O
+de,O
+novo,O
+SMAD4,B-Gene
+mutations,O
+were,O
+identified,O
+in,O
+eight,O
+unrelated,O
+subjects,O
+.,O
+ , 
+Both,O
+mutations,O
+were,O
+missense,O
+changes,O
+altering,O
+Ile500,O
+within,O
+the,O
+evolutionary,O
+conserved,O
+MAD,O
+homology,O
+2,O
+domain,O
+,,O
+a,O
+well,O
+known,O
+mutational,O
+hot,O
+spot,O
+in,O
+malignancies,O
+.,O
+ , 
+Structural,O
+analyses,O
+suggest,O
+that,O
+the,O
+substituted,O
+residues,O
+are,O
+likely,O
+to,O
+perturb,O
+the,O
+binding,O
+properties,O
+of,O
+the,O
+mutant,O
+protein,O
+to,O
+signaling,O
+partners,O
+.,O
+ , 
+Although,O
+SMAD4,B-Gene
+has,O
+been,O
+established,O
+as,O
+a,O
+tumor,O
+suppressor,O
+gene,O
+somatically,O
+mutated,O
+in,O
+pancreatic,O
+,,O
+gastrointestinal,O
+,,O
+and,O
+skin,O
+cancers,O
+,,O
+and,O
+germline,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+lesions,O
+and,O
+deletions,O
+of,O
+this,O
+gene,O
+have,O
+been,O
+documented,O
+to,O
+cause,O
+disorders,O
+that,O
+predispose,O
+individuals,O
+to,O
+gastrointestinal,O
+cancer,O
+and,O
+vascular,O
+dysplasias,O
+,,O
+the,O
+present,O
+report,O
+identifies,O
+a,O
+previously,O
+unrecognized,O
+class,O
+of,O
+mutations,O
+in,O
+the,O
+gene,O
+with,O
+profound,O
+impact,O
+on,O
+development,O
+and,O
+growth,O
+.,O
+ , 
+#7825576
+Autosomal,O
+dominant,O
+familial,O
+spastic,O
+paraplegia,O
+:,O
+reduction,O
+of,O
+the,O
+FSP1,B-Gene
+candidate,O
+region,O
+on,O
+chromosome,O
+14q,O
+to,O
+7,O
+cM,O
+and,O
+locus,O
+heterogeneity,O
+.,O
+ , 
+Three,O
+large,O
+pedigrees,O
+of,O
+German,O
+descent,O
+with,O
+autosomal,O
+dominant,O
+",O
+pure,O
+",O
+familial,O
+spastic,O
+paraplegia,O
+(,O
+FSP,O
+),O
+were,O
+characterized,O
+clinically,O
+and,O
+genetically,O
+.,O
+ , 
+Haplotype,O
+and,O
+linkage,O
+analyses,O
+,,O
+with,O
+microsatellites,O
+covering,O
+the,O
+FSP,O
+region,O
+on,O
+chromosome,O
+14q,O
+(,O
+locus,O
+FSP1,B-Gene
+),I-Gene
+,,O
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+performed,O
+.,O
+ , 
+In,O
+pedigree,O
+W,O
+,,O
+we,O
+found,O
+a,O
+haplotype,O
+that,O
+cosegregates,O
+with,O
+the,O
+disease,O
+and,O
+observed,O
+three,O
+crossing,O
+-,O
+over,O
+events,O
+,,O
+reducing,O
+the,O
+FSP1,B-Gene
+candidate,O
+region,O
+to,O
+7,O
+cM,O
+;,O
+in,O
+addition,O
+,,O
+the,O
+observation,O
+of,O
+apparent,O
+anticipation,O
+in,O
+this,O
+family,O
+suggests,O
+a,O
+trinucleotide,O
+repeat,O
+expansion,O
+as,O
+the,O
+mutation,O
+.,O
+ , 
+In,O
+pedigrees,O
+D,O
+and,O
+S,O
+,,O
+the,O
+gene,O
+locus,O
+could,O
+be,O
+excluded,O
+from,O
+the,O
+whole,O
+FSP1,B-Gene
+region,O
+,,O
+confirming,O
+the,O
+locus,O
+heterogeneity,O
+of,O
+autosomal,O
+dominant,O
+FSP,O
+.,O
+ , 
+#15365995
+Germline,O
+mutations,O
+in,O
+MLH1,B-Gene
+,,I-Gene
+MSH2,B-Gene
+and,O
+MSH6,B-Gene
+in,O
+Korean,O
+hereditary,O
+non,O
+-,O
+polyposis,O
+colorectal,O
+cancer,O
+families,O
+.,O
+ , 
+Hereditary,O
+non,O
+-,O
+polyposis,O
+colorectal,O
+cancer,O
+(,O
+HNPCC,O
+),O
+,,O
+the,O
+most,O
+common,O
+hereditary,O
+colon,O
+cancer,O
+syndrome,O
+,,O
+is,O
+a,O
+dominant,O
+disorder,O
+caused,O
+by,O
+germline,O
+defects,O
+in,O
+mismatch,B-Gene
+repair,I-Gene
+(,B-Gene
+MMR,I-Gene
+),I-Gene
+genes,O
+.,O
+ , 
+Identification,O
+of,O
+MMR,B-Gene
+gene,O
+mutations,O
+can,O
+have,O
+direct,O
+clinical,O
+implications,O
+in,O
+counseling,O
+and,O
+management,O
+of,O
+HNPCC,O
+families,O
+.,O
+ , 
+We,O
+screened,O
+44,O
+HNPCC,O
+and,O
+97,O
+suspected,O
+HNPCC,O
+Korean,O
+families,O
+for,O
+germline,O
+mutations,O
+in,O
+three,O
+MMR,B-Gene
+genes,O
+:,O
+MLH1,B-Gene
+,,I-Gene
+MSH2,B-Gene
+and,O
+MSH6,B-Gene
+.,I-Gene
+ , 
+We,O
+identified,O
+twelve,O
+novel,O
+mutations,O
+:,O
+nine,O
+in,O
+MLH1(c.632_633insT,B-SNP
+,,I-SNP
+c.808_811delACTT,B-SNP
+,,I-SNP
+c.845C,B-SNP
+>,I-SNP
+G,I-SNP
+,,I-SNP
+c.1625A,B-SNP
+>,I-SNP
+C,I-SNP
+,,I-SNP
+c.1730,B-SNP
++,I-SNP
+1delG,I-SNP
+,,I-SNP
+c.1907T,B-SNP
+>,I-SNP
+C,I-SNP
+,,I-SNP
+c.1918C,B-SNP
+>,I-SNP
+T,I-SNP
+,,I-SNP
+c.2104,B-SNP
+-,I-SNP
+2A,I-SNP
+>,I-SNP
+G,I-SNP
+and,O
+c.2170T,B-SNP
+>,I-SNP
+A,I-SNP
+),I-SNP
+,,O
+two,O
+in,O
+MSH2,B-Gene
+(,B-SNP
+c.1886A,I-SNP
+>,I-SNP
+G,I-SNP
+,,I-SNP
+c.1316_1318delCCT,B-SNP
+),I-SNP
+and,O
+one,O
+in,O
+MSH6,B-Gene
+(,B-SNP
+c.3488A,I-SNP
+>,I-SNP
+T,I-SNP
+),I-SNP
+.,O
+ , 
+In,O
+addition,O
+,,O
+two,O
+statically,O
+significant,O
+cSNPs,O
+in,O
+MLH1,B-Gene
+:,I-Gene
+c.1128T,B-SNP
+>,I-SNP
+C,I-SNP
+(,O
+p=0.008,O
+in,O
+HNPCC,O
+and,O
+p=0.037,O
+in,O
+early,O
+-,O
+onset,O
+CRC,O
+),O
+and,O
+c.2168C,B-SNP
+>,I-SNP
+A,I-SNP
+(,O
+p<0.001,O
+in,O
+HNPCC,O
+),O
+.,O
+ , 
+Interestingly,O
+,,O
+the,O
+most,O
+frequent,O
+mutation,O
+,,O
+c.1757_1758insC,B-SNP
+in,O
+MLH1,B-Gene
+,,I-Gene
+was,O
+a,O
+founder,O
+mutation,O
+inherited,O
+from,O
+a,O
+common,O
+Korean,O
+ancestor,O
+.,O
+ , 
+#10739764
+Different,O
+mutations,O
+in,O
+the,O
+LMNA,B-Gene
+gene,O
+cause,O
+autosomal,O
+dominant,O
+and,O
+autosomal,O
+recessive,O
+Emery,O
+-,O
+Dreifuss,O
+muscular,O
+dystrophy,O
+.,O
+ , 
+Emery,O
+-,O
+Dreifuss,O
+muscular,O
+dystrophy,O
+(,O
+EMD,O
+),O
+is,O
+a,O
+condition,O
+characterized,O
+by,O
+the,O
+clinical,O
+triad,O
+of,O
+early,O
+-,O
+onset,O
+contractures,O
+,,O
+progressive,O
+weakness,O
+in,O
+humeroperoneal,O
+muscles,O
+,,O
+and,O
+cardiomyopathy,O
+with,O
+conduction,O
+block,O
+.,O
+ , 
+The,O
+disease,O
+was,O
+described,O
+for,O
+the,O
+first,O
+time,O
+as,O
+an,O
+X,O
+-,O
+linked,O
+muscular,O
+dystrophy,O
+,,O
+but,O
+autosomal,O
+dominant,O
+and,O
+autosomal,O
+recessive,O
+forms,O
+were,O
+reported,O
+.,O
+ , 
+The,O
+genes,O
+for,O
+X,O
+-,O
+linked,O
+EMD,O
+and,O
+autosomal,O
+dominant,O
+EMD,O
+(,O
+AD,O
+-,O
+EMD,O
+),O
+were,O
+identified,O
+.,O
+ , 
+We,O
+report,O
+here,O
+that,O
+heterozygote,O
+mutations,O
+in,O
+LMNA,B-Gene
+,,I-Gene
+the,O
+gene,O
+for,O
+AD,O
+-,O
+EMD,O
+,,O
+may,O
+cause,O
+diverse,O
+phenotypes,O
+ranging,O
+from,O
+typical,O
+EMD,O
+to,O
+no,O
+phenotypic,O
+effect,O
+.,O
+ , 
+Our,O
+results,O
+show,O
+that,O
+LMNA,B-Gene
+mutations,O
+are,O
+also,O
+responsible,O
+for,O
+the,O
+recessive,O
+form,O
+of,O
+the,O
+disease,O
+.,O
+ , 
+Our,O
+results,O
+give,O
+further,O
+support,O
+to,O
+the,O
+notion,O
+that,O
+different,O
+genetic,O
+forms,O
+of,O
+EMD,O
+have,O
+a,O
+common,O
+pathophysiological,O
+background,O
+.,O
+ , 
+The,O
+distribution,O
+of,O
+the,O
+mutations,O
+in,O
+AD,O
+-,O
+EMD,O
+patients,O
+(,O
+in,O
+the,O
+tail,O
+and,O
+in,O
+the,O
+2A,O
+rod,O
+domain,O
+),O
+suggests,O
+that,O
+unique,O
+interactions,O
+between,O
+lamin,O
+A,O
+/,O
+C,O
+and,O
+other,O
+nuclear,O
+components,O
+exist,O
+that,O
+have,O
+an,O
+important,O
+role,O
+in,O
+cardiac,O
+and,O
+skeletal,O
+muscle,O
+function,O
+.,O
+ , 
+#15459972
+Novel,O
+and,O
+recurrent,O
+mutations,O
+clustered,O
+in,O
+the,O
+von,O
+Willebrand,O
+factor,O
+A,O
+domain,O
+of,O
+MATN3,B-Gene
+in,O
+multiple,O
+epiphyseal,O
+dysplasia,O
+.,O
+ , 
+Multiple,O
+epiphyseal,O
+dysplasia,O
+(,O
+MED,O
+),O
+is,O
+a,O
+common,O
+skeletal,O
+dysplasia,O
+characterized,O
+by,O
+joint,O
+pain,O
+and,O
+stiffness,O
+,,O
+delayed,O
+and,O
+irregular,O
+ossification,O
+of,O
+epiphyses,O
+,,O
+and,O
+early,O
+-,O
+onset,O
+osteoarthritis,O
+.,O
+ , 
+Six,O
+genes,O
+responsible,O
+for,O
+MED,O
+have,O
+been,O
+identified,O
+,,O
+including,O
+COMP,B-Gene
+,,I-Gene
+COL9A1,B-Gene
+,,I-Gene
+COL9A2,B-Gene
+,,I-Gene
+COL9A3,B-Gene
+,,I-Gene
+DSTDT,B-Gene
+and,O
+MATN3,B-Gene
+.,I-Gene
+ , 
+MATN3,B-Gene
+encodes,O
+matrilin-3,B-Gene
+,,I-Gene
+a,O
+cartilage,O
+-,O
+specific,O
+extracellular,O
+matrix,O
+protein,O
+.,O
+ , 
+To,O
+date,O
+,,O
+seven,O
+different,O
+MATN3,B-Gene
+mutations,O
+have,O
+been,O
+identified,O
+;,O
+all,O
+are,O
+located,O
+within,O
+the,O
+beta,O
+-,O
+sheet,O
+regions,O
+of,O
+the,O
+von,O
+Willebrand,O
+factor,O
+type,O
+A,O
+(,O
+vWFA,O
+),O
+domain,O
+,,O
+which,O
+is,O
+encoded,O
+by,O
+exon,O
+2,O
+.,O
+ , 
+We,O
+examined,O
+MATN3,B-Gene
+mutations,O
+in27,O
+Japanese,O
+MED,O
+patients,O
+who,O
+were,O
+possibly,O
+autosomal,O
+dominant,O
+inheritance,O
+and,O
+had,O
+been,O
+excluded,O
+for,O
+COMP,O
+mutations,O
+.,O
+ , 
+Ten,O
+of,O
+them,O
+had,O
+a,O
+positive,O
+family,O
+history,O
+.,O
+ , 
+We,O
+examined,O
+all,O
+eight,O
+exons,O
+of,O
+MATN3,B-Gene
+by,O
+PCR,O
+and,O
+direct,O
+sequencing,O
+from,O
+genomic,O
+DNA,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+four,O
+missense,O
+mutations,O
+in,O
+eight,O
+unrelated,O
+families,O
+;,O
+two,O
+are,O
+novel,O
+,,O
+and,O
+two,O
+have,O
+been,O
+characterized,O
+previously,O
+.,O
+ , 
+Like,O
+previously,O
+characterized,O
+MATN3,B-Gene
+mutations,O
+,,O
+those,O
+identified,O
+in,O
+this,O
+study,O
+are,O
+clustered,O
+within,O
+exon,O
+2,O
+,,O
+specifically,O
+in,O
+and,O
+around,O
+the,O
+2nd,O
+beta,O
+-,O
+sheet,O
+region,O
+of,O
+the,O
+vWFA,O
+domain,O
+(,O
+aa,O
+.,O
+ , 
+120,O
+-,O
+127,O
+),O
+.,O
+ , 
+Contrary,O
+to,O
+the,O
+previous,O
+assumption,O
+that,O
+the,O
+MATN3,B-Gene
+mutation,O
+in,O
+MED,O
+is,O
+confined,O
+to,O
+the,O
+beta,O
+-,O
+sheet,O
+regions,O
+,,O
+one,O
+novel,O
+mutation,O
+(,B-SNP
+p.,I-SNP
+F105S,I-SNP
+),I-SNP
+is,O
+located,O
+outside,O
+the,O
+beta,O
+-,O
+sheet,O
+region,O
+,,O
+within,O
+an,O
+alpha,O
+-,O
+helix,O
+region,O
+.,O
+ , 
+#22405088
+Exome,O
+sequencing,O
+reveals,O
+mutations,O
+in,O
+TRPV3,B-Gene
+as,O
+a,O
+cause,O
+of,O
+Olmsted,O
+syndrome,O
+.,O
+ , 
+Olmsted,O
+syndrome,O
+(,O
+OS,O
+),O
+is,O
+a,O
+rare,O
+congenital,O
+disorder,O
+characterized,O
+by,O
+palmoplantar,O
+and,O
+periorificial,O
+keratoderma,O
+,,O
+alopecia,O
+in,O
+most,O
+cases,O
+,,O
+and,O
+severe,O
+itching,O
+.,O
+ , 
+The,O
+genetic,O
+basis,O
+for,O
+OS,O
+remained,O
+unidentified,O
+.,O
+ , 
+Using,O
+whole,O
+-,O
+exome,O
+sequencing,O
+of,O
+case,O
+-,O
+parents,O
+trios,O
+,,O
+we,O
+have,O
+identified,O
+a,O
+de,O
+novo,O
+missense,O
+mutation,O
+in,O
+TRPV3,B-Gene
+that,O
+produces,O
+p.,B-SNP
+Gly573Ser,I-SNP
+in,O
+an,O
+individual,O
+with,O
+OS,O
+.,O
+ , 
+Nucleotide,O
+sequencing,O
+of,O
+five,O
+additional,O
+affected,O
+individuals,O
+also,O
+revealed,O
+missense,O
+mutations,O
+in,O
+TRPV3,B-Gene
+(,O
+which,O
+produced,O
+p.,B-SNP
+Gly573Ser,I-SNP
+in,O
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+cases,O
+and,O
+p.,B-SNP
+Gly573Cys,I-SNP
+and,O
+p.,B-SNP
+Trp692Gly,I-SNP
+in,O
+one,O
+case,O
+each,O
+),O
+.,O
+ , 
+Encoding,O
+a,O
+transient,B-Gene
+receptor,I-Gene
+potential,I-Gene
+vanilloid-3,I-Gene
+cation,I-Gene
+channel,I-Gene
+,,I-Gene
+TRPV3,B-Gene
+is,O
+primarily,O
+expressed,O
+in,O
+the,O
+skin,O
+,,O
+hair,O
+follicles,O
+,,O
+brain,O
+,,O
+and,O
+spinal,O
+cord,O
+.,O
+ , 
+In,O
+transfected,O
+HEK293,O
+cells,O
+expressing,O
+TRPV3,B-Gene
+mutants,O
+,,O
+much,O
+larger,O
+inward,O
+currents,O
+were,O
+recorded,O
+,,O
+probably,O
+because,O
+of,O
+the,O
+constitutive,O
+opening,O
+of,O
+the,O
+mutants,O
+.,O
+ , 
+These,O
+gain,O
+-,O
+of,O
+-,O
+function,O
+mutations,O
+might,O
+lead,O
+to,O
+elevated,O
+apoptosis,O
+of,O
+keratinocytes,O
+and,O
+consequent,O
+skin,O
+hyperkeratosis,O
+in,O
+the,O
+affected,O
+individuals,O
+.,O
+ , 
+Our,O
+findings,O
+suggest,O
+that,O
+TRPV3,B-Gene
+plays,O
+essential,O
+roles,O
+in,O
+skin,O
+keratinization,O
+,,O
+hair,O
+growth,O
+,,O
+and,O
+possibly,O
+itching,O
+sensation,O
+in,O
+humans,O
+and,O
+selectively,O
+targeting,O
+TRPV3,B-Gene
+could,O
+provide,O
+therapeutic,O
+potential,O
+for,O
+keratinization,O
+or,O
+itching,O
+-,O
+related,O
+skin,O
+disorders,O
+.,O
+ , 
+#19732864
+Allele,O
+-,O
+specific,O
+chromatin,O
+remodeling,O
+in,O
+the,O
+ZPBP2,B-Gene
+/,B-Gene
+GSDMB,I-Gene
+/,B-Gene
+ORMDL3,I-Gene
+locus,O
+associated,O
+with,O
+the,O
+risk,O
+of,O
+asthma,O
+and,O
+autoimmune,O
+disease,O
+.,O
+ , 
+Common,O
+SNPs,O
+in,O
+the,O
+chromosome,O
+17q12,O
+-,O
+q21,O
+region,O
+alter,O
+the,O
+risk,O
+for,O
+asthma,O
+,,O
+type,O
+1,O
+diabetes,O
+,,O
+primary,O
+biliary,O
+cirrhosis,O
+,,O
+and,O
+Crohn,O
+disease,O
+.,O
+ , 
+Previous,O
+reports,O
+by,O
+us,O
+and,O
+others,O
+have,O
+linked,O
+the,O
+disease,O
+-,O
+associated,O
+genetic,O
+variants,O
+with,O
+changes,O
+in,O
+expression,O
+of,O
+GSDMB,B-Gene
+and,O
+ORMDL3,B-Gene
+transcripts,O
+in,O
+human,O
+lymphoblastoid,O
+cell,O
+lines,O
+(,O
+LCLs,O
+),O
+.,O
+ , 
+The,O
+variants,O
+also,O
+alter,O
+regulation,O
+of,O
+other,O
+transcripts,O
+,,O
+and,O
+this,O
+domain,O
+-,O
+wide,O
+cis,O
+-,O
+regulatory,O
+effect,O
+suggests,O
+a,O
+mechanism,O
+involving,O
+long,O
+-,O
+range,O
+chromatin,O
+interactions,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+further,O
+dissect,O
+the,O
+disease,O
+-,O
+linked,O
+haplotype,O
+and,O
+identify,O
+putative,O
+causal,O
+DNA,O
+variants,O
+via,O
+a,O
+combination,O
+of,O
+genetic,O
+and,O
+functional,O
+analyses,O
+.,O
+ , 
+First,O
+,,O
+high,O
+-,O
+throughput,O
+resequencing,O
+of,O
+the,O
+region,O
+and,O
+genotyping,O
+of,O
+potential,O
+candidate,O
+variants,O
+were,O
+performed,O
+.,O
+ , 
+Next,O
+,,O
+additional,O
+mapping,O
+of,O
+allelic,O
+expression,O
+differences,O
+in,O
+Yoruba,O
+HapMap,O
+LCLs,O
+allowed,O
+us,O
+to,O
+fine,O
+-,O
+map,O
+the,O
+basis,O
+of,O
+the,O
+cis,O
+-,O
+regulatory,O
+differences,O
+to,O
+a,O
+handful,O
+of,O
+candidate,O
+functional,O
+variants,O
+.,O
+ , 
+Functional,O
+assays,O
+identified,O
+allele,O
+-,O
+specific,O
+differences,O
+in,O
+nucleosome,O
+distribution,O
+,,O
+an,O
+allele,O
+-,O
+specific,O
+association,O
+with,O
+the,O
+insulator,O
+protein,O
+CTCF,B-Gene
+,,I-Gene
+as,O
+well,O
+as,O
+a,O
+weak,O
+promoter,O
+activity,O
+for,O
+rs12936231,O
+.,O
+ , 
+Overall,O
+,,O
+this,O
+study,O
+shows,O
+a,O
+common,O
+disease,O
+allele,O
+linked,O
+to,O
+changes,O
+in,O
+CTCF,B-Gene
+binding,O
+and,O
+nucleosome,O
+occupancy,O
+leading,O
+to,O
+altered,O
+domain,O
+-,O
+wide,O
+cis,O
+-,O
+regulation,O
+.,O
+ , 
+Finally,O
+,,O
+a,O
+strong,O
+association,O
+between,O
+asthma,O
+and,O
+cis,O
+-,O
+regulatory,O
+haplotypes,O
+was,O
+observed,O
+in,O
+three,O
+independent,O
+family,O
+-,O
+based,O
+cohorts,O
+(,O
+p,O
+=,O
+1.78,O
+x,O
+10(-8,O
+),O
+),O
+.,O
+ , 
+This,O
+study,O
+demonstrates,O
+the,O
+requirement,O
+of,O
+multiple,O
+parallel,O
+allele,O
+-,O
+specific,O
+tools,O
+for,O
+the,O
+investigation,O
+of,O
+noncoding,O
+disease,O
+variants,O
+and,O
+functional,O
+fine,O
+-,O
+mapping,O
+of,O
+human,O
+disease,O
+-,O
+associated,O
+haplotypes,O
+.,O
+ , 
+#1284538
+Four,O
+new,O
+mutations,O
+of,O
+the,O
+CFTR,B-Gene
+gene,O
+(,B-SNP
+541delC,I-SNP
+,,I-SNP
+R347H,B-SNP
+,,I-SNP
+R352Q,B-SNP
+,,I-SNP
+E585X,B-SNP
+),I-SNP
+detected,O
+by,O
+DGGE,O
+analysis,O
+in,O
+Italian,O
+CF,O
+patients,O
+,,O
+associated,O
+with,O
+different,O
+clinical,O
+phenotypes,O
+.,O
+ , 
+The,O
+delta,B-SNP
+508,I-SNP
+mutation,O
+accounts,O
+for,O
+about,O
+53,O
+%,O
+of,O
+the,O
+molecular,O
+defects,O
+causing,O
+cystic,O
+fibrosis,O
+(,O
+CF,O
+),O
+in,O
+Italy,O
+.,O
+ , 
+The,O
+numerous,O
+additional,O
+mutations,O
+detected,O
+so,O
+far,O
+are,O
+all,O
+relatively,O
+rare,O
+,,O
+and,O
+about,O
+30,O
+%,O
+of,O
+CF,O
+chromosomes,O
+carries,O
+unknown,O
+mutations,O
+in,O
+our,O
+patients,O
+.,O
+ , 
+In,O
+order,O
+to,O
+identify,O
+the,O
+non,B-SNP
+-,I-SNP
+delta,I-SNP
+F508,I-SNP
+mutations,O
+causing,O
+CF,O
+in,O
+our,O
+population,O
+,,O
+we,O
+performed,O
+GC,O
+-,O
+clamped,O
+denaturing,O
+gradient,O
+gel,O
+electrophoresis,O
+(,O
+DGGE,O
+),O
+on,O
+9,O
+exons,O
+of,O
+the,O
+cystic,B-Gene
+fibrosis,I-Gene
+transmembrane,I-Gene
+conductance,I-Gene
+regulator,I-Gene
+(,B-Gene
+CFTR,I-Gene
+),I-Gene
+gene,O
+in,O
+a,O
+sample,O
+of,O
+86,O
+Italian,O
+CF,O
+patients,O
+carrying,O
+unknown,O
+mutations,O
+on,O
+at,O
+least,O
+one,O
+chromosome,O
+.,O
+ , 
+Direct,O
+sequencing,O
+of,O
+17,O
+samples,O
+showing,O
+an,O
+altered,O
+electrophoretic,O
+mobility,O
+allowed,O
+the,O
+identification,O
+of,O
+four,O
+new,O
+mutations,O
+(,B-SNP
+541delC,I-SNP
+,,I-SNP
+R347H,B-SNP
+,,I-SNP
+R352Q,B-SNP
+,,I-SNP
+and,O
+E585X,B-SNP
+),I-SNP
+,,O
+five,O
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+already,O
+known,O
+(,B-SNP
+G85E,I-SNP
+,,I-SNP
+I148,B-SNP
+T,I-SNP
+,,I-SNP
+G178R,B-SNP
+,,I-SNP
+1078delT,B-SNP
+,,I-SNP
+and,O
+R347P,B-SNP
+),I-SNP
+,,O
+and,O
+one,O
+rare,O
+variant,O
+(,B-SNP
+1898,I-SNP
++,I-SNP
+3A-->G,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+strategy,O
+based,O
+on,O
+GC,O
+-,O
+clamped,O
+DGGE,O
+represents,O
+an,O
+efficient,O
+and,O
+rapid,O
+approach,O
+for,O
+mutation,O
+detection,O
+for,O
+those,O
+genetic,O
+diseases,O
+,,O
+such,O
+as,O
+CF,O
+,,O
+in,O
+which,O
+a,O
+large,O
+number,O
+of,O
+rare,O
+molecular,O
+defects,O
+has,O
+been,O
+described,O
+.,O
+ , 
+#20226436
+A,O
+follow,O
+-,O
+up,O
+study,O
+of,O
+a,O
+genome,O
+-,O
+wide,O
+association,O
+scan,O
+identifies,O
+a,O
+susceptibility,O
+locus,O
+for,O
+venous,O
+thrombosis,O
+on,O
+chromosome,O
+6p24.1,O
+.,O
+ , 
+To,O
+identify,O
+genetic,O
+susceptibility,O
+factors,O
+conferring,O
+increased,O
+risk,O
+of,O
+venous,O
+thrombosis,O
+(,O
+VT,O
+),O
+,,O
+we,O
+conducted,O
+a,O
+multistage,O
+study,O
+,,O
+following,O
+results,O
+of,O
+a,O
+previously,O
+published,O
+GWAS,O
+that,O
+failed,O
+to,O
+detect,O
+loci,O
+for,O
+developing,O
+VT,O
+.,O
+ , 
+Using,O
+a,O
+collection,O
+of,O
+5862,O
+cases,O
+with,O
+VT,O
+and,O
+7112,O
+healthy,O
+controls,O
+,,O
+we,O
+identified,O
+the,O
+HIVEP1,B-Gene
+locus,O
+on,O
+chromosome,O
+6p24.1,O
+as,O
+a,O
+susceptibility,O
+locus,O
+for,O
+VT,O
+.,O
+ , 
+Indeed,O
+,,O
+the,O
+HIVEP1,B-Gene
+rs169713C,O
+allele,O
+was,O
+associated,O
+with,O
+an,O
+increased,O
+risk,O
+for,O
+VT,O
+,,O
+with,O
+an,O
+odds,O
+ratio,O
+of,O
+1.20,O
+(,O
+95,O
+%,O
+confidence,O
+interval,O
+1.13,O
+-,O
+1.27,O
+,,O
+p,O
+=,O
+2.86,O
+x,O
+10(-9,O
+),O
+),O
+.,O
+ , 
+HIVEP1,B-Gene
+codes,O
+for,O
+a,O
+protein,O
+that,O
+participates,O
+in,O
+the,O
+transcriptional,O
+regulation,O
+of,O
+inflammatory,O
+target,O
+genes,O
+by,O
+binding,O
+specific,O
+DNA,O
+sequences,O
+in,O
+their,O
+promoter,O
+and,O
+enhancer,O
+regions,O
+.,O
+ , 
+The,O
+current,O
+results,O
+provide,O
+the,O
+identification,O
+of,O
+a,O
+locus,O
+involved,O
+in,O
+VT,O
+susceptibility,O
+that,O
+lies,O
+outside,O
+the,O
+traditional,O
+coagulation,O
+/,O
+fibrinolysis,O
+pathway,O
+.,O
+ , 
+#18387595
+On,O
+the,O
+replication,O
+of,O
+genetic,O
+associations,O
+:,O
+timing,O
+can,O
+be,O
+everything,O
+!,O
+ , 
+The,O
+failure,O
+of,O
+researchers,O
+to,O
+replicate,O
+genetic,O
+-,O
+association,O
+findings,O
+is,O
+most,O
+commonly,O
+attributed,O
+to,O
+insufficient,O
+statistical,O
+power,O
+,,O
+population,O
+stratification,O
+,,O
+or,O
+various,O
+forms,O
+of,O
+between,O
+-,O
+study,O
+heterogeneity,O
+or,O
+environmental,O
+influences.(1,O
+),O
+ , 
+Here,O
+,,O
+we,O
+illustrate,O
+another,O
+potential,O
+cause,O
+for,O
+nonreplications,O
+that,O
+has,O
+so,O
+far,O
+not,O
+received,O
+much,O
+attention,O
+in,O
+the,O
+literature,O
+.,O
+ , 
+We,O
+illustrate,O
+that,O
+the,O
+strength,O
+of,O
+a,O
+genetic,O
+effect,O
+can,O
+vary,O
+by,O
+age,O
+,,O
+causing,O
+",O
+age,O
+-,O
+varying,O
+associations,O
+.,O
+",O
+ , 
+If,O
+not,O
+taken,O
+into,O
+account,O
+during,O
+the,O
+design,O
+and,O
+the,O
+analysis,O
+of,O
+a,O
+study,O
+,,O
+age,O
+-,O
+varying,O
+genetic,O
+associations,O
+can,O
+cause,O
+nonreplication,O
+.,O
+ , 
+By,O
+using,O
+the,O
+100,O
+K,O
+SNP,O
+scan,O
+of,O
+the,O
+Framingham,O
+Heart,O
+Study,O
+,,O
+we,O
+identified,O
+an,O
+age,O
+-,O
+varying,O
+association,O
+between,O
+a,O
+SNP,O
+in,O
+ROBO1,B-Gene
+and,O
+obesity,O
+and,O
+hypothesized,O
+an,O
+age,O
+-,O
+gene,O
+interaction,O
+.,O
+ , 
+This,O
+finding,O
+was,O
+followed,O
+up,O
+in,O
+eight,O
+independent,O
+samples,O
+comprising,O
+13,584,O
+individuals,O
+.,O
+ , 
+The,O
+association,O
+was,O
+replicated,O
+in,O
+five,O
+of,O
+the,O
+eight,O
+studies,O
+,,O
+showing,O
+an,O
+age,O
+-,O
+dependent,O
+relationship,O
+(,O
+one,O
+-,O
+sided,O
+combined,O
+p,O
+=,O
+3.92,O
+x,O
+10(-9,O
+),O
+,,O
+combined,O
+p,O
+value,O
+from,O
+pediatric,O
+cohorts,O
+=,O
+2.21,O
+x,O
+10(-8,O
+),O
+,,O
+combined,O
+p,O
+value,O
+from,O
+adult,O
+cohorts,O
+=,O
+0.00422,O
+),O
+.,O
+ , 
+Furthermore,O
+,,O
+this,O
+study,O
+illustrates,O
+that,O
+it,O
+is,O
+difficult,O
+for,O
+cross,O
+-,O
+sectional,O
+study,O
+designs,O
+to,O
+detect,O
+age,O
+-,O
+varying,O
+associations,O
+.,O
+ , 
+If,O
+the,O
+specifics,O
+of,O
+age-,O
+or,O
+time,O
+-,O
+varying,O
+genetic,O
+effects,O
+are,O
+not,O
+considered,O
+in,O
+the,O
+selection,O
+of,O
+both,O
+the,O
+follow,O
+-,O
+up,O
+samples,O
+and,O
+in,O
+the,O
+statistical,O
+analysis,O
+,,O
+important,O
+genetic,O
+associations,O
+may,O
+be,O
+missed,O
+.,O
+ , 
+#10521310
+A,O
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+genome,O
+screen,O
+in,O
+sib,O
+pairs,O
+affected,O
+by,O
+Gilles,O
+de,O
+la,O
+Tourette,O
+syndrome,O
+.,O
+ , 
+The,O
+Tourette,O
+Syndrome,O
+Association,O
+International,O
+Consortium,O
+for,O
+Genetics,O
+.,O
+ , 
+Gilles,O
+de,O
+la,O
+Tourette,O
+syndrome,O
+is,O
+a,O
+neuropsychiatric,O
+disorder,O
+characterized,O
+by,O
+waxing,O
+and,O
+waning,O
+multiple,O
+motor,O
+and,O
+phonic,O
+tics,O
+with,O
+a,O
+complex,O
+mode,O
+of,O
+inheritance,O
+.,O
+ , 
+Previous,O
+attempts,O
+,,O
+which,O
+used,O
+large,O
+multigenerational,O
+families,O
+to,O
+localize,O
+susceptibility,O
+loci,O
+,,O
+have,O
+been,O
+unsuccessful,O
+.,O
+ , 
+In,O
+this,O
+report,O
+,,O
+the,O
+results,O
+of,O
+the,O
+first,O
+systematic,O
+genome,O
+scan,O
+,,O
+using,O
+76,O
+affected,O
+-,O
+sib,O
+-,O
+pair,O
+families,O
+with,O
+a,O
+total,O
+of,O
+110,O
+sib,O
+pairs,O
+,,O
+are,O
+summarized,O
+.,O
+ , 
+While,O
+no,O
+results,O
+reached,O
+acceptable,O
+statistical,O
+significance,O
+,,O
+the,O
+multipoint,O
+maximum,O
+-,O
+likelihood,O
+scores,O
+(,O
+MLS,O
+),O
+for,O
+two,O
+regions,O
+(,O
+4q,O
+and,O
+8p,O
+),O
+were,O
+suggestive,O
+(,O
+MLS,O
+>,O
+2.0,O
+),O
+.,O
+ , 
+Four,O
+additional,O
+genomic,O
+regions,O
+also,O
+gave,O
+multipoint,O
+MLS,O
+scores,O
+between,O
+1.0,O
+and,O
+2.0,O
+.,O
+ , 
+#11058905
+Six,O
+novel,O
+MEN1,B-Gene
+gene,O
+mutations,O
+in,O
+sporadic,O
+parathyroid,O
+tumors,O
+.,O
+ , 
+We,O
+report,O
+nine,O
+mutations,O
+of,O
+the,O
+multiple,B-Gene
+endocrine,I-Gene
+neoplasia,I-Gene
+type,I-Gene
+1,I-Gene
+(,B-Gene
+MEN1,I-Gene
+),I-Gene
+gene,O
+in,O
+sporadic,O
+parathyroid,O
+adenomas,O
+.,O
+ , 
+Six,O
+of,O
+them,O
+have,O
+not,O
+previously,O
+been,O
+described,O
+:,O
+E60X,B-SNP
+,,I-SNP
+P32R,B-SNP
+,,I-SNP
+261delA,B-SNP
+,,I-SNP
+934,B-SNP
++,I-SNP
+2T-->G,I-SNP
+,,I-SNP
+S443P,B-SNP
+,,I-SNP
+and,O
+1593insC.,B-SNP
+ , 
+The,O
+tissue,O
+samples,O
+were,O
+initially,O
+submitted,O
+to,O
+LOH,O
+analysis,O
+at,O
+11q13,O
+followed,O
+by,O
+SSCP,O
+screening,O
+of,O
+LOH,O
+-,O
+positive,O
+samples,O
+.,O
+ , 
+Mutations,O
+were,O
+identified,O
+by,O
+direct,O
+sequencing,O
+and,O
+subcloning,O
+.,O
+ , 
+Three,O
+(,B-SNP
+E60X,I-SNP
+,,I-SNP
+P32R,B-SNP
+,,I-SNP
+and,O
+261delA,B-SNP
+),I-SNP
+were,O
+in,O
+exon,O
+2,O
+,,O
+one,O
+(,O
+934,O
++,O
+2bp,O
+),O
+in,O
+the,O
+splice,O
+junction,O
+of,O
+exon,O
+5,O
+,,O
+one,O
+(,B-SNP
+S443P,I-SNP
+),I-SNP
+in,O
+exon,O
+9,O
+,,O
+and,O
+one,O
+(,B-SNP
+1593insC,I-SNP
+),I-SNP
+in,O
+exon,O
+10,O
+.,O
+ , 
+The,O
+3,O
+mutations,O
+in,O
+exon,O
+2,O
+were,O
+associated,O
+with,O
+loss,O
+and/or,O
+creation,O
+of,O
+a,O
+restriction,O
+site,O
+.,O
+ , 
+The,O
+corresponding,O
+germline,O
+sequence,O
+of,O
+the,O
+MEN1,B-Gene
+gene,O
+was,O
+normal,O
+.,O
+ , 
+Most,O
+mutations,O
+would,O
+likely,O
+result,O
+in,O
+a,O
+nonfunctional,O
+menin,O
+protein,O
+,,O
+and,O
+therefore,O
+in,O
+the,O
+loss,O
+of,O
+a,O
+tumor,O
+suppressor,O
+protein,O
+.,O
+ , 
+#9718347
+Molecular,O
+analysis,O
+of,O
+9p,O
+deletions,O
+associated,O
+with,O
+XY,O
+sex,O
+reversal,O
+:,O
+refining,O
+the,O
+localization,O
+of,O
+a,O
+sex,O
+-,O
+determining,O
+gene,O
+to,O
+the,O
+tip,O
+of,O
+the,O
+chromosome,O
+.,O
+ , 
+#11102997
+A,O
+de,O
+novo,O
+adrenoleukodystrophy,B-Gene
+gene,O
+(,B-Gene
+ABCD1,I-Gene
+),I-Gene
+mutation,O
+S636I,B-SNP
+without,O
+detectable,O
+ABCD1,B-Gene
+protein,O
+and,O
+a,O
+R104C,B-SNP
+mutation,O
+with,O
+normal,O
+amounts,O
+of,O
+protein,O
+from,O
+an,O
+Austrian,O
+patient,O
+collective,O
+.,O
+ , 
+#22703880
+Spinal,O
+muscular,O
+atrophy,O
+associated,O
+with,O
+progressive,O
+myoclonic,O
+epilepsy,O
+is,O
+caused,O
+by,O
+mutations,O
+in,O
+ASAH1,B-Gene
+.,I-Gene
+ , 
+Spinal,O
+muscular,O
+atrophy,O
+(,O
+SMA,O
+),O
+is,O
+a,O
+clinically,O
+and,O
+genetically,O
+heterogeneous,O
+disease,O
+characterized,O
+by,O
+the,O
+degeneration,O
+of,O
+lower,O
+motor,O
+neurons,O
+.,O
+ , 
+The,O
+most,O
+frequent,O
+form,O
+is,O
+linked,O
+to,O
+mutations,O
+in,O
+SMN1,B-Gene
+.,I-Gene
+ , 
+Childhood,O
+SMA,O
+associated,O
+with,O
+progressive,O
+myoclonic,O
+epilepsy,O
+(,O
+SMA,O
+-,O
+PME,O
+),O
+has,O
+been,O
+reported,O
+as,O
+a,O
+rare,O
+autosomal,O
+-,O
+recessive,O
+condition,O
+unlinked,O
+to,O
+mutations,O
+in,O
+SMN1,B-Gene
+.,I-Gene
+ , 
+Through,O
+linkage,O
+analysis,O
+,,O
+homozygosity,O
+mapping,O
+,,O
+and,O
+exome,O
+sequencing,O
+in,O
+three,O
+unrelated,O
+SMA,O
+-,O
+PME,O
+-,O
+affected,O
+families,O
+,,O
+we,O
+identified,O
+a,O
+homozygous,O
+missense,O
+mutation,O
+(,B-SNP
+c.125C,I-SNP
+>,I-SNP
+T,I-SNP
+ , 
+[,B-SNP
+p.,I-SNP
+Thr42Met,I-SNP
+],I-SNP
+),O
+in,O
+exon,O
+2,O
+of,O
+ASAH1,B-Gene
+in,O
+the,O
+affected,O
+children,O
+of,O
+two,O
+families,O
+and,O
+the,O
+same,O
+mutation,O
+associated,O
+with,O
+a,O
+deletion,O
+of,O
+the,O
+whole,O
+gene,O
+in,O
+the,O
+third,O
+family,O
+.,O
+ , 
+Expression,O
+studies,O
+of,O
+the,O
+c.125C,B-SNP
+>,I-SNP
+T,I-SNP
+mutant,O
+cDNA,O
+in,O
+Farber,O
+fibroblasts,O
+showed,O
+that,O
+acid,O
+-,O
+ceramidase,O
+activity,O
+was,O
+only,O
+32,O
+%,O
+of,O
+that,O
+generated,O
+by,O
+normal,O
+cDNA,O
+.,O
+ , 
+This,O
+reduced,O
+activity,O
+was,O
+able,O
+to,O
+normalize,O
+the,O
+ceramide,O
+level,O
+in,O
+Farber,O
+cells,O
+,,O
+raising,O
+the,O
+question,O
+of,O
+the,O
+pathogenic,O
+mechanism,O
+underlying,O
+the,O
+CNS,O
+involvement,O
+in,O
+deficient,O
+cells,O
+.,O
+ , 
+Morpholino,O
+knockdown,O
+of,O
+the,O
+ASAH1,B-Gene
+ortholog,O
+in,O
+zebrafish,O
+led,O
+to,O
+a,O
+marked,O
+loss,O
+of,O
+motor,O
+-,O
+neuron,O
+axonal,O
+branching,O
+,,O
+a,O
+loss,O
+that,O
+is,O
+associated,O
+with,O
+increased,O
+apoptosis,O
+in,O
+the,O
+spinal,O
+cord,O
+.,O
+ , 
+Our,O
+results,O
+reveal,O
+a,O
+wide,O
+phenotypic,O
+spectrum,O
+associated,O
+with,O
+ASAH1,B-Gene
+mutations,O
+.,O
+ , 
+An,O
+acid,O
+-,O
+ceramidase,O
+activity,O
+below,O
+10,O
+%,O
+results,O
+in,O
+Farber,O
+disease,O
+,,O
+an,O
+early,O
+-,O
+onset,O
+disease,O
+starting,O
+with,O
+subcutaneous,O
+lipogranulomata,O
+,,O
+joint,O
+pain,O
+,,O
+and,O
+hoarseness,O
+of,O
+the,O
+voice,O
+,,O
+whereas,O
+a,O
+higher,O
+residual,O
+activity,O
+might,O
+be,O
+responsible,O
+for,O
+SMA,O
+-,O
+PME,O
+,,O
+a,O
+later,O
+-,O
+onset,O
+phenotype,O
+restricted,O
+to,O
+the,O
+CNS,O
+and,O
+starting,O
+with,O
+lower,O
+-,O
+motor,O
+-,O
+neuron,O
+disease,O
+.,O
+ , 
+#10739770
+The,O
+gene,O
+for,O
+May,O
+-,O
+Hegglin,O
+anomaly,O
+localizes,O
+to,O
+a,O
+<,O
+1,O
+-,O
+Mb,O
+region,O
+on,O
+chromosome,O
+22q12.3,O
+-,O
+13.1,O
+.,O
+ , 
+The,O
+May,O
+-,O
+Hegglin,O
+anomaly,O
+(,O
+MHA,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+platelet,O
+disorder,O
+of,O
+unknown,O
+etiology,O
+.,O
+ , 
+It,O
+is,O
+characterized,O
+by,O
+thrombocytopenia,O
+,,O
+giant,O
+platelets,O
+,,O
+and,O
+leukocyte,O
+inclusion,O
+bodies,O
+,,O
+and,O
+affected,O
+heterozygotes,O
+are,O
+predisposed,O
+to,O
+bleeding,O
+episodes,O
+.,O
+ , 
+The,O
+MHA,B-Gene
+gene,O
+has,O
+recently,O
+been,O
+localized,O
+,,O
+by,O
+means,O
+of,O
+linkage,O
+analysis,O
+,,O
+to,O
+a,O
+13.6,O
+-,O
+cM,O
+region,O
+on,O
+chromosome,O
+22,O
+,,O
+and,O
+the,O
+complete,O
+chromosome,O
+22,O
+sequence,O
+has,O
+been,O
+reported,O
+.,O
+ , 
+We,O
+recently,O
+performed,O
+a,O
+genome,O
+scan,O
+for,O
+the,O
+MHA,B-Gene
+gene,O
+in,O
+29,O
+members,O
+of,O
+a,O
+large,O
+,,O
+multigenerational,O
+Italian,O
+family,O
+,,O
+and,O
+we,O
+now,O
+confirm,O
+that,O
+the,O
+MHA,B-Gene
+locus,O
+is,O
+on,O
+chromosome,O
+22q12,O
+.,O
+ , 
+3,O
+-,O
+13.1,O
+.,O
+ , 
+The,O
+maximal,O
+two,O
+-,O
+point,O
+LOD,O
+score,O
+of,O
+4.50,O
+was,O
+achieved,O
+with,O
+the,O
+use,O
+of,O
+marker,O
+D22S283,O
+,,O
+at,O
+a,O
+recombination,O
+fraction,O
+of.05,O
+.,O
+ , 
+Haplotype,O
+analysis,O
+narrowed,O
+the,O
+MHA,B-Gene
+critical,O
+region,O
+to,O
+6.6,O
+cM,O
+between,O
+markers,O
+D22S683,O
+and,O
+D22S1177,O
+.,O
+ , 
+It,O
+is,O
+of,O
+note,O
+that,O
+the,O
+chromosome,O
+22,O
+sequence,O
+allowed,O
+all,O
+markers,O
+to,O
+be,O
+ordered,O
+correctly,O
+,,O
+identified,O
+all,O
+the,O
+candidate,O
+genes,O
+and,O
+predicted,O
+genes,O
+,,O
+and,O
+specifically,O
+determined,O
+the,O
+physical,O
+size,O
+of,O
+the,O
+MHA,B-Gene
+region,O
+to,O
+be,O
+0,O
+.,O
+ , 
+7,O
+ , 
+Mb,O
+.,O
+ , 
+These,O
+results,O
+significantly,O
+narrow,O
+the,O
+region,O
+in,O
+which,O
+the,O
+MHA,B-Gene
+gene,O
+is,O
+located,O
+,,O
+and,O
+they,O
+represent,O
+the,O
+first,O
+use,O
+of,O
+chromosome,O
+22,O
+data,O
+to,O
+positionally,O
+clone,O
+a,O
+disease,O
+gene,O
+.,O
+ , 
+#19375058
+A,O
+nonsense,O
+mutation,O
+in,O
+COQ9,B-Gene
+causes,O
+autosomal,O
+-,O
+recessive,O
+neonatal,O
+-,O
+onset,O
+primary,O
+coenzyme,O
+Q10,O
+deficiency,O
+:,O
+a,O
+potentially,O
+treatable,O
+form,O
+of,O
+mitochondrial,O
+disease,O
+.,O
+ , 
+Coenzyme,O
+Q(10,O
+),O
+is,O
+a,O
+mobile,O
+lipophilic,O
+electron,O
+carrier,O
+located,O
+in,O
+the,O
+inner,O
+mitochondrial,O
+membrane,O
+.,O
+ , 
+Defects,O
+of,O
+coenzyme,O
+Q(10,O
+),O
+biosynthesis,O
+represent,O
+one,O
+of,O
+the,O
+few,O
+treatable,O
+mitochondrial,O
+diseases,O
+.,O
+ , 
+We,O
+genotyped,O
+a,O
+patient,O
+with,O
+primary,O
+coenzyme,O
+Q(10,O
+),O
+deficiency,O
+who,O
+presented,O
+with,O
+neonatal,O
+lactic,O
+acidosis,O
+and,O
+later,O
+developed,O
+multisytem,O
+disease,O
+including,O
+intractable,O
+seizures,O
+,,O
+global,O
+developmental,O
+delay,O
+,,O
+hypertrophic,O
+cardiomyopathy,O
+,,O
+and,O
+renal,O
+tubular,O
+dysfunction,O
+.,O
+ , 
+Cultured,O
+skin,O
+fibroblasts,O
+from,O
+the,O
+patient,O
+had,O
+a,O
+coenzyme,O
+Q(10,O
+),O
+biosynthetic,O
+rate,O
+of,O
+11,O
+%,O
+of,O
+normal,O
+controls,O
+and,O
+accumulated,O
+an,O
+abnormal,O
+metabolite,O
+that,O
+we,O
+believe,O
+to,O
+be,O
+a,O
+biosynthetic,O
+intermediate,O
+.,O
+ , 
+In,O
+view,O
+of,O
+the,O
+rarity,O
+of,O
+coenzyme,O
+Q(10,O
+),O
+deficiency,O
+,,O
+we,O
+hypothesized,O
+that,O
+the,O
+disease,O
+-,O
+causing,O
+gene,O
+might,O
+lie,O
+in,O
+a,O
+region,O
+of,O
+ancestral,O
+homozygosity,O
+by,O
+descent,O
+.,O
+ , 
+Data,O
+from,O
+an,O
+Illumina,O
+HumanHap550,O
+array,O
+were,O
+analyzed,O
+with,O
+BeadStudio,O
+software,O
+.,O
+ , 
+Sixteen,O
+regions,O
+of,O
+homozygosity,O
+>,O
+1.5,O
+Mb,O
+were,O
+identified,O
+in,O
+the,O
+affected,O
+infant,O
+.,O
+ , 
+Two,O
+of,O
+these,O
+regions,O
+included,O
+the,O
+loci,O
+of,O
+two,O
+of,O
+16,O
+candidate,O
+genes,O
+implicated,O
+in,O
+human,O
+coenzyme,O
+Q(10,O
+),O
+biosynthesis,O
+.,O
+ , 
+Sequence,O
+analysis,O
+demonstrated,O
+a,O
+homozygous,O
+stop,O
+mutation,O
+affecting,O
+a,O
+highly,O
+conserved,O
+residue,O
+of,O
+COQ9,B-Gene
+,,I-Gene
+leading,O
+to,O
+the,O
+truncation,O
+of,O
+75,O
+amino,O
+acids,O
+.,O
+ , 
+Site,O
+-,O
+directed,O
+mutagenesis,O
+targeting,O
+the,O
+equivalent,O
+residue,O
+in,O
+the,O
+yeast,O
+Saccharomyces,O
+cerevisiae,O
+abolished,O
+respiratory,O
+growth,O
+.,O
+ , 
+#21549336
+Nonsense,O
+mutations,O
+in,O
+SMPX,B-Gene
+,,I-Gene
+encoding,O
+a,O
+protein,O
+responsive,O
+to,O
+physical,O
+force,O
+,,O
+result,O
+in,O
+X,O
+-,O
+chromosomal,O
+hearing,O
+loss,O
+.,O
+ , 
+The,O
+fact,O
+that,O
+hereditary,O
+hearing,O
+loss,O
+is,O
+the,O
+most,O
+common,O
+sensory,O
+disorder,O
+in,O
+humans,O
+is,O
+reflected,O
+by,O
+,,O
+among,O
+other,O
+things,O
+,,O
+an,O
+extraordinary,O
+allelic,O
+and,O
+nonallelic,O
+genetic,O
+heterogeneity,O
+.,O
+ , 
+X,O
+-,O
+chromosomal,O
+hearing,O
+impairment,O
+represents,O
+only,O
+a,O
+minor,O
+fraction,O
+of,O
+all,O
+cases,O
+.,O
+ , 
+In,O
+a,O
+study,O
+of,O
+a,O
+Spanish,O
+family,O
+the,O
+locus,O
+for,O
+one,O
+of,O
+the,O
+X,O
+-,O
+chromosomal,O
+forms,O
+was,O
+assigned,O
+to,O
+Xp22,O
+(,B-Gene
+DFNX4,I-Gene
+),I-Gene
+.,O
+ , 
+We,O
+mapped,O
+the,O
+disease,O
+locus,O
+in,O
+the,O
+same,O
+chromosomal,O
+region,O
+in,O
+a,O
+large,O
+German,O
+pedigree,O
+with,O
+X,O
+-,O
+chromosomal,O
+nonsyndromic,O
+hearing,O
+impairment,O
+by,O
+using,O
+genome,O
+-,O
+wide,O
+linkage,O
+analysis,O
+.,O
+ , 
+Males,O
+presented,O
+with,O
+postlingual,O
+hearing,O
+loss,O
+and,O
+onset,O
+at,O
+ages,O
+3,O
+-,O
+7,O
+,,O
+whereas,O
+onset,O
+in,O
+female,O
+carriers,O
+was,O
+in,O
+the,O
+second,O
+to,O
+third,O
+decades,O
+.,O
+ , 
+Targeted,O
+DNA,O
+capture,O
+with,O
+high,O
+-,O
+throughput,O
+sequencing,O
+detected,O
+a,O
+nonsense,O
+mutation,O
+in,O
+the,O
+small,O
+muscle,O
+protein,O
+,,O
+X,O
+-,O
+linked,O
+(,B-Gene
+SMPX,I-Gene
+),I-Gene
+of,O
+affected,O
+individuals,O
+.,O
+ , 
+We,O
+identified,O
+another,O
+nonsense,O
+mutation,O
+in,O
+SMPX,B-Gene
+in,O
+patients,O
+from,O
+the,O
+Spanish,O
+family,O
+who,O
+were,O
+previously,O
+analyzed,O
+to,O
+map,O
+DFNX4,B-Gene
+.,I-Gene
+ , 
+SMPX,B-Gene
+encodes,O
+an,O
+88,O
+amino,O
+acid,O
+,,O
+cytoskeleton,O
+-,O
+associated,O
+protein,O
+that,O
+is,O
+responsive,O
+to,O
+mechanical,O
+stress,O
+.,O
+ , 
+The,O
+presence,O
+of,O
+Smpx,B-Gene
+in,O
+hair,O
+cells,O
+and,O
+supporting,O
+cells,O
+of,O
+the,O
+murine,O
+cochlea,O
+indicates,O
+its,O
+role,O
+in,O
+the,O
+inner,O
+ear,O
+.,O
+ , 
+The,O
+nonsense,O
+mutations,O
+detected,O
+in,O
+the,O
+two,O
+families,O
+suggest,O
+a,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mechanism,O
+underlying,O
+this,O
+form,O
+of,O
+hearing,O
+impairment,O
+.,O
+ , 
+Results,O
+obtained,O
+after,O
+heterologous,O
+overexpression,O
+of,O
+SMPX,B-Gene
+proteins,O
+were,O
+compatible,O
+with,O
+this,O
+assumption,O
+.,O
+ , 
+Because,O
+responsivity,O
+to,O
+physical,O
+force,O
+is,O
+a,O
+characteristic,O
+feature,O
+of,O
+the,O
+protein,O
+,,O
+we,O
+propose,O
+that,O
+long,O
+-,O
+term,O
+maintenance,O
+of,O
+mechanically,O
+stressed,O
+inner,O
+-,O
+ear,O
+cells,O
+critically,O
+depends,O
+on,O
+SMPX,B-Gene
+function,O
+.,O
+ , 
+#8401541
+Two,O
+new,O
+mutations,O
+at,O
+the,O
+adenosine,B-Gene
+deaminase,I-Gene
+(,B-Gene
+ADA,I-Gene
+),I-Gene
+locus,O
+(,B-SNP
+Q254X,I-SNP
+and,O
+del,B-SNP
+nt1050,I-SNP
+-,I-SNP
+54,I-SNP
+),I-SNP
+unusual,O
+for,O
+not,O
+being,O
+missense,O
+mutations,O
+.,O
+ , 
+#1346075
+Mechanisms,O
+of,O
+ring,O
+chromosome,O
+formation,O
+in,O
+11,O
+cases,O
+of,O
+human,O
+ring,O
+chromosome,O
+21,O
+.,O
+ , 
+We,O
+studied,O
+the,O
+mechanism,O
+of,O
+ring,O
+chromosome,O
+21,O
+(,O
+r(21,O
+),O
+),O
+formation,O
+in,O
+13,O
+patients,O
+(,O
+11,O
+unique,O
+r(21)s,O
+),O
+,,O
+consisting,O
+of,O
+7,O
+from,O
+five,O
+families,O
+with,O
+familial,O
+r(21,O
+),O
+and,O
+6,O
+with,O
+de,O
+novo,O
+r(21,O
+),O
+.,O
+ , 
+The,O
+copy,O
+number,O
+of,O
+chromosome,O
+21,O
+sequences,O
+in,O
+the,O
+rings,O
+of,O
+these,O
+patients,O
+was,O
+determined,O
+by,O
+quantitative,O
+dosage,O
+analyses,O
+for,O
+13,O
+loci,O
+on,O
+21q,O
+.,O
+ , 
+Nine,O
+of,O
+11,O
+r(21)s,O
+,,O
+including,O
+the,O
+5,O
+familial,O
+r(21)s,O
+,,O
+showed,O
+no,O
+evidence,O
+for,O
+duplication,O
+of,O
+21q,O
+sequences,O
+but,O
+did,O
+show,O
+molecular,O
+evidence,O
+of,O
+partial,O
+deletion,O
+of,O
+21q,O
+.,O
+ , 
+These,O
+data,O
+were,O
+consistent,O
+with,O
+the,O
+breakage,O
+and,O
+reunion,O
+of,O
+short-,O
+and,O
+long,O
+-,O
+arm,O
+regions,O
+to,O
+form,O
+the,O
+r(21,O
+),O
+,,O
+resulting,O
+in,O
+deletion,O
+of,O
+varying,O
+amounts,O
+of,O
+21q22.1,O
+to,O
+21qter,O
+.,O
+ , 
+The,O
+data,O
+from,O
+one,O
+individual,O
+who,O
+had,O
+a,O
+Down,O
+syndrome,O
+phenotype,O
+were,O
+consistent,O
+with,O
+asymmetric,O
+breakage,O
+and,O
+reunion,O
+of,O
+21q,O
+sequences,O
+from,O
+an,O
+intermediate,O
+isochromosome,O
+or,O
+Robertsonian,O
+translocation,O
+chromosome,O
+as,O
+reported,O
+by,O
+Wong,O
+et,O
+al,O
+.,O
+ , 
+Another,O
+patient,O
+,,O
+who,O
+also,O
+exhibited,O
+Down,O
+syndrome,O
+,,O
+showed,O
+evidence,O
+of,O
+a,O
+third,O
+mechanism,O
+of,O
+ring,O
+formation,O
+.,O
+ , 
+The,O
+likely,O
+initial,O
+event,O
+was,O
+breakage,O
+and,O
+reunion,O
+of,O
+the,O
+short,O
+and,O
+long,O
+arms,O
+,,O
+resulting,O
+in,O
+a,O
+small,O
+r(21,O
+),O
+,,O
+followed,O
+by,O
+a,O
+sister,O
+-,O
+chromatid,O
+exchange,O
+resulting,O
+in,O
+a,O
+double,O
+-,O
+sized,O
+and,O
+symmetrically,O
+dicentric,O
+r(21,O
+),O
+.,O
+ , 
+The,O
+phenotype,O
+of,O
+patients,O
+correlated,O
+well,O
+with,O
+the,O
+extent,O
+of,O
+deletion,O
+or,O
+duplication,O
+of,O
+chromosome,O
+21,O
+sequences,O
+.,O
+ , 
+These,O
+data,O
+demonstrate,O
+three,O
+mechanisms,O
+of,O
+r(21,O
+),O
+formation,O
+and,O
+show,O
+that,O
+the,O
+phenotype,O
+of,O
+r(21,O
+),O
+patients,O
+varies,O
+with,O
+the,O
+extent,O
+of,O
+chromosome,O
+21,O
+monosomy,O
+or,O
+trisomy,O
+.,O
+ , 
+#11410843
+The,O
+presence,O
+of,O
+mitochondrial,O
+haplogroup,O
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+from,O
+South,O
+Siberia,O
+.,O
+ , 
+#10533067
+Analysis,O
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+TSC1,B-Gene
+and,O
+TSC2,B-Gene
+for,O
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+in,O
+126,O
+unrelated,O
+patients,O
+with,O
+tuberous,O
+sclerosis,O
+.,O
+ , 
+Tuberous,O
+sclerosis,O
+complex,O
+(,O
+TSC,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+disorder,O
+characterized,O
+by,O
+the,O
+development,O
+of,O
+multiple,O
+hamartomas,O
+involving,O
+many,O
+organs,O
+.,O
+ , 
+About,O
+two,O
+-,O
+thirds,O
+of,O
+the,O
+cases,O
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+sporadic,O
+and,O
+appear,O
+to,O
+represent,O
+new,O
+mutations,O
+.,O
+ , 
+With,O
+the,O
+cloning,O
+of,O
+two,O
+causative,O
+genes,O
+,,O
+TSC1,B-Gene
+and,O
+TSC2,B-Gene
+it,O
+is,O
+now,O
+possible,O
+to,O
+analyze,O
+both,O
+genes,O
+in,O
+TSC,O
+patients,O
+and,O
+identify,O
+germline,O
+mutations,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+the,O
+mutational,O
+analysis,O
+of,O
+the,O
+entire,O
+coding,O
+region,O
+of,O
+both,O
+TSC1,B-Gene
+and,O
+TSC2,B-Gene
+genes,O
+in,O
+126,O
+unrelated,O
+TSC,O
+patients,O
+,,O
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+40,O
+familial,O
+and,O
+86,O
+sporadic,O
+cases,O
+,,O
+by,O
+single,O
+-,O
+stranded,O
+conformational,O
+polymorphism,O
+(,O
+SSCP,O
+),O
+analysis,O
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+.,O
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+Mutations,O
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+a,O
+total,O
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+74,O
+(,O
+59,O
+%,O
+),O
+cases,O
+,,O
+including,O
+16,O
+TSC1,B-Gene
+mutations,O
+(,O
+5,O
+sporadic,O
+and,O
+11,O
+familial,O
+cases,O
+),O
+and,O
+58,O
+TSC2,B-Gene
+mutations,O
+(,O
+42,O
+sporadic,O
+and,O
+16,O
+familial,O
+cases,O
+),O
+.,O
+ , 
+Overall,O
+,,O
+significantly,O
+more,O
+TSC2,B-Gene
+mutations,O
+were,O
+found,O
+in,O
+our,O
+population,O
+,,O
+with,O
+a,O
+relatively,O
+equal,O
+distribution,O
+of,O
+mutations,O
+between,O
+TSC1,B-Gene
+and,O
+TSC2,B-Gene
+among,O
+the,O
+familial,O
+cases,O
+,,O
+but,O
+a,O
+marked,O
+underrepresentation,O
+of,O
+TSC1,B-Gene
+mutations,O
+among,O
+the,O
+sporadic,O
+cases,O
+(,O
+P,O
+=,O
+0.0035,O
+,,O
+Fisher,O
+'s,O
+exact,O
+test,O
+),O
+.,O
+ , 
+All,O
+TSC1,B-Gene
+mutations,O
+were,O
+predicted,O
+to,O
+be,O
+protein,O
+truncating,O
+.,O
+ , 
+However,O
+,,O
+in,O
+TSC2,B-Gene
+13,O
+missense,O
+mutations,O
+were,O
+found,O
+,,O
+five,O
+clustering,O
+in,O
+the,O
+GAP,O
+-,O
+related,O
+domain,O
+and,O
+three,O
+others,O
+occurring,O
+in,O
+exon,O
+16,O
+.,O
+ , 
+Upon,O
+comparison,O
+of,O
+clinical,O
+manifestations,O
+,,O
+including,O
+the,O
+incidence,O
+of,O
+intellectual,O
+disability,O
+,,O
+we,O
+could,O
+not,O
+find,O
+any,O
+observable,O
+differences,O
+between,O
+TSC1,B-Gene
+and,O
+TSC2,B-Gene
+patients,O
+.,O
+ , 
+Our,O
+data,O
+help,O
+define,O
+the,O
+distribution,O
+and,O
+spectrum,O
+of,O
+mutations,O
+associated,O
+with,O
+the,O
+TSC,B-Gene
+loci,O
+and,O
+will,O
+be,O
+useful,O
+for,O
+both,O
+understanding,O
+the,O
+function,O
+of,O
+these,O
+genes,O
+as,O
+well,O
+as,O
+genetic,O
+counseling,O
+in,O
+patients,O
+with,O
+the,O
+disease,O
+.,O
+ , 
+#8257990
+Base,O
+substitutions,O
+in,O
+the,O
+human,O
+dystrophin,O
+gene,O
+:,O
+detection,O
+by,O
+using,O
+the,O
+single,O
+-,O
+strand,O
+conformation,O
+polymorphism,O
+(,O
+SSCP,O
+),O
+technique,O
+.,O
+ , 
+We,O
+have,O
+established,O
+the,O
+experimental,O
+conditions,O
+to,O
+screen,O
+twenty,O
+regions,O
+of,O
+the,O
+dystrophin,O
+gene,O
+using,O
+the,O
+method,O
+of,O
+single,O
+-,O
+strand,O
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+(,O
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+),O
+analysis,O
+.,O
+ , 
+The,O
+aim,O
+of,O
+this,O
+study,O
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+to,O
+identify,O
+point,O
+mutations,O
+in,O
+patients,O
+with,O
+Duchenne,O
+or,O
+Becker,O
+muscular,O
+dystrophy,O
+(,O
+DMD,O
+or,O
+BMD,O
+),O
+who,O
+have,O
+no,O
+gross,O
+DNA,O
+rearrangements,O
+detectable,O
+by,O
+Southern,O
+blot,O
+analysis,O
+or,O
+multiplex,O
+exon,O
+amplification,O
+.,O
+ , 
+The,O
+investigation,O
+of,O
+thirteen,O
+patients,O
+using,O
+this,O
+procedure,O
+resulted,O
+in,O
+the,O
+detection,O
+of,O
+seven,O
+sequence,O
+polymorphisms,O
+(,O
+four,O
+identified,O
+in,O
+this,O
+study,O
+),O
+that,O
+will,O
+be,O
+useful,O
+allelic,O
+markers,O
+in,O
+familial,O
+DNA,O
+analysis,O
+.,O
+ , 
+Three,O
+rare,O
+sequence,O
+variants,O
+could,O
+be,O
+found,O
+(,O
+two,O
+of,O
+them,O
+being,O
+novel,O
+variants,O
+),O
+but,O
+we,O
+were,O
+unable,O
+to,O
+demonstrate,O
+mutations,O
+that,O
+could,O
+be,O
+clearly,O
+sufficient,O
+to,O
+be,O
+responsible,O
+for,O
+the,O
+phenotype,O
+.,O
+ , 
+This,O
+analysis,O
+confirmed,O
+the,O
+efficiency,O
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+the,O
+SSCP,O
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+for,O
+the,O
+detection,O
+of,O
+nucleotide,O
+substitutions,O
+.,O
+ , 
+Application,O
+of,O
+this,O
+approach,O
+to,O
+mutation,O
+or,O
+polymorphism,O
+detection,O
+to,O
+other,O
+exons,O
+of,O
+the,O
+gene,O
+will,O
+improve,O
+carrier,O
+and,O
+prenatal,O
+diagnosis,O
+.,O
+ , 
+#18449911
+Evaluation,O
+of,O
+in,O
+silico,O
+splice,O
+tools,O
+for,O
+decision,O
+-,O
+making,O
+in,O
+molecular,O
+diagnosis,O
+.,O
+ , 
+It,O
+appears,O
+that,O
+all,O
+types,O
+of,O
+genomic,O
+nucleotide,O
+variations,O
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+be,O
+deleterious,O
+by,O
+affecting,O
+normal,O
+pre,O
+-,O
+mRNA,O
+splicing,O
+via,O
+disruption,O
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+splice,O
+site,O
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+sequences,O
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+As,O
+it,O
+is,O
+neither,O
+pertinent,O
+nor,O
+realistic,O
+to,O
+perform,O
+functional,O
+testing,O
+for,O
+all,O
+of,O
+these,O
+variants,O
+,,O
+it,O
+is,O
+important,O
+to,O
+identify,O
+those,O
+that,O
+could,O
+lead,O
+to,O
+a,O
+splice,O
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+in,O
+order,O
+to,O
+restrict,O
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+the,O
+most,O
+appropriate,O
+cases,O
+.,O
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+Web,O
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+tools,O
+designed,O
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+such,O
+predictions,O
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+We,O
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+tools,O
+(,O
+Splice,O
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+Prediction,O
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+Neural,O
+Network,O
+[,O
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+[,O
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+Automated,O
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+Analyses,O
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+[,O
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+Splicing,O
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+Relative,O
+Enhancer,O
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+Silencer,O
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+Enrichment,O
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+different,O
+RB1,O
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+(,O
+31,O
+intronic,O
+and,O
+eight,O
+exonic,O
+),O
+.,O
+ , 
+These,O
+39,O
+patients,O
+were,O
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+for,O
+abnormal,O
+splicing,O
+using,O
+puromycin,O
+-,O
+treated,O
+cell,O
+lines,O
+and,O
+the,O
+results,O
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+the,O
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+As,O
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+AG,O
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+A,O
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+(,O
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+19,O
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+Overall,O
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+results,O
+suggest,O
+that,O
+a,O
+combination,O
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+complementary,O
+in,O
+silico,O
+tools,O
+is,O
+necessary,O
+to,O
+guide,O
+molecular,O
+geneticists,O
+(,O
+balance,O
+between,O
+the,O
+time,O
+and,O
+cost,O
+required,O
+by,O
+RNA,O
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+the,O
+risk,O
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+a,O
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+silico,O
+tool,O
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+tool,O
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+#8981969
+Prevalence,O
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+parental,O
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+novo,O
+RET,B-Gene
+mutations,O
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+multiple,O
+endocrine,O
+neoplasia,O
+type,O
+2A,O
+and,O
+familial,O
+medullary,O
+thyroid,O
+carcinoma,O
+.,O
+ , 
+Le,O
+Groupe,O
+d'Etude,O
+des,O
+Tumeurs,O
+a,O
+Calcitonine,O
+.,O
+ , 
+#10408782
+Molecular,O
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+phenylalanine,O
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+in,O
+Chile,O
+.,O
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+Mutations,O
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+brief,O
+no,O
+.,O
+243,O
+.,O
+ , 
+Online,O
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+ , 
+Both,O
+the,O
+haplotype,O
+distribution,O
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+the,O
+mutational,O
+spectrum,O
+of,O
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+phenylalanine,B-Gene
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+PAH,I-Gene
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+),O
+population,O
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+Mutation,O
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+was,O
+performed,O
+using,O
+a,O
+combined,O
+approach,O
+of,O
+screening,O
+for,O
+common,O
+European,O
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+Oriental,O
+mutations,O
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+application,O
+of,O
+the,O
+DGGE,O
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+in,O
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+uncharacterized,O
+alleles,O
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+A,O
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+16,O
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+two,O
+novel,O
+ones,O
+,,O
+Q232X,B-SNP
+and,O
+IVS11nt5,B-SNP
+.,I-SNP
+ , 
+The,O
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+mutations,O
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+IVS10nt-11,B-SNP
+and,O
+V388,B-SNP
+M,I-SNP
+present,O
+both,O
+in,O
+the,O
+13,O
+%,O
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+the,O
+mutant,O
+chromosomes,O
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+The,O
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+mutations,O
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+.,O
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+The,O
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+including,O
+VNTR,O
+and,O
+STR,O
+alleles,O
+,,O
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+examined,O
+to,O
+investigated,O
+the,O
+origin,O
+and,O
+distribution,O
+of,O
+PAH,O
+alleles,O
+in,O
+Chile,O
+.,O
+ , 
+Our,O
+results,O
+are,O
+consistent,O
+with,O
+Southern,O
+Europeans,O
+as,O
+the,O
+major,O
+source,O
+of,O
+PAH,O
+mutations,O
+in,O
+Latin,O
+America,O
+.,O
+ , 
+However,O
+,,O
+we,O
+have,O
+also,O
+detected,O
+mutations,O
+from,O
+East,O
+and,O
+Central,O
+Europe,O
+,,O
+such,O
+IVS12nt1,B-SNP
+,,I-SNP
+R408W,B-SNP
+and,O
+R252W.,B-SNP
+ , 
+It,O
+is,O
+clear,O
+that,O
+the,O
+PKU,O
+mutation,O
+present,O
+in,O
+each,O
+Latin,O
+American,O
+country,O
+varies,O
+with,O
+the,O
+demographic,O
+profile,O
+and,O
+specific,O
+mutation,O
+scanning,O
+is,O
+necessary,O
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+each,O
+population,O
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+diagnostic,O
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+prognostic,O
+purposes,O
+.,O
+ , 
+The,O
+correlation,O
+between,O
+the,O
+genotypes,O
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+the,O
+phenotypes,O
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+consistent,O
+with,O
+the,O
+emerging,O
+pattern,O
+of,O
+mutation,O
+severity,O
+deduced,O
+from,O
+previous,O
+studies,O
+in,O
+related,O
+populations,O
+.,O
+ , 
+#17668385
+Mutations,O
+in,O
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+BRWD3,B-Gene
+gene,O
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+with,O
+macrocephaly,O
+.,O
+ , 
+In,O
+the,O
+course,O
+of,O
+systematic,O
+screening,O
+of,O
+the,O
+X,O
+-,O
+chromosome,O
+coding,O
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+250,O
+families,O
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+nonsyndromic,O
+X,O
+-,O
+linked,O
+mental,O
+retardation,O
+(,O
+XLMR,O
+),O
+,,O
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+families,O
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+identified,O
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+truncating,O
+mutations,O
+in,O
+BRWD3,B-Gene
+,,I-Gene
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+a,O
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+domain,O
+-,O
+containing,O
+protein,O
+.,O
+ , 
+In,O
+both,O
+families,O
+,,O
+the,O
+mutation,O
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+the,O
+phenotype,O
+in,O
+affected,O
+males,O
+.,O
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+Affected,O
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+have,O
+macrocephaly,O
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+a,O
+prominent,O
+forehead,O
+,,O
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+cupped,O
+ears,O
+,,O
+and,O
+mild,O
+-,O
+to,O
+-,O
+moderate,O
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+disability,O
+.,O
+ , 
+No,O
+truncating,O
+variants,O
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+520,O
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+BRWD3,B-Gene
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+macrocephaly,O
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+may,O
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+disease,O
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+#21194677
+Identification,O
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+PDHX,B-Gene
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+Systemic,O
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+We,O
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+to,O
+replicate,O
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+putative,O
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+at,O
+11p13,O
+not,O
+yet,O
+exceeding,O
+genome,O
+-,O
+wide,O
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+5,O
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+10(-8,O
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+controls,O
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+Asian,O
+origin,O
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+We,O
+observed,O
+robust,O
+association,O
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+both,O
+rs2732552,O
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+0.83,O
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+and,O
+rs387619,O
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+7.7,O
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+10(-7,O
+),O
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+),O
+in,O
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+European,O
+samples,O
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+1.82,O
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+0.81,O
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+and,O
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+0.80,O
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+A,O
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+This,O
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+#14722921
+Context,O
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+their,O
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+data,O
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+human,O
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+that,O
+cause,O
+mendelian,O
+diseases,O
+.,O
+ , 
+We,O
+confirm,O
+that,O
+periodic,O
+sequences,O
+consisting,O
+of,O
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+Mutability,O
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+three,O
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+.,O
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+In,O
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+detected,O
+for,O
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+,,O
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+purine,O
+-,O
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+in,O
+our,O
+sample,O
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+many,O
+others,O
+are,O
+not,O
+mutagenic,O
+.,O
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+Data,O
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+hot,O
+spots,O
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+deletion,O
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+Comprehensive,O
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+of,O
+lengths,O
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+eight,O
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+YYYTG,O
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+sequences,O
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+by,O
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+hot,O
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+Possible,O
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+(,O
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+identified,O
+.,O
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+Two,O
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+thirds,O
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+,,O
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+80,O
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+a,O
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+#12325018
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+integrated,O
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+site,O
+-,O
+directed,O
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+in,O
+transcription,O
+factor,O
+binding,O
+sites,O
+.,O
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+Since,O
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+draft,O
+,,O
+single,O
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+(,O
+SNP,O
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+one,O
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+We,O
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+integrated,O
+database,O
+-,O
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+By,O
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+input,O
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+in,O
+DNA,O
+binding,O
+to,O
+the,O
+unknown,O
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+.,O
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+Our,O
+system,O
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+,,O
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+well,O
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+site,O
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+data,O
+.,O
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+Experimental,O
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+rSNP_Guide,O
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+on,O
+functionally,O
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+human,O
+TDO2and,B-Gene
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+Additional,O
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+analysis,O
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+gammaA,B-Gene
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+#16380905
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+440,O
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+64,O
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+Bipolar,O
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+genetic,O
+evidence,O
+,,O
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+No,O
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+Genetic,O
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+We,O
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+genomewide,O
+association,O
+studies,O
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+single,O
+-,O
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+SNP,O
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+64,O
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+genes,O
+(,O
+440,O
+SNPs,O
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+the,O
+basis,O
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+linkage,O
+or,O
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+biological,O
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+We,O
+genotyped,O
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+of,O
+6.9,O
+SNPs,O
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+gene,O
+,,O
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+density,O
+of,O
+1,O
+SNP,O
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+11.9,O
+kb,O
+in,O
+323,O
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+I,O
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+274,O
+schizophrenia,O
+or,O
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+trios,O
+.,O
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+Using,O
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+SNP,O
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+based,O
+transmission,O
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+disequilibrium,O
+tests,O
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+on,O
+the,O
+basis,O
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+association,O
+(,O
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+Six,O
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+(,B-Gene
+DAO,I-Gene
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+DAO,B-Gene
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+associated,O
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+Six,O
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+(,B-Gene
+RGS4,I-Gene
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+schizoaffective,O
+disorder,O
+;,O
+five,O
+replicate,O
+previous,O
+associations,O
+,,O
+and,O
+one,O
+,,O
+GRID1,B-Gene
+,,I-Gene
+shows,O
+a,O
+novel,O
+association,O
+with,O
+schizophrenia,O
+.,O
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+In,O
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+,,O
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+(,B-Gene
+DPYSL2,I-Gene
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+DTNBP1,B-Gene
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+These,O
+results,O
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+to,O
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+ , 
+They,O
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+these,O
+two,O
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+involve,O
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+-,O
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+pathways,O
+.,O
+ , 
+#14691730
+The,O
+PARK8,B-Gene
+locus,O
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+further,O
+delineation,O
+of,O
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+disease,O
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+Recently,O
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+PARK8,I-Gene
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+Linkage,O
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+linkage,O
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+region,O
+.,O
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+Criteria,O
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+least,O
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+one,O
+generation,O
+.,O
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+A,O
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+29,O
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+candidate,O
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+.,O
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+One,O
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+Under,O
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+only,O
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+,,O
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+total,O
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+,,O
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+estimated,O
+proportion,O
+of,O
+families,O
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+linkage,O
+of,O
+0.32,O
+.,O
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+This,O
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+.,O
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+Two,O
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+linkage,O
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+,,O
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+multipoint,O
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+an,O
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+-,O
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+1.67,O
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+),O
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+When,O
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+-,O
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+calculated,O
+,,O
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+combined,O
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+3.92,O
+(,O
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+A,O
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+LOD,O
+score,O
+1.68,O
+,,O
+P=.0027,O
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+On,O
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+basis,O
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+D,O
+,,O
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+1,O
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+clone,O
+AC025253,O
+(,O
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+Our,O
+data,O
+provide,O
+evidence,O
+that,O
+the,O
+PARK8,B-Gene
+locus,O
+is,O
+responsible,O
+for,O
+the,O
+disease,O
+in,O
+a,O
+subset,O
+of,O
+families,O
+of,O
+white,O
+ancestry,O
+with,O
+autosomal,O
+dominant,O
+parkinsonism,O
+,,O
+suggesting,O
+that,O
+it,O
+could,O
+be,O
+a,O
+more,O
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+locus,O
+.,O
+ , 
+#18179903
+Mutation,O
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+CHRNA1,B-Gene
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+,,I-Gene
+and,O
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+fetal,O
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+.,O
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+Multiple,O
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+(,O
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+),O
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+Previously,O
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+recessive,O
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+embryonal,B-Gene
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+,,O
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+that,O
+pterygia,O
+resulted,O
+from,O
+fetal,O
+akinesia,O
+.,O
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+We,O
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+that,O
+mutations,O
+in,O
+acetylcholine,O
+receptor,O
+-,O
+related,O
+genes,O
+might,O
+also,O
+result,O
+in,O
+a,O
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+phenotype,O
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+so,O
+we,O
+analyzed,O
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+CHRNG,B-Gene
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+CHRNA1,B-Gene
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+CHRNA1,B-Gene
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+,,O
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+RAPSN,B-Gene
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+c.1177,B-SNP
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+1178delAA,I-SNP
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+was,O
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+in,O
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+family,O
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+three,O
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+lethal,O
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+sequence,O
+.,O
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+Previously,O
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+the,O
+hypothesis,O
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+rapsyn,O
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+myasthenia,O
+,,O
+more,O
+severe,O
+loss,O
+of,O
+function,O
+can,O
+result,O
+in,O
+a,O
+lethal,O
+fetal,O
+akinesia,O
+phenotype,O
+.,O
+ , 
+#17999359
+RAD51,B-Gene
+135G-->C,B-SNP
+modifies,O
+breast,O
+cancer,O
+risk,O
+among,O
+BRCA2,B-Gene
+mutation,O
+carriers,O
+:,O
+results,O
+from,O
+a,O
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+of,O
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+.,O
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+RAD51,B-Gene
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+-,O
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+BRCA1,B-Gene
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+A,O
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+5,O
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+We,O
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+8,512,O
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+RAD51,B-Gene
+135G-->C,B-SNP
+SNP,O
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+We,O
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+evidence,O
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+(,O
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+BRCA2,B-Gene
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+In,O
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+135G-->C,B-SNP
+variant,O
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+RAD51,B-Gene
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+5,O
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+Thus,O
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+RAD51,B-Gene
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+#8651297
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+Patient,O
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+termination,O
+.,O
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+His,O
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+health,O
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+despite,O
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+GK,B-Gene
+activity,O
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+Patient,O
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+GK,B-Gene
+deficiency,O
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+a,O
+severe,O
+phenotype,O
+involving,O
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+retardation,O
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+growth,O
+delay,O
+,,O
+bone,O
+dysplasia,O
+,,O
+and,O
+seizures,O
+,,O
+similar,O
+to,O
+the,O
+severe,O
+phenotype,O
+of,O
+one,O
+of,O
+the,O
+first,O
+described,O
+cases,O
+of,O
+GK,O
+deficiency,O
+.,O
+ , 
+His,O
+younger,O
+brother,O
+,,O
+patient,O
+3,O
+,,O
+also,O
+had,O
+GK,B-Gene
+deficiency,O
+,,O
+but,O
+so,O
+far,O
+his,O
+development,O
+has,O
+been,O
+normal,O
+.,O
+ , 
+GK,B-Gene
+exon,O
+17,O
+was,O
+deleted,O
+in,O
+both,O
+brothers,O
+,,O
+implicating,O
+additional,O
+factors,O
+in,O
+causation,O
+of,O
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+severe,O
+phenotype,O
+of,O
+patient,O
+2,O
+.,O
+ , 
+Patient,O
+4,O
+had,O
+both,O
+GK,B-Gene
+deficiency,O
+with,O
+mental,O
+retardation,O
+and,O
+a,O
+GK,B-Gene
+missense,O
+mutation,O
+(,B-SNP
+D440V,I-SNP
+),I-SNP
+.,O
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+Possible,O
+explanations,O
+for,O
+the,O
+phenotypic,O
+variation,O
+of,O
+these,O
+four,O
+patients,O
+include,O
+ascertainment,O
+bias,O
+;,O
+metabolic,O
+or,O
+environmental,O
+stress,O
+as,O
+a,O
+precipitating,O
+factor,O
+in,O
+revealing,O
+GK,O
+-,O
+related,O
+changes,O
+,,O
+as,O
+has,O
+previously,O
+been,O
+described,O
+in,O
+juvenile,O
+GK,B-Gene
+deficiency,O
+;,O
+and,O
+interactions,O
+with,O
+functional,O
+polymorphisms,O
+in,O
+other,O
+genes,O
+that,O
+alter,O
+the,O
+effect,O
+of,O
+GK,B-Gene
+deficiency,O
+on,O
+normal,O
+development,O
+.,O
+ , 
+#16960810
+Familial,O
+chilblain,O
+lupus,O
+,,O
+a,O
+monogenic,O
+form,O
+of,O
+cutaneous,O
+lupus,O
+erythematosus,O
+,,O
+maps,O
+to,O
+chromosome,O
+3p,O
+.,O
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+Systemic,O
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+prototypic,O
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+disease,O
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+Apart,O
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+deficiencies,O
+of,O
+complement,O
+factors,O
+,,O
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+occur,O
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+association,O
+with,O
+other,O
+autoimmune,O
+diseases,O
+or,O
+high,O
+susceptibility,O
+to,O
+bacterial,O
+infections,O
+,,O
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+is,O
+multifactorial,O
+in,O
+nature,O
+.,O
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+Cutaneous,O
+findings,O
+are,O
+a,O
+hallmark,O
+of,O
+the,O
+disease,O
+and,O
+manifest,O
+either,O
+alone,O
+or,O
+in,O
+association,O
+with,O
+internal,O
+-,O
+organ,O
+disease,O
+.,O
+ , 
+We,O
+describe,O
+a,O
+novel,O
+genodermatosis,O
+characterized,O
+by,O
+painful,O
+bluish,O
+-,O
+red,O
+inflammatory,O
+papular,O
+or,O
+nodular,O
+lesions,O
+in,O
+acral,O
+locations,O
+such,O
+as,O
+fingers,O
+,,O
+toes,O
+,,O
+nose,O
+,,O
+cheeks,O
+,,O
+and,O
+ears,O
+.,O
+ , 
+The,O
+lesions,O
+sometimes,O
+appear,O
+plaquelike,O
+and,O
+tend,O
+to,O
+ulcerate,O
+.,O
+ , 
+Manifestation,O
+usually,O
+begins,O
+in,O
+early,O
+childhood,O
+and,O
+is,O
+precipitated,O
+by,O
+cold,O
+and,O
+wet,O
+exposure,O
+.,O
+ , 
+Apart,O
+from,O
+arthralgias,O
+,,O
+there,O
+is,O
+no,O
+evidence,O
+for,O
+internal,O
+-,O
+organ,O
+disease,O
+or,O
+an,O
+increased,O
+susceptibility,O
+to,O
+infection,O
+.,O
+ , 
+Histological,O
+findings,O
+include,O
+a,O
+deep,O
+inflammatory,O
+infiltrate,O
+with,O
+perivascular,O
+distribution,O
+and,O
+granular,O
+deposits,O
+of,O
+immunoglobulins,O
+and,O
+complement,O
+along,O
+the,O
+basement,O
+membrane,O
+.,O
+ , 
+Some,O
+affected,O
+individuals,O
+show,O
+antinuclear,O
+antibodies,O
+or,O
+immune,O
+complex,O
+formation,O
+,,O
+whereas,O
+cryoglobulins,O
+or,O
+cold,O
+agglutinins,O
+are,O
+absent,O
+.,O
+ , 
+Thus,O
+,,O
+the,O
+findings,O
+are,O
+consistent,O
+with,O
+chilblain,O
+lupus,O
+,,O
+a,O
+rare,O
+form,O
+of,O
+cutaneous,O
+lupus,O
+erythematosus,O
+.,O
+ , 
+Investigation,O
+of,O
+a,O
+large,O
+German,O
+kindred,O
+with,O
+18,O
+affected,O
+members,O
+suggests,O
+a,O
+highly,O
+penetrant,O
+trait,O
+with,O
+autosomal,O
+dominant,O
+inheritance,O
+.,O
+ , 
+By,O
+single,O
+-,O
+nucleotide,O
+-,O
+polymorphism,O
+-,O
+based,O
+genomewide,O
+linkage,O
+analysis,O
+,,O
+the,O
+locus,O
+was,O
+mapped,O
+to,O
+chromosome,O
+3p,O
+.,O
+ , 
+Haplotype,O
+analysis,O
+defined,O
+the,O
+locus,O
+to,O
+a,O
+13.8,O
+-,O
+cM,O
+interval,O
+with,O
+a,O
+LOD,O
+score,O
+of,O
+5.04,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+description,O
+of,O
+a,O
+monogenic,O
+form,O
+of,O
+cutaneous,O
+lupus,O
+erythematosus,O
+.,O
+ , 
+Identification,O
+of,O
+the,O
+gene,O
+responsible,O
+for,O
+familial,O
+chilblain,O
+lupus,O
+may,O
+shed,O
+light,O
+on,O
+the,O
+pathogenesis,O
+of,O
+common,O
+forms,O
+of,O
+connective,O
+-,O
+tissue,O
+disease,O
+such,O
+as,O
+systemic,O
+lupus,O
+erythematosus,O
+.,O
+ , 
+#1415242
+A,O
+problem,O
+-,O
+based,O
+learning,O
+approach,O
+to,O
+teaching,O
+medical,O
+genetics,O
+.,O
+ , 
+A,O
+newly,O
+developed,O
+problem,O
+-,O
+based,O
+medical,O
+genetics,O
+course,O
+that,O
+was,O
+integrated,O
+into,O
+the,O
+fourth,O
+-,O
+year,O
+medical,O
+school,O
+curriculum,O
+of,O
+the,O
+University,O
+of,O
+Texas,O
+Health,O
+Science,O
+Center,O
+at,O
+San,O
+Antonio,O
+is,O
+described,O
+.,O
+ , 
+To,O
+provide,O
+a,O
+basic,O
+genetic,O
+background,O
+for,O
+the,O
+clinical,O
+rotations,O
+,,O
+a,O
+supplemental,O
+computer,O
+tutorial,O
+is,O
+required,O
+during,O
+the,O
+second,O
+year,O
+.,O
+ , 
+These,O
+two,O
+formats,O
+prepare,O
+the,O
+medical,O
+students,O
+to,O
+recognize,O
+genetic,O
+diseases,O
+,,O
+to,O
+provide,O
+basic,O
+genetic,O
+counseling,O
+in,O
+their,O
+daily,O
+practice,O
+,,O
+and,O
+to,O
+appropriately,O
+refer,O
+patients,O
+to,O
+genetic,O
+specialists,O
+.,O
+ , 
+#8644710
+The,O
+age,O
+of,O
+human,O
+mutation,O
+:,O
+genealogical,O
+and,O
+linkage,O
+disequilibrium,O
+analysis,O
+of,O
+the,O
+CLN5,B-Gene
+mutation,O
+in,O
+the,O
+Finnish,O
+population,O
+.,O
+ , 
+Variant,O
+late,O
+infantile,O
+neuronal,O
+ceroid,O
+lipofuscinosis,O
+(,O
+vLINCL,O
+),O
+is,O
+an,O
+autosomal,O
+recessive,O
+progressive,O
+encephalopathy,O
+of,O
+childhood,O
+enriched,O
+in,O
+the,O
+western,O
+part,O
+of,O
+Finland,O
+,,O
+with,O
+a,O
+local,O
+incidence,O
+of,O
+1,O
+in,O
+1500,O
+.,O
+ , 
+We,O
+recently,O
+assigned,O
+the,O
+locus,O
+for,O
+vLINCL,O
+,,O
+CLN5,B-Gene
+,,I-Gene
+to,O
+13q21.1,O
+-,O
+q32,O
+.,O
+ , 
+In,O
+the,O
+present,O
+study,O
+,,O
+the,O
+haplotype,O
+analysis,O
+of,O
+Finnish,O
+CLN5,B-Gene
+chromosomes,O
+provides,O
+evidence,O
+that,O
+one,O
+single,O
+mutation,O
+causes,O
+vLINCL,O
+in,O
+the,O
+Finnish,O
+population,O
+.,O
+ , 
+Eight,O
+microsatellite,O
+markers,O
+closely,O
+linked,O
+to,O
+the,O
+CLN5,B-Gene
+gene,O
+on,O
+chromosome,O
+13q,O
+were,O
+analyzed,O
+,,O
+to,O
+study,O
+identity,O
+by,O
+descent,O
+by,O
+shared,O
+haplotype,O
+analysis,O
+.,O
+ , 
+One,O
+single,O
+haplotype,O
+formed,O
+by,O
+flanking,O
+markers,O
+D13S160,O
+and,O
+D13S162,O
+in,O
+strong,O
+linkage,O
+disequilibrium,O
+(,O
+P,O
+<,O
+.0001,O
+),O
+was,O
+present,O
+in,O
+81,O
+%,O
+of,O
+disease,O
+-,O
+bearing,O
+chromosomes,O
+.,O
+ , 
+Allele,O
+4,O
+at,O
+the,O
+marker,O
+locus,O
+D13S162,O
+was,O
+detected,O
+in,O
+94,O
+%,O
+of,O
+disease,O
+-,O
+bearing,O
+chromosomes,O
+.,O
+ , 
+To,O
+evaluate,O
+the,O
+age,O
+of,O
+the,O
+CLN5,B-Gene
+mutation,O
+by,O
+virtue,O
+of,O
+its,O
+restricted,O
+geographical,O
+distribution,O
+,,O
+church,O
+records,O
+were,O
+used,O
+to,O
+identify,O
+the,O
+common,O
+ancestors,O
+for,O
+18,O
+vLINCL,O
+families,O
+diagnosed,O
+in,O
+Finland,O
+.,O
+ , 
+The,O
+pedigrees,O
+of,O
+the,O
+vLINCL,O
+ancestors,O
+merged,O
+on,O
+many,O
+occasions,O
+,,O
+which,O
+also,O
+supports,O
+a,O
+single,O
+founder,O
+mutation,O
+that,O
+obviously,O
+happened,O
+20,O
+to,O
+30,O
+generations,O
+ago,O
+(,O
+i.e.,O
+,,O
+approximately,O
+500,O
+years,O
+ago,O
+),O
+in,O
+this,O
+isolated,O
+population,O
+.,O
+ , 
+Linkage,O
+disequilibrium,O
+was,O
+detected,O
+with,O
+seven,O
+markers,O
+covering,O
+an,O
+extended,O
+genetic,O
+distance,O
+of,O
+11,O
+cM,O
+,,O
+which,O
+further,O
+supports,O
+the,O
+young,O
+age,O
+of,O
+the,O
+CLN5,B-Gene
+mutation,O
+.,O
+ , 
+When,O
+the,O
+results,O
+of,O
+genealogical,O
+and,O
+linkage,O
+disequilibrium,O
+studies,O
+were,O
+combined,O
+,,O
+the,O
+CLN5,B-Gene
+gene,O
+was,O
+predicted,O
+to,O
+lie,O
+approximately,O
+200,O
+-,O
+400,O
+kb,O
+(,O
+total,O
+range,O
+30,O
+-,O
+1360,O
+kb,O
+),O
+from,O
+the,O
+closest,O
+marker,O
+D13S162,O
+.,O
+ , 
+#11443547
+Mutations,O
+in,O
+the,O
+sepiapterin,B-Gene
+reductase,I-Gene
+gene,O
+cause,O
+a,O
+novel,O
+tetrahydrobiopterin,O
+-,O
+dependent,O
+monoamine,O
+-,O
+neurotransmitter,O
+deficiency,O
+without,O
+hyperphenylalaninemia,O
+.,O
+ , 
+Classic,O
+tetrahydrobiopterin,O
+(,O
+BH(4,O
+),O
+),O
+ , 
+deficiencies,O
+are,O
+characterized,O
+by,O
+hyperphenylalaninemia,O
+and,O
+deficiency,O
+of,O
+monoamine,O
+neurotransmitters,O
+.,O
+ , 
+In,O
+this,O
+article,O
+,,O
+we,O
+report,O
+two,O
+patients,O
+with,O
+progressive,O
+psychomotor,O
+retardation,O
+,,O
+dystonia,O
+,,O
+severe,O
+dopamine,O
+and,O
+serotonin,O
+deficiencies,O
+(,O
+low,O
+levels,O
+of,O
+5,O
+-,O
+hydroxyindoleacetic,O
+and,O
+homovanillic,O
+acids,O
+),O
+,,O
+and,O
+abnormal,O
+pterin,O
+pattern,O
+(,O
+high,O
+levels,O
+of,O
+biopterin,O
+and,O
+dihydrobiopterin,O
+),O
+in,O
+cerebrospinal,O
+fluid,O
+.,O
+ , 
+Furthermore,O
+,,O
+they,O
+presented,O
+with,O
+normal,O
+urinary,O
+pterins,O
+and,O
+without,O
+hyperphenylalaninemia,O
+.,O
+ , 
+Investigation,O
+of,O
+skin,O
+fibroblasts,O
+revealed,O
+inactive,O
+sepiapterin,O
+reductase,O
+(,O
+SR,O
+),O
+,,O
+the,O
+enzyme,O
+catalyzing,O
+the,O
+final,O
+two,O
+-,O
+step,O
+reaction,O
+in,O
+the,O
+biosynthesis,O
+of,O
+BH(4,O
+),O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+SPR,B-Gene
+gene,O
+were,O
+detected,O
+in,O
+both,O
+patients,O
+and,O
+their,O
+family,O
+members,O
+.,O
+ , 
+One,O
+patient,O
+was,O
+homozygous,O
+for,O
+a,O
+TC-->CT,O
+dinucleotide,O
+exchange,O
+,,O
+predicting,O
+a,O
+truncated,O
+SR,O
+(,B-SNP
+Q119X,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+other,O
+patient,O
+was,O
+a,O
+compound,O
+heterozygote,O
+for,O
+a,O
+genomic,O
+5,O
+-,O
+bp,O
+deletion,O
+(,B-SNP
+1397,I-SNP
+-,I-SNP
+1401delAGAAC,I-SNP
+),I-SNP
+resulting,O
+in,O
+abolished,O
+SPR,B-Gene
+-,I-Gene
+gene,I-Gene
+expression,O
+and,O
+an,O
+A-->G,O
+transition,O
+leading,O
+to,O
+an,O
+R150,B-SNP
+G,I-SNP
+amino,O
+acid,O
+substitution,O
+and,O
+to,O
+inactive,O
+SR,O
+as,O
+confirmed,O
+by,O
+recombinant,O
+expression,O
+.,O
+ , 
+The,O
+absence,O
+of,O
+hyperphenylalaninemia,O
+and,O
+the,O
+presence,O
+of,O
+normal,O
+urinary,O
+pterin,O
+metabolites,O
+and,O
+of,O
+normal,O
+SR,O
+-,O
+like,O
+activity,O
+in,O
+red,O
+blood,O
+cells,O
+may,O
+be,O
+explained,O
+by,O
+alternative,O
+pathways,O
+for,O
+the,O
+final,O
+two,O
+-,O
+step,O
+reaction,O
+of,O
+BH(4,O
+),O
+biosynthesis,O
+in,O
+peripheral,O
+and,O
+neuronal,O
+tissues,O
+.,O
+ , 
+We,O
+propose,O
+that,O
+,,O
+for,O
+the,O
+biosynthesis,O
+of,O
+BH(4,O
+),O
+in,O
+peripheral,O
+tissues,O
+,,O
+SR,O
+activity,O
+may,O
+be,O
+substituted,O
+by,O
+aldose,B-Gene
+reductase,I-Gene
+(,B-Gene
+AR,I-Gene
+),I-Gene
+,,O
+carbonyl,B-Gene
+reductase,I-Gene
+(,B-Gene
+CR,I-Gene
+),I-Gene
+,,O
+and,O
+dihydrofolate,B-Gene
+reductase,I-Gene
+,,I-Gene
+whereas,O
+,,O
+in,O
+the,O
+brain,O
+,,O
+only,O
+AR,O
+and,O
+CR,O
+are,O
+fully,O
+present,O
+.,O
+ , 
+Thus,O
+,,O
+autosomal,O
+recessive,O
+SR,O
+deficiency,O
+leads,O
+to,O
+BH(4,O
+),O
+and,O
+to,O
+neurotransmitter,O
+deficiencies,O
+without,O
+hyperphenylalaninemia,O
+and,O
+may,O
+not,O
+be,O
+detected,O
+by,O
+neonatal,O
+screening,O
+for,O
+phenylketonuria,O
+.,O
+ , 
+#8019556
+Mutations,O
+in,O
+PAX3,B-Gene
+associated,O
+with,O
+Waardenburg,O
+syndrome,O
+type,O
+I.,O
+Waardenburg,O
+syndrome,O
+(,O
+WS,O
+),O
+types,O
+I,O
+,,O
+II,O
+,,O
+and,O
+III,O
+(,O
+McKusick,O
+#,O
+14882,O
+,,O
+#,O
+19351,O
+,,O
+and,O
+#,O
+19350,O
+),O
+are,O
+related,O
+autosomal,O
+dominant,O
+disorders,O
+characterized,O
+by,O
+sensorineural,O
+hearing,O
+loss,O
+,,O
+dystopia,O
+canthorum,O
+,,O
+pigmentary,O
+disturbances,O
+,,O
+and,O
+other,O
+developmental,O
+defects,O
+.,O
+ , 
+Disease,O
+causing,O
+PAX3,B-Gene
+mutations,O
+have,O
+been,O
+identified,O
+in,O
+a,O
+few,O
+families,O
+from,O
+each,O
+of,O
+the,O
+three,O
+disease,O
+subtypes,O
+,,O
+WS,O
+-,O
+I,O
+,,O
+WS,O
+-,O
+II,O
+,,O
+and,O
+WS,O
+-,O
+III,O
+.,O
+ , 
+In,O
+others,O
+,,O
+although,O
+the,O
+mutations,O
+have,O
+not,O
+been,O
+pinpointed,O
+,,O
+linkage,O
+with,O
+the,O
+PAX3,B-Gene
+locus,O
+on,O
+chromosome,O
+2q35,O
+has,O
+been,O
+demonstrated,O
+.,O
+ , 
+The,O
+PAX3,B-Gene
+protein,O
+is,O
+a,O
+transcription,O
+factor,O
+that,O
+contains,O
+both,O
+a,O
+paired,O
+-,O
+domain,O
+and,O
+a,O
+homeodomain,O
+DNA,O
+binding,O
+motif,O
+and,O
+appears,O
+to,O
+play,O
+a,O
+key,O
+role,O
+during,O
+embryogenesis,O
+.,O
+ , 
+In,O
+this,O
+report,O
+,,O
+we,O
+describe,O
+two,O
+mutations,O
+in,O
+the,O
+human,O
+PAX3,B-Gene
+gene,O
+that,O
+cause,O
+WS,O
+type,O
+I.,O
+One,O
+mutation,O
+is,O
+a,O
+deletion,O
+/,O
+frameshift,O
+in,O
+the,O
+paired,O
+-,O
+domain,O
+of,O
+PAX3,B-Gene
+and,O
+results,O
+in,O
+a,O
+protein,O
+without,O
+functional,O
+DNA,O
+binding,O
+domains,O
+.,O
+ , 
+The,O
+second,O
+mutation,O
+is,O
+a,O
+single,O
+-,O
+base,O
+substitution,O
+and,O
+results,O
+in,O
+a,O
+premature,O
+termination,O
+codon,O
+in,O
+the,O
+homeodomain,O
+of,O
+PAX3,B-Gene
+.,I-Gene
+ , 
+This,O
+is,O
+the,O
+first,O
+demonstration,O
+of,O
+a,O
+mutation,O
+in,O
+the,O
+homeodomain,O
+DNA,O
+binding,O
+motif,O
+in,O
+this,O
+protein,O
+resulting,O
+in,O
+WS,O
+and,O
+one,O
+of,O
+the,O
+few,O
+examples,O
+of,O
+a,O
+mutation,O
+in,O
+a,O
+homeodomain,O
+of,O
+any,O
+protein,O
+that,O
+results,O
+in,O
+human,O
+disease,O
+.,O
+ , 
+#17436254
+Mutations,O
+in,O
+TCF4,B-Gene
+,,I-Gene
+encoding,O
+a,O
+class,O
+I,O
+basic,O
+helix,O
+-,O
+loop,O
+-,O
+helix,O
+transcription,O
+factor,O
+,,O
+are,O
+responsible,O
+for,O
+Pitt,O
+-,O
+Hopkins,O
+syndrome,O
+,,O
+a,O
+severe,O
+epileptic,O
+encephalopathy,O
+associated,O
+with,O
+autonomic,O
+dysfunction,O
+.,O
+ , 
+Pitt,O
+-,O
+Hopkins,O
+syndrome,O
+(,O
+PHS,O
+),O
+is,O
+a,O
+rare,O
+syndromic,O
+encephalopathy,O
+characterized,O
+by,O
+daily,O
+bouts,O
+of,O
+hyperventilation,O
+and,O
+a,O
+facial,O
+gestalt,O
+.,O
+ , 
+We,O
+report,O
+a,O
+1.8,O
+-,O
+Mb,O
+de,O
+novo,O
+microdeletion,O
+on,O
+chromosome,O
+18q21.1,O
+,,O
+identified,O
+by,O
+array,O
+-,O
+comparative,O
+genomic,O
+hybridization,O
+in,O
+one,O
+patient,O
+with,O
+PHS,O
+.,O
+ , 
+We,O
+subsequently,O
+identified,O
+two,O
+de,O
+novo,O
+heterozygous,O
+missense,O
+mutations,O
+of,O
+a,O
+conserved,O
+amino,O
+acid,O
+in,O
+the,O
+basic,O
+region,O
+of,O
+the,O
+TCF4,B-Gene
+gene,O
+in,O
+three,O
+additional,O
+subjects,O
+with,O
+PHS,O
+.,O
+ , 
+These,O
+findings,O
+demonstrate,O
+that,O
+TCF4,B-Gene
+anomalies,O
+are,O
+responsible,O
+for,O
+PHS,O
+and,O
+provide,O
+the,O
+first,O
+evidence,O
+of,O
+a,O
+human,O
+disorder,O
+related,O
+to,O
+class,O
+I,O
+basic,O
+helix,O
+-,O
+loop,O
+-,O
+helix,O
+transcription,O
+-,O
+factor,O
+defects,O
+(,O
+also,O
+known,O
+as,O
+",O
+E,O
+proteins,O
+",O
+),O
+.,O
+ , 
+Moreover,O
+,,O
+our,O
+data,O
+may,O
+shed,O
+new,O
+light,O
+on,O
+the,O
+normal,O
+processes,O
+underlying,O
+autonomic,O
+nervous,O
+system,O
+development,O
+and,O
+maintenance,O
+of,O
+an,O
+appropriate,O
+ventilatory,O
+neuronal,O
+circuitry,O
+.,O
+ , 
+#17436249
+Measuring,O
+European,O
+population,O
+stratification,O
+with,O
+microarray,O
+genotype,O
+data,O
+.,O
+ , 
+A,O
+proper,O
+understanding,O
+of,O
+population,O
+genetic,O
+stratification,O
+--,O
+differences,O
+in,O
+individual,O
+ancestry,O
+within,O
+a,O
+population,O
+--,O
+is,O
+crucial,O
+in,O
+attempts,O
+to,O
+find,O
+genes,O
+for,O
+complex,O
+traits,O
+through,O
+association,O
+mapping,O
+.,O
+ , 
+We,O
+report,O
+on,O
+genomewide,O
+typing,O
+of,O
+approximately,O
+10,000,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+in,O
+297,O
+individuals,O
+,,O
+to,O
+explore,O
+population,O
+structure,O
+in,O
+Europeans,O
+of,O
+known,O
+and,O
+unknown,O
+ancestry,O
+.,O
+ , 
+The,O
+results,O
+reveal,O
+the,O
+presence,O
+of,O
+several,O
+significant,O
+axes,O
+of,O
+stratification,O
+,,O
+most,O
+prominently,O
+in,O
+a,O
+northern,O
+-,O
+southeastern,O
+trend,O
+,,O
+but,O
+also,O
+along,O
+an,O
+east,O
+-,O
+west,O
+axis,O
+.,O
+ , 
+We,O
+also,O
+demonstrate,O
+the,O
+selection,O
+and,O
+application,O
+of,O
+EuroAIMs,O
+(,O
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+informative,O
+markers,O
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+ancestry,O
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+correction,O
+.,O
+ , 
+The,O
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+CEPH,O
+(,O
+Centre,O
+d'Etude,O
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+Polymorphisme,O
+Humain,O
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+Utah,O
+sample,O
+panels,O
+,,O
+often,O
+used,O
+as,O
+proxies,O
+for,O
+European,O
+populations,O
+,,O
+are,O
+found,O
+to,O
+reflect,O
+different,O
+subsets,O
+of,O
+the,O
+continent,O
+'s,O
+ancestry,O
+.,O
+ , 
+#21665002
+A,O
+congenital,O
+muscular,O
+dystrophy,O
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+mitochondrial,O
+structural,O
+abnormalities,O
+caused,O
+by,O
+defective,O
+de,O
+novo,O
+phosphatidylcholine,O
+biosynthesis,O
+.,O
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+Congenital,O
+muscular,O
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+a,O
+heterogeneous,O
+group,O
+of,O
+inherited,O
+muscle,O
+diseases,O
+characterized,O
+clinically,O
+by,O
+muscle,O
+weakness,O
+and,O
+hypotonia,O
+in,O
+early,O
+infancy,O
+.,O
+ , 
+A,O
+number,O
+of,O
+genes,O
+harboring,O
+causative,O
+mutations,O
+have,O
+been,O
+identified,O
+,,O
+but,O
+several,O
+cases,O
+of,O
+congenital,O
+muscular,O
+dystrophy,O
+remain,O
+molecularly,O
+unresolved,O
+.,O
+ , 
+We,O
+examined,O
+15,O
+individuals,O
+with,O
+a,O
+congenital,O
+muscular,O
+dystrophy,O
+characterized,O
+by,O
+early,O
+-,O
+onset,O
+muscle,O
+wasting,O
+,,O
+mental,O
+retardation,O
+,,O
+and,O
+peculiar,O
+enlarged,O
+mitochondria,O
+that,O
+are,O
+prevalent,O
+toward,O
+the,O
+periphery,O
+of,O
+the,O
+fibers,O
+but,O
+are,O
+sparse,O
+in,O
+the,O
+center,O
+on,O
+muscle,O
+biopsy,O
+,,O
+and,O
+we,O
+have,O
+identified,O
+homozygous,O
+or,O
+compound,O
+heterozygous,O
+mutations,O
+in,O
+the,O
+gene,O
+encoding,O
+choline,B-Gene
+kinase,I-Gene
+beta,I-Gene
+(,B-Gene
+CHKB,I-Gene
+),I-Gene
+.,O
+ , 
+This,O
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+the,O
+first,O
+enzymatic,O
+step,O
+in,O
+a,O
+biosynthetic,O
+pathway,O
+for,O
+phosphatidylcholine,O
+,,O
+the,O
+most,O
+abundant,O
+phospholipid,O
+in,O
+eukaryotes,O
+.,O
+ , 
+In,O
+muscle,O
+of,O
+three,O
+affected,O
+individuals,O
+with,O
+nonsense,O
+mutations,O
+,,O
+choline,O
+kinase,O
+activities,O
+were,O
+undetectable,O
+,,O
+and,O
+phosphatidylcholine,O
+levels,O
+were,O
+decreased,O
+.,O
+ , 
+We,O
+identified,O
+the,O
+human,O
+disease,O
+caused,O
+by,O
+disruption,O
+of,O
+a,O
+phospholipid,O
+de,O
+novo,O
+biosynthetic,O
+pathway,O
+,,O
+demonstrating,O
+the,O
+pivotal,O
+role,O
+of,O
+phosphatidylcholine,O
+in,O
+muscle,O
+and,O
+brain,O
+.,O
+ , 
+#21786366
+Exome,O
+sequencing,O
+identifies,O
+MRPL3,B-Gene
+mutation,O
+in,O
+mitochondrial,O
+cardiomyopathy,O
+.,O
+ , 
+By,O
+combining,O
+exome,O
+sequencing,O
+in,O
+conjunction,O
+with,O
+genetic,O
+mapping,O
+,,O
+we,O
+have,O
+identified,O
+the,O
+first,O
+mutation,O
+in,O
+large,O
+mitochondrial,O
+ribosomal,O
+protein,O
+MRPL3,B-Gene
+in,O
+a,O
+family,O
+of,O
+four,O
+sibs,O
+with,O
+hypertrophic,O
+cardiomyopathy,O
+,,O
+psychomotor,O
+retardation,O
+,,O
+and,O
+multiple,O
+respiratory,O
+chain,O
+deficiency,O
+.,O
+ , 
+Affected,O
+sibs,O
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+compound,O
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+for,O
+a,O
+missense,O
+MRPL3,B-Gene
+mutation,O
+(,B-SNP
+P317R,I-SNP
+),I-SNP
+and,O
+a,O
+large,O
+-,O
+scale,O
+deletion,O
+,,O
+inherited,O
+from,O
+the,O
+mother,O
+and,O
+the,O
+father,O
+,,O
+respectively,O
+.,O
+ , 
+These,O
+mutations,O
+were,O
+shown,O
+to,O
+alter,O
+ribosome,O
+assembly,O
+and,O
+cause,O
+a,O
+mitochondrial,O
+translation,O
+deficiency,O
+in,O
+cultured,O
+skin,O
+fibroblasts,O
+resulting,O
+in,O
+an,O
+abnormal,O
+assembly,O
+of,O
+several,O
+complexes,O
+of,O
+the,O
+respiratory,O
+chain,O
+.,O
+ , 
+This,O
+observation,O
+gives,O
+support,O
+to,O
+the,O
+view,O
+that,O
+exome,O
+sequencing,O
+combined,O
+with,O
+genetic,O
+mapping,O
+is,O
+a,O
+powerful,O
+approach,O
+for,O
+the,O
+identification,O
+of,O
+new,O
+genes,O
+of,O
+mitochondrial,O
+disorders,O
+.,O
+ , 
+#12506336
+CD36,B-Gene
+polymorphism,O
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+associated,O
+with,O
+protection,O
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+cerebral,O
+malaria,O
+.,O
+ , 
+The,O
+human,O
+protein,O
+CD36,B-Gene
+is,O
+a,O
+major,O
+receptor,O
+for,O
+Plasmodium,O
+falciparum,O
+-,O
+infected,O
+erythrocytes,O
+and,O
+contributes,O
+to,O
+the,O
+pathology,O
+of,O
+P.,O
+falciparum,O
+malaria,O
+.,O
+ , 
+We,O
+performed,O
+variation,O
+screening,O
+of,O
+the,O
+CD36,B-Gene
+gene,O
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+examined,O
+the,O
+possible,O
+association,O
+between,O
+CD36,B-Gene
+polymorphisms,O
+and,O
+the,O
+severity,O
+of,O
+malaria,O
+in,O
+475,O
+adult,O
+Thai,O
+patients,O
+with,O
+P.,O
+falciparum,O
+malaria,O
+.,O
+ , 
+Accordingly,O
+,,O
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+nine,O
+CD36,B-Gene
+polymorphisms,O
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+a,O
+high,O
+-,O
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+(,O
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+allele,O
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+ , 
+Of,O
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+,,O
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+frequencies,O
+of,O
+the,O
+-14T-->C,B-SNP
+allele,O
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+the,O
+upstream,O
+promoter,O
+region,O
+and,O
+the,O
+-53G-->T,B-SNP
+allele,O
+in,O
+the,O
+downstream,O
+promoter,O
+region,O
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+significantly,O
+decreased,O
+in,O
+patients,O
+with,O
+cerebral,O
+malaria,O
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+to,O
+those,O
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+mild,O
+malaria,O
+(,O
+P=.016,O
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+-14T-->C,B-SNP
+and,O
+P=.050,O
+for,O
+-53G-->T,B-SNP
+),I-SNP
+.,O
+ , 
+The,O
+analysis,O
+of,O
+linkage,O
+disequilibrium,O
+(,O
+LD,O
+),O
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+the,O
+nine,O
+common,O
+polymorphisms,O
+revealed,O
+that,O
+there,O
+are,O
+two,O
+blocks,O
+with,O
+strong,O
+LD,O
+in,O
+the,O
+CD36,B-Gene
+gene,O
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+that,O
+the,O
+-14T-->C,B-SNP
+and,O
+-53G-->T,B-SNP
+polymorphisms,O
+are,O
+within,O
+the,O
+upstream,O
+block,O
+of,O
+35,O
+kb,O
+from,O
+the,O
+upstream,O
+promoter,O
+to,O
+exon,O
+8,O
+.,O
+ , 
+Further,O
+association,O
+testing,O
+after,O
+the,O
+second,O
+variation,O
+screening,O
+in,O
+the,O
+upstream,O
+block,O
+indicated,O
+that,O
+the,O
+in3(TG)(12,O
+),O
+(,O
+i.e.,O
+,,O
+12,O
+TG,O
+repeats,O
+in,O
+intron,O
+3,O
+),O
+allele,O
+is,O
+most,O
+strongly,O
+associated,O
+with,O
+the,O
+reduction,O
+in,O
+the,O
+risk,O
+of,O
+cerebral,O
+malaria,O
+(,O
+odds,O
+ratio,O
+0.59,O
+;,O
+95,O
+%,O
+confidence,O
+interval,O
+0.40,O
+-,O
+0.87,O
+;,O
+P=.0069,O
+),O
+.,O
+ , 
+We,O
+found,O
+,,O
+by,O
+reverse,O
+-,O
+transcriptase,O
+PCR,O
+amplification,O
+,,O
+that,O
+in3(TG)(12,O
+),O
+is,O
+involved,O
+in,O
+the,O
+nonproduction,O
+of,O
+the,O
+variant,O
+CD36,B-Gene
+transcript,O
+that,O
+lacks,O
+exons,O
+4,O
+and,O
+5,O
+.,O
+ , 
+Since,O
+exon,O
+5,O
+of,O
+the,O
+gene,O
+is,O
+known,O
+to,O
+encode,O
+the,O
+ligand,O
+-,O
+binding,O
+domain,O
+for,O
+P.,O
+falciparum,O
+-,O
+infected,O
+erythrocytes,O
+,,O
+in3(TG)(12,O
+),O
+itself,O
+or,O
+a,O
+primary,O
+variant,O
+on,O
+the,O
+haplotype,O
+with,O
+in3(TG)(12,O
+),O
+may,O
+be,O
+responsible,O
+for,O
+protection,O
+from,O
+cerebral,O
+malaria,O
+in,O
+Thailand,O
+.,O
+ , 
+Results,O
+of,O
+the,O
+present,O
+study,O
+suggest,O
+that,O
+LD,O
+mapping,O
+has,O
+potential,O
+for,O
+detecting,O
+a,O
+disease,O
+-,O
+associated,O
+variant,O
+on,O
+the,O
+basis,O
+of,O
+haplotype,O
+blocks,O
+.,O
+ , 
+#9042906
+Congenital,O
+anomalies,O
+and,O
+childhood,O
+cancer,O
+in,O
+Great,O
+Britain,O
+.,O
+ , 
+The,O
+presence,O
+of,O
+cancer,O
+and,O
+a,O
+congenital,O
+anomaly,O
+in,O
+the,O
+same,O
+child,O
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+be,O
+explained,O
+in,O
+certain,O
+cases,O
+by,O
+an,O
+underlying,O
+genetic,O
+abnormality,O
+.,O
+ , 
+The,O
+study,O
+of,O
+these,O
+associations,O
+may,O
+lead,O
+to,O
+the,O
+identification,O
+of,O
+genes,O
+that,O
+are,O
+important,O
+in,O
+both,O
+processes,O
+.,O
+ , 
+We,O
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+examined,O
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+records,O
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+20,304,O
+children,O
+with,O
+cancer,O
+in,O
+Britain,O
+,,O
+who,O
+were,O
+entered,O
+into,O
+the,O
+National,O
+Registry,O
+of,O
+Childhood,O
+Tumors,O
+(,O
+NRCT,O
+),O
+during,O
+1971,O
+-,O
+86,O
+,,O
+for,O
+the,O
+presence,O
+of,O
+congenital,O
+anomalies,O
+.,O
+ , 
+The,O
+frequency,O
+of,O
+anomalies,O
+was,O
+much,O
+higher,O
+among,O
+children,O
+with,O
+solid,O
+tumors,O
+(,O
+4.4,O
+%,O
+),O
+than,O
+among,O
+those,O
+with,O
+leukemia,O
+or,O
+lymphoma,O
+(,O
+2.6,O
+%,O
+;,O
+P,O
+<,O
+.0001,O
+),O
+.,O
+ , 
+The,O
+types,O
+of,O
+cancer,O
+with,O
+the,O
+highest,O
+rates,O
+of,O
+anomalies,O
+were,O
+Wilms,O
+tumor,O
+(,O
+8.1,O
+%,O
+),O
+,,O
+Ewing,O
+sarcoma,O
+(,O
+5.8,O
+%,O
+),O
+,,O
+hepatoblastoma,O
+(,O
+6.4,O
+%,O
+),O
+,,O
+and,O
+gonadal,O
+and,O
+germ,O
+-,O
+cell,O
+tumors,O
+(,O
+6.4,O
+%,O
+),O
+.,O
+ , 
+Cases,O
+of,O
+spina,O
+bifida,O
+and,O
+abnormalities,O
+of,O
+the,O
+eye,O
+,,O
+ribs,O
+,,O
+and,O
+spine,O
+were,O
+more,O
+common,O
+in,O
+children,O
+with,O
+cancer,O
+than,O
+among,O
+population,O
+-,O
+based,O
+controls,O
+.,O
+ , 
+Future,O
+studies,O
+may,O
+be,O
+directed,O
+toward,O
+identifying,O
+the,O
+developmental,O
+pathways,O
+and,O
+the,O
+relevant,O
+genes,O
+that,O
+are,O
+involved,O
+in,O
+the,O
+overlap,O
+between,O
+pediatric,O
+cancer,O
+and,O
+malformation,O
+.,O
+ , 
+#17492639
+Characterization,O
+of,O
+a,O
+familial,O
+t(16;22,O
+),O
+balanced,O
+translocation,O
+associated,O
+with,O
+congenital,O
+cataract,O
+leads,O
+to,O
+identification,O
+of,O
+a,O
+novel,O
+gene,O
+,,O
+TMEM114,B-Gene
+,,I-Gene
+expressed,O
+in,O
+the,O
+lens,O
+and,O
+disrupted,O
+by,O
+the,O
+translocation,O
+.,O
+ , 
+Molecular,O
+characterization,O
+of,O
+chromosomal,O
+rearrangements,O
+is,O
+a,O
+powerful,O
+resource,O
+in,O
+identification,O
+of,O
+genes,O
+associated,O
+with,O
+monogenic,O
+disorders,O
+.,O
+ , 
+We,O
+describe,O
+the,O
+molecular,O
+characterization,O
+of,O
+a,O
+balanced,O
+familial,O
+chromosomal,O
+translocation,O
+,,O
+t(16;22)(p13.3;q11.2,B-SNP
+),I-SNP
+,,I-SNP
+segregating,O
+with,O
+congenital,O
+lamellar,O
+cataract,O
+.,O
+ , 
+This,O
+led,O
+to,O
+the,O
+discovery,O
+of,O
+a,O
+cluster,O
+of,O
+lens,O
+-,O
+derived,O
+expressed,O
+sequence,O
+tags,O
+(,O
+ESTs,O
+),O
+close,O
+to,O
+the,O
+16p13.3,O
+breakpoint,O
+.,O
+ , 
+This,O
+region,O
+harbors,O
+a,O
+locus,O
+associated,O
+with,O
+cataract,O
+and,O
+microphthalmia,O
+.,O
+ , 
+Long,O
+-,O
+range,O
+PCR,O
+and,O
+16p13.3,O
+breakpoint,O
+sequencing,O
+identified,O
+genomic,O
+sequence,O
+in,O
+a,O
+human,O
+genome,O
+sequence,O
+gap,O
+,,O
+ , 
+and,O
+ , 
+allowed,O
+identification,O
+of,O
+a,O
+novel,O
+four,O
+-,O
+exon,O
+gene,O
+,,O
+designated,O
+TMEM114,B-Gene
+,,I-Gene
+which,O
+encodes,O
+a,O
+predicted,O
+protein,O
+of,O
+223,O
+amino,O
+acids,O
+.,O
+ , 
+The,O
+breakpoint,O
+lies,O
+in,O
+the,O
+promoter,O
+region,O
+of,O
+TMEM114,B-Gene
+and,O
+separates,O
+the,O
+gene,O
+from,O
+predicted,O
+eye,O
+-,O
+specific,O
+upstream,O
+transcription,O
+factor,O
+binding,O
+sites,O
+.,O
+ , 
+There,O
+is,O
+sequence,O
+conservation,O
+among,O
+orthologs,O
+down,O
+to,O
+zebrafish,O
+.,O
+ , 
+The,O
+protein,O
+is,O
+predicted,O
+to,O
+contain,O
+four,O
+transmembrane,O
+domains,O
+with,O
+homology,O
+to,O
+the,O
+lens,O
+intrinsic,O
+membrane,O
+protein,O
+,,O
+LIM2,B-Gene
+(,O
+also,O
+known,O
+as,O
+MP20,B-Gene
+),I-Gene
+,,O
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+PMP-22,B-Gene
+/,B-Gene
+EMP,I-Gene
+/,B-Gene
+MP20,I-Gene
+family,O
+.,O
+ , 
+TMEM114,B-Gene
+mutation,O
+screening,O
+in,O
+130,O
+congenital,O
+cataract,O
+patients,O
+revealed,O
+missense,O
+mutations,O
+leading,O
+to,O
+the,O
+exchange,O
+of,O
+highly,O
+-,O
+conserved,O
+amino,O
+acids,O
+in,O
+the,O
+first,O
+extracellular,O
+domain,O
+of,O
+the,O
+protein,O
+(,B-SNP
+p.,I-SNP
+I35,I-SNP
+T,I-SNP
+,,I-SNP
+p.,B-SNP
+F106L,I-SNP
+),I-SNP
+in,O
+two,O
+separate,O
+patients,O
+and,O
+their,O
+reportedly,O
+healthy,O
+sibling,O
+and,O
+mother,O
+,,O
+respectively,O
+.,O
+ , 
+In,O
+the,O
+lens,O
+,,O
+Tmem114,B-Gene
+shows,O
+expression,O
+in,O
+the,O
+lens,O
+epithelial,O
+cells,O
+extending,O
+into,O
+the,O
+transitional,O
+zone,O
+where,O
+early,O
+fiber,O
+differentiation,O
+occurs,O
+.,O
+ , 
+Our,O
+findings,O
+implicate,O
+dysregulation,O
+of,O
+expression,O
+of,O
+this,O
+novel,O
+human,O
+gene,O
+,,O
+TMEM114,B-Gene
+,,I-Gene
+in,O
+mammalian,O
+cataract,O
+formation,O
+.,O
+ , 
+#7977378
+High,O
+-,O
+resolution,O
+meiotic,O
+and,O
+physical,O
+mapping,O
+of,O
+the,O
+best,O
+vitelliform,O
+macular,O
+dystrophy,O
+(,B-Gene
+VMD2,I-Gene
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+pericentromeric,O
+chromosome,O
+11,O
+.,O
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+Best,O
+vitelliform,O
+macular,O
+dystrophy,O
+(,B-Gene
+VMD2,I-Gene
+),I-Gene
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+previously,O
+been,O
+linked,O
+to,O
+several,O
+microsatellite,O
+markers,O
+from,O
+chromosome,O
+11,O
+.,O
+ , 
+Subsequently,O
+,,O
+additional,O
+genetic,O
+studies,O
+have,O
+refined,O
+the,O
+Best,O
+disease,O
+region,O
+to,O
+a,O
+3.7,O
+-,O
+cM,O
+interval,O
+flanked,O
+by,O
+markers,O
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+D11S903,O
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+PYGM,B-Gene
+.,I-Gene
+ , 
+To,O
+further,O
+narrow,O
+the,O
+interval,O
+containing,O
+the,O
+Best,O
+disease,O
+gene,O
+and,O
+to,O
+obtain,O
+an,O
+estimate,O
+of,O
+the,O
+physical,O
+size,O
+of,O
+the,O
+minimal,O
+candidate,O
+region,O
+,,O
+we,O
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+a,O
+combination,O
+of,O
+high,O
+-,O
+resolution,O
+PCR,O
+hybrid,O
+mapping,O
+and,O
+analysis,O
+of,O
+recombinant,O
+Best,O
+disease,O
+chromosomes,O
+.,O
+ , 
+We,O
+identified,O
+six,O
+markers,O
+from,O
+within,O
+the,O
+D11S903,O
+-,O
+PYGM,O
+interval,O
+that,O
+show,O
+no,O
+recombination,O
+with,O
+the,O
+defective,O
+gene,O
+in,O
+three,O
+multigeneration,O
+Best,O
+disease,O
+pedigrees,O
+.,O
+ , 
+Our,O
+hybrid,O
+panel,O
+localizes,O
+these,O
+markers,O
+on,O
+either,O
+side,O
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+the,O
+centromere,O
+on,O
+chromosome,O
+11,O
+.,O
+ , 
+The,O
+closest,O
+markers,O
+flanking,O
+the,O
+disease,O
+gene,O
+are,O
+at,O
+D11S986,O
+in,O
+band,O
+p12,O
+-,O
+11.22,O
+on,O
+the,O
+short,O
+arm,O
+and,O
+at,O
+D11S480,O
+in,O
+band,O
+q13.2,O
+-,O
+13.3,O
+on,O
+the,O
+proximal,O
+long,O
+arm,O
+.,O
+ , 
+This,O
+study,O
+demonstrates,O
+that,O
+the,O
+physical,O
+size,O
+of,O
+the,O
+Best,O
+disease,O
+region,O
+is,O
+exceedingly,O
+larger,O
+than,O
+previously,O
+estimated,O
+from,O
+the,O
+genetic,O
+data,O
+,,O
+because,O
+of,O
+the,O
+proximity,O
+of,O
+the,O
+defective,O
+gene,O
+to,O
+the,O
+centromere,O
+of,O
+chromosome,O
+11,O
+.,O
+ , 
+#18446851
+Parkes,O
+Weber,O
+syndrome,O
+,,O
+vein,O
+of,O
+Galen,O
+aneurysmal,O
+malformation,O
+,,O
+and,O
+other,O
+fast,O
+-,O
+flow,O
+vascular,O
+anomalies,O
+are,O
+caused,O
+by,O
+RASA1,B-Gene
+mutations,O
+.,O
+ , 
+Capillary,O
+malformation,O
+-,O
+arteriovenous,O
+malformation,O
+(,O
+CM,O
+-,O
+AVM,O
+),O
+is,O
+a,O
+newly,O
+recognized,O
+autosomal,O
+dominant,O
+disorder,O
+,,O
+caused,O
+by,O
+mutations,O
+in,O
+the,O
+RASA1,B-Gene
+gene,O
+in,O
+six,O
+families,O
+.,O
+ , 
+Here,O
+we,O
+report,O
+42,O
+novel,O
+RASA1,B-Gene
+mutations,O
+and,O
+the,O
+associated,O
+phenotype,O
+in,O
+44,O
+families,O
+.,O
+ , 
+The,O
+penetrance,O
+and,O
+de,O
+novo,O
+occurrence,O
+were,O
+high,O
+.,O
+ , 
+All,O
+affected,O
+individuals,O
+presented,O
+multifocal,O
+capillary,O
+malformations,O
+(,O
+CMs,O
+),O
+,,O
+which,O
+represent,O
+the,O
+hallmark,O
+of,O
+the,O
+disorder,O
+.,O
+ , 
+Importantly,O
+,,O
+one,O
+-,O
+third,O
+had,O
+fast,O
+-,O
+flow,O
+vascular,O
+lesions,O
+.,O
+ , 
+Among,O
+them,O
+,,O
+we,O
+observed,O
+severe,O
+intracranial,O
+AVMs,O
+,,O
+including,O
+vein,O
+of,O
+Galen,O
+aneurysmal,O
+malformation,O
+,,O
+which,O
+were,O
+symptomatic,O
+at,O
+birth,O
+or,O
+during,O
+infancy,O
+,,O
+extracranial,O
+AVM,O
+of,O
+the,O
+face,O
+and,O
+extremities,O
+,,O
+and,O
+Parkes,O
+Weber,O
+syndrome,O
+(,O
+PKWS,O
+),O
+,,O
+previously,O
+considered,O
+sporadic,O
+and,O
+nongenetic,O
+.,O
+ , 
+These,O
+fast,O
+-,O
+flow,O
+lesions,O
+can,O
+be,O
+differed,O
+from,O
+the,O
+other,O
+two,O
+genetic,O
+AVMs,O
+seen,O
+in,O
+hereditary,O
+hemorrhagic,O
+telangiectasia,O
+(,O
+HHT,O
+),O
+and,O
+in,O
+phosphatase,O
+and,O
+tensin,O
+homolog,O
+(,O
+PTEN,O
+),O
+hamartomatous,O
+tumor,O
+syndrome,O
+.,O
+ , 
+Finally,O
+,,O
+some,O
+CM,O
+-,O
+AVM,O
+patients,O
+had,O
+neural,O
+tumors,O
+reminiscent,O
+of,O
+neurofibromatosis,O
+type,O
+1,O
+or,O
+2,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+extensive,O
+study,O
+on,O
+the,O
+phenotypes,O
+associated,O
+with,O
+RASA1,B-Gene
+mutations,O
+,,O
+and,O
+unravels,O
+their,O
+wide,O
+heterogeneity,O
+.,O
+ , 
+#7977356
+High,O
+-,O
+resolution,O
+linkage,O
+-,O
+disequilibrium,O
+mapping,O
+of,O
+the,O
+cartilage,O
+-,O
+hair,O
+hypoplasia,O
+gene,O
+.,O
+ , 
+We,O
+recently,O
+assigned,O
+the,O
+gene,O
+for,O
+an,O
+autosomal,O
+recessive,O
+skeletal,O
+dysplasia,O
+,,O
+cartilage,O
+-,O
+hair,O
+hypoplasia,O
+(,B-Gene
+CHH,I-Gene
+),I-Gene
+,,O
+to,O
+9p21,O
+-,O
+p13,O
+in,O
+Finnish,O
+and,O
+Amish,O
+families,O
+.,O
+ , 
+An,O
+association,O
+was,O
+observed,O
+between,O
+CHH,B-Gene
+and,O
+alleles,O
+at,O
+D9S163,O
+in,O
+both,O
+family,O
+series,O
+,,O
+suggesting,O
+that,O
+these,O
+loci,O
+are,O
+in,O
+linkage,O
+disequilibrium,O
+and,O
+close,O
+to,O
+each,O
+other,O
+.,O
+ , 
+Here,O
+we,O
+extended,O
+these,O
+studies,O
+by,O
+exploiting,O
+the,O
+linkage,O
+-,O
+disequilibrium,O
+information,O
+that,O
+can,O
+be,O
+obtained,O
+from,O
+families,O
+with,O
+a,O
+single,O
+affected,O
+child,O
+,,O
+and,O
+we,O
+studied,O
+66,O
+Finnish,O
+CHH,B-Gene
+families,O
+with,O
+seven,O
+microsatellite,O
+markers,O
+.,O
+ , 
+The,O
+analysis,O
+based,O
+on,O
+the,O
+Luria,O
+and,O
+Delbrück,O
+(,O
+1943,O
+),O
+method,O
+and,O
+adapted,O
+to,O
+the,O
+study,O
+of,O
+human,O
+founder,O
+populations,O
+suggests,O
+that,O
+the,O
+distance,O
+between,O
+CHH,B-Gene
+and,O
+D9S163,O
+is,O
+approximately,O
+0.3,O
+cM.,O
+ , 
+An,O
+eight,O
+-,O
+point,O
+linkage,O
+analysis,O
+modified,O
+to,O
+take,O
+advantage,O
+of,O
+all,O
+possible,O
+information,O
+in,O
+15,O
+Finnish,O
+and,O
+17,O
+Amish,O
+families,O
+was,O
+capable,O
+of,O
+narrowing,O
+the,O
+likely,O
+location,O
+of,O
+CHH,B-Gene
+to,O
+within,O
+an,O
+interval,O
+of,O
+1.7,O
+cM,O
+on,O
+a,O
+male,O
+map,O
+.,O
+ , 
+The,O
+peak,O
+lod,O
+score,O
+of,O
+54.92,O
+was,O
+attained,O
+0.03,O
+and,O
+0.1,O
+cM,O
+proximal,O
+to,O
+D9S163,O
+on,O
+the,O
+male,O
+and,O
+female,O
+maps,O
+,,O
+respectively,O
+.,O
+ , 
+These,O
+results,O
+confirm,O
+the,O
+power,O
+of,O
+genetic,O
+resolution,O
+,,O
+that,O
+lies,O
+in,O
+the,O
+study,O
+of,O
+linkage,O
+disequilibrium,O
+in,O
+well,O
+-,O
+defined,O
+founder,O
+populations,O
+with,O
+one,O
+major,O
+ancestral,O
+disease,O
+mutation,O
+.,O
+ , 
+#19931040
+Simultaneous,O
+genotype,O
+calling,O
+and,O
+haplotype,O
+phasing,O
+improves,O
+genotype,O
+accuracy,O
+and,O
+reduces,O
+false,O
+-,O
+positive,O
+associations,O
+for,O
+genome,O
+-,O
+wide,O
+association,O
+studies,O
+.,O
+ , 
+We,O
+present,O
+a,O
+novel,O
+method,O
+for,O
+simultaneous,O
+genotype,O
+calling,O
+and,O
+haplotype,O
+-,O
+phase,O
+inference,O
+.,O
+ , 
+Our,O
+method,O
+employs,O
+the,O
+computationally,O
+efficient,O
+BEAGLE,O
+haplotype,O
+-,O
+frequency,O
+model,O
+,,O
+which,O
+can,O
+be,O
+applied,O
+to,O
+large,O
+-,O
+scale,O
+studies,O
+with,O
+millions,O
+of,O
+markers,O
+and,O
+thousands,O
+of,O
+samples,O
+.,O
+ , 
+We,O
+compare,O
+genotype,O
+calls,O
+made,O
+with,O
+our,O
+method,O
+to,O
+genotype,O
+calls,O
+made,O
+with,O
+the,O
+BIRDSEED,O
+,,O
+CHIAMO,O
+,,O
+GenCall,O
+,,O
+and,O
+ILLUMINUS,O
+genotype,O
+-,O
+calling,O
+methods,O
+,,O
+using,O
+genotype,O
+data,O
+from,O
+the,O
+Illumina,O
+550,O
+K,O
+and,O
+Affymetrix,O
+500,O
+K,O
+arrays,O
+.,O
+ , 
+We,O
+show,O
+that,O
+our,O
+method,O
+has,O
+higher,O
+genotype,O
+-,O
+call,O
+accuracy,O
+and,O
+yields,O
+fewer,O
+uncalled,O
+genotypes,O
+than,O
+competing,O
+methods,O
+.,O
+ , 
+We,O
+perform,O
+single,O
+-,O
+marker,O
+analysis,O
+of,O
+data,O
+from,O
+the,O
+Wellcome,O
+Trust,O
+Case,O
+Control,O
+Consortium,O
+bipolar,O
+disorder,O
+and,O
+type,O
+2,O
+diabetes,O
+studies,O
+.,O
+ , 
+For,O
+bipolar,O
+disorder,O
+,,O
+the,O
+genotype,O
+calls,O
+in,O
+the,O
+original,O
+study,O
+yield,O
+25,O
+markers,O
+with,O
+apparent,O
+false,O
+-,O
+positive,O
+association,O
+with,O
+bipolar,O
+disorder,O
+at,O
+a,O
+p,O
+<,O
+10(-7,O
+),O
+significance,O
+level,O
+,,O
+whereas,O
+genotype,O
+calls,O
+made,O
+with,O
+our,O
+method,O
+yield,O
+no,O
+associated,O
+markers,O
+at,O
+this,O
+significance,O
+threshold,O
+.,O
+ , 
+Conversely,O
+,,O
+for,O
+markers,O
+with,O
+replicated,O
+association,O
+with,O
+type,O
+2,O
+diabetes,O
+,,O
+there,O
+is,O
+good,O
+concordance,O
+between,O
+genotype,O
+calls,O
+used,O
+in,O
+the,O
+original,O
+study,O
+and,O
+calls,O
+made,O
+by,O
+our,O
+method,O
+.,O
+ , 
+Results,O
+from,O
+single,O
+-,O
+marker,O
+and,O
+haplotypic,O
+analysis,O
+of,O
+our,O
+method,O
+'s,O
+genotype,O
+calls,O
+for,O
+the,O
+bipolar,O
+disorder,O
+study,O
+indicate,O
+that,O
+our,O
+method,O
+is,O
+highly,O
+effective,O
+at,O
+eliminating,O
+genotyping,O
+artifacts,O
+that,O
+cause,O
+false,O
+-,O
+positive,O
+associations,O
+in,O
+genome,O
+-,O
+wide,O
+association,O
+studies,O
+.,O
+ , 
+Our,O
+new,O
+genotype,O
+-,O
+calling,O
+methods,O
+are,O
+implemented,O
+in,O
+the,O
+BEAGLE,O
+and,O
+BEAGLECALL,O
+software,O
+packages,O
+.,O
+ , 
+#8533759
+Phenylketonuria,O
+mutation,O
+analysis,O
+in,O
+Northern,O
+Ireland,O
+:,O
+a,O
+rapid,O
+stepwise,O
+approach,O
+.,O
+ , 
+We,O
+present,O
+a,O
+multistep,O
+approach,O
+for,O
+the,O
+rapid,O
+analysis,O
+of,O
+phenylketonuria,O
+(,O
+PKU,O
+),O
+mutations,O
+.,O
+ , 
+In,O
+the,O
+first,O
+step,O
+,,O
+three,O
+common,O
+mutations,O
+and,O
+a,O
+polymorphic,O
+short,O
+tandem,O
+repeat,O
+(,O
+STR,O
+),O
+system,O
+are,O
+rapidly,O
+analyzed,O
+with,O
+a,O
+fluorescent,O
+multiplex,O
+assay,O
+.,O
+ , 
+In,O
+the,O
+second,O
+step,O
+,,O
+minihaplotypes,O
+combining,O
+STR,O
+and,O
+VNTR,O
+data,O
+are,O
+used,O
+to,O
+determine,O
+rare,O
+mutations,O
+likely,O
+to,O
+be,O
+present,O
+in,O
+an,O
+investigated,O
+patient,O
+,,O
+which,O
+are,O
+then,O
+confirmed,O
+by,O
+restriction,O
+enzyme,O
+analysis,O
+.,O
+ , 
+The,O
+remaining,O
+mutations,O
+are,O
+analyzed,O
+with,O
+denaturant,O
+gradient,O
+-,O
+gel,O
+electrophoresis,O
+and,O
+sequencing,O
+.,O
+ , 
+The,O
+first,O
+two,O
+steps,O
+together,O
+identify,O
+both,O
+mutations,O
+in,O
+90%-95,O
+%,O
+of,O
+PKU,B-Gene
+patients,O
+,,O
+and,O
+results,O
+can,O
+be,O
+obtained,O
+within,O
+2,O
+d.,O
+ , 
+We,O
+have,O
+investigated,O
+121,O
+Northern,O
+Irish,O
+families,O
+with,O
+hyperphenylalaninemia,O
+,,O
+including,O
+virtually,O
+all,O
+patients,O
+born,O
+since,O
+1972,O
+,,O
+and,O
+have,O
+found,O
+34,O
+different,O
+mutations,O
+on,O
+241,O
+of,O
+the,O
+242,O
+mutant,O
+alleles,O
+.,O
+ , 
+Three,O
+mutations,O
+(,B-SNP
+R408W,I-SNP
+,,I-SNP
+I65,B-SNP
+T,I-SNP
+,,I-SNP
+and,O
+F39L,B-SNP
+),I-SNP
+account,O
+for,O
+57.5,O
+%,O
+of,O
+mutations,O
+,,O
+while,O
+14,O
+mutations,O
+occur,O
+with,O
+a,O
+frequency,O
+of,O
+1%-6,O
+%,O
+.,O
+ , 
+The,O
+present,O
+analysis,O
+system,O
+is,O
+efficient,O
+and,O
+inexpensive,O
+and,O
+is,O
+particularly,O
+well,O
+suited,O
+to,O
+routine,O
+mutation,O
+analysis,O
+in,O
+a,O
+diagnostic,O
+setting,O
+.,O
+ , 
+#21529752
+The,O
+essential,O
+role,O
+of,O
+centrosomal,O
+NDE1,B-Gene
+in,O
+human,O
+cerebral,O
+cortex,O
+neurogenesis,O
+.,O
+ , 
+We,O
+investigated,O
+three,O
+families,O
+whose,O
+offspring,O
+had,O
+extreme,O
+microcephaly,O
+at,O
+birth,O
+and,O
+profound,O
+mental,O
+retardation,O
+.,O
+ , 
+Brain,O
+scans,O
+and,O
+postmortem,O
+data,O
+showed,O
+that,O
+affected,O
+individuals,O
+had,O
+brains,O
+less,O
+than,O
+10,O
+%,O
+of,O
+expected,O
+size,O
+(,O
+≤10,O
+standard,O
+deviation,O
+),O
+and,O
+that,O
+in,O
+addition,O
+to,O
+a,O
+massive,O
+reduction,O
+in,O
+neuron,O
+production,O
+they,O
+displayed,O
+partially,O
+deficient,O
+cortical,O
+lamination,O
+(,O
+microlissencephaly,O
+),O
+.,O
+ , 
+Other,O
+ ,O
+body,O
+systems,O
+were,O
+apparently,O
+unaffected,O
+and,O
+overall,O
+growth,O
+was,O
+normal,O
+.,O
+ , 
+We,O
+found,O
+two,O
+distinct,O
+homozygous,O
+mutations,O
+of,O
+NDE1,B-Gene
+,,I-Gene
+c.83,B-SNP
++,I-SNP
+1G,I-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+Ala29GlnfsX114,I-SNP
+),I-SNP
+in,O
+a,O
+Turkish,O
+family,O
+and,O
+c.684_685del,B-SNP
+(,B-SNP
+p.,I-SNP
+Pro229TrpfsX85,I-SNP
+),I-SNP
+in,O
+two,O
+families,O
+of,O
+Pakistani,O
+origin,O
+.,O
+ , 
+Using,O
+patient,O
+cells,O
+,,O
+we,O
+found,O
+that,O
+c.83,B-SNP
++,I-SNP
+1G,I-SNP
+>,I-SNP
+T,I-SNP
+led,O
+to,O
+the,O
+use,O
+of,O
+a,O
+novel,O
+splice,O
+site,O
+and,O
+to,O
+a,O
+frameshift,O
+after,O
+NDE1,B-Gene
+exon,O
+2,O
+.,O
+ , 
+Transfection,O
+of,O
+tagged,O
+NDE1,B-Gene
+constructs,O
+showed,O
+that,O
+the,O
+c.684_685del,B-SNP
+mutation,O
+resulted,O
+in,O
+a,O
+NDE1,B-Gene
+that,O
+was,O
+unable,O
+to,O
+localize,O
+to,O
+the,O
+centrosome,O
+.,O
+ , 
+By,O
+staining,O
+a,O
+patient,O
+-,O
+derived,O
+cell,O
+line,O
+that,O
+carried,O
+the,O
+c.83,B-SNP
++,I-SNP
+1G,I-SNP
+>,I-SNP
+T,I-SNP
+mutation,O
+,,O
+we,O
+found,O
+that,O
+this,O
+endogeneously,O
+expressed,O
+mutated,O
+protein,O
+equally,O
+failed,O
+to,O
+localize,O
+to,O
+the,O
+centrosome,O
+.,O
+ , 
+By,O
+examining,O
+human,O
+and,O
+mouse,O
+embryonic,O
+brains,O
+,,O
+we,O
+determined,O
+that,O
+NDE1,B-Gene
+is,O
+highly,O
+expressed,O
+in,O
+neuroepithelial,O
+cells,O
+of,O
+the,O
+developing,O
+cerebral,O
+cortex,O
+,,O
+particularly,O
+at,O
+the,O
+centrosome,O
+.,O
+ , 
+We,O
+show,O
+that,O
+NDE1,B-Gene
+accumulates,O
+on,O
+the,O
+mitotic,O
+spindle,O
+of,O
+apical,O
+neural,O
+precursors,O
+in,O
+early,O
+neurogenesis,O
+.,O
+ , 
+Thus,O
+,,O
+NDE1,B-Gene
+deficiency,O
+causes,O
+both,O
+a,O
+severe,O
+failure,O
+of,O
+neurogenesis,O
+and,O
+a,O
+deficiency,O
+in,O
+cortical,O
+lamination,O
+.,O
+ , 
+Our,O
+data,O
+further,O
+highlight,O
+the,O
+importance,O
+of,O
+the,O
+centrosome,O
+in,O
+multiple,O
+aspects,O
+of,O
+neurodevelopment,O
+.,O
+ , 
+#7599639
+Novel,O
+(,B-SNP
+cys152,I-SNP
+>,I-SNP
+arg,I-SNP
+),I-SNP
+missense,O
+mutation,O
+in,O
+an,O
+Arab,O
+patient,O
+with,O
+Canavan,O
+disease,O
+.,O
+ , 
+#1729895
+Decreased,O
+fecundability,O
+in,O
+Hutterite,O
+couples,O
+sharing,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
+.,I-Gene
+ , 
+To,O
+study,O
+the,O
+effects,O
+of,O
+parental,O
+HLA,B-Gene
+sharing,O
+on,O
+pregnancy,O
+outcome,O
+,,O
+we,O
+initiated,O
+population,O
+-,O
+based,O
+studies,O
+in,O
+the,O
+Hutterites,O
+.,O
+ , 
+We,O
+previously,O
+reported,O
+longer,O
+intervals,O
+from,O
+marriage,O
+to,O
+each,O
+birth,O
+among,O
+couples,O
+sharing,O
+HLA,B-Gene
+,,I-Gene
+particularly,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
+.,I-Gene
+ , 
+In,O
+the,O
+present,O
+report,O
+,,O
+we,O
+present,O
+the,O
+results,O
+of,O
+a,O
+prospective,O
+,,O
+5,O
+-,O
+year,O
+study,O
+of,O
+fecundability,O
+and,O
+fetal,O
+loss,O
+rates,O
+in,O
+this,O
+population,O
+.,O
+ , 
+Between,O
+April,O
+1986,O
+and,O
+April,O
+1991,O
+,,O
+154,O
+pregnancies,O
+were,O
+observed,O
+in,O
+104,O
+couples,O
+.,O
+ , 
+The,O
+median,O
+number,O
+of,O
+months,O
+of,O
+unprotected,O
+intercourse,O
+to,O
+a,O
+positive,O
+pregnancy,O
+test,O
+was,O
+significantly,O
+longer,O
+among,O
+couples,O
+sharing,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
+who,O
+stopped,O
+nursing,O
+prior,O
+to,O
+the,O
+first,O
+menses,O
+as,O
+compared,O
+with,O
+couples,O
+not,O
+sharing,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
+who,O
+stopped,O
+nursing,O
+prior,O
+to,O
+the,O
+first,O
+menses,O
+(,O
+5.1,O
+vs.,O
+2.0,O
+mo,O
+,,O
+respectively,O
+;,O
+P,O
+=,O
+.016,O
+),O
+.,O
+ , 
+Fetal,O
+loss,O
+rates,O
+were,O
+increased,O
+among,O
+couples,O
+sharing,O
+HLA,B-Gene
+-,I-Gene
+B,I-Gene
+as,O
+compared,O
+with,O
+couples,O
+not,O
+sharing,O
+HLA,B-Gene
+-,I-Gene
+B,I-Gene
+(,O
+.23,O
+vs.,O
+.12,O
+,,O
+respectively,O
+;,O
+P,O
+=,O
+.041,O
+,,O
+adjusted,O
+for,O
+age,O
+,,O
+gravidity,O
+,,O
+and,O
+kinship,O
+),O
+.,O
+ , 
+These,O
+data,O
+suggest,O
+that,O
+our,O
+earlier,O
+observations,O
+of,O
+increased,O
+birth,O
+interval,O
+lengths,O
+among,O
+Hutterite,O
+couples,O
+sharing,O
+HLA,B-Gene
+were,O
+predominantly,O
+due,O
+to,O
+longer,O
+intervals,O
+until,O
+a,O
+clinical,O
+pregnancy,O
+among,O
+couples,O
+sharing,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
+and,O
+,,O
+to,O
+a,O
+lesser,O
+degree,O
+,,O
+were,O
+due,O
+to,O
+increased,O
+fetal,O
+loss,O
+rates,O
+among,O
+couples,O
+sharing,O
+HLA,B-Gene
+-,I-Gene
+B.,I-Gene
+ , 
+#19896112
+CNTNAP2,B-Gene
+and,O
+NRXN1,B-Gene
+are,O
+mutated,O
+in,O
+autosomal,O
+-,O
+recessive,O
+Pitt,O
+-,O
+Hopkins,O
+-,O
+like,O
+mental,O
+retardation,O
+and,O
+determine,O
+the,O
+level,O
+of,O
+a,O
+common,O
+synaptic,O
+protein,O
+in,O
+Drosophila,O
+.,O
+ , 
+Heterozygous,O
+copy,O
+-,O
+number,O
+variants,O
+and,O
+SNPs,O
+of,O
+CNTNAP2,B-Gene
+and,O
+NRXN1,B-Gene
+,,I-Gene
+two,O
+distantly,O
+related,O
+members,O
+of,O
+the,O
+neurexin,O
+superfamily,O
+,,O
+have,O
+been,O
+repeatedly,O
+associated,O
+with,O
+a,O
+wide,O
+spectrum,O
+of,O
+neuropsychiatric,O
+disorders,O
+,,O
+such,O
+as,O
+developmental,O
+language,O
+disorders,O
+,,O
+autism,O
+spectrum,O
+disorders,O
+,,O
+epilepsy,O
+,,O
+and,O
+schizophrenia,O
+.,O
+ , 
+We,O
+now,O
+identified,O
+homozygous,O
+and,O
+compound,O
+-,O
+heterozygous,O
+deletions,O
+and,O
+mutations,O
+via,O
+molecular,O
+karyotyping,O
+and,O
+mutational,O
+screening,O
+in,O
+CNTNAP2,B-Gene
+and,O
+NRXN1,B-Gene
+in,O
+four,O
+patients,O
+with,O
+severe,O
+mental,O
+retardation,O
+(,O
+MR,O
+),O
+and,O
+variable,O
+features,O
+,,O
+such,O
+as,O
+autistic,O
+behavior,O
+,,O
+epilepsy,O
+,,O
+and,O
+breathing,O
+anomalies,O
+,,O
+phenotypically,O
+overlapping,O
+with,O
+Pitt,O
+-,O
+Hopkins,O
+syndrome,O
+.,O
+ , 
+With,O
+a,O
+frequency,O
+of,O
+at,O
+least,O
+1,O
+%,O
+in,O
+our,O
+cohort,O
+of,O
+179,O
+patients,O
+,,O
+recessive,O
+defects,O
+in,O
+CNTNAP2,B-Gene
+appear,O
+to,O
+significantly,O
+contribute,O
+to,O
+severe,O
+MR,O
+.,O
+ , 
+Whereas,O
+the,O
+established,O
+synaptic,O
+role,O
+of,O
+NRXN1,B-Gene
+suggests,O
+that,O
+synaptic,O
+defects,O
+contribute,O
+to,O
+the,O
+associated,O
+neuropsychiatric,O
+disorders,O
+and,O
+to,O
+severe,O
+MR,O
+as,O
+reported,O
+here,O
+,,O
+evidence,O
+for,O
+a,O
+synaptic,O
+role,O
+of,O
+the,O
+CNTNAP2,O
+-,O
+encoded,O
+protein,O
+CASPR2,B-Gene
+has,O
+so,O
+far,O
+been,O
+lacking,O
+.,O
+ , 
+Using,O
+Drosophila,O
+as,O
+a,O
+model,O
+,,O
+we,O
+now,O
+show,O
+that,O
+,,O
+as,O
+known,O
+for,O
+fly,O
+Nrx,B-Gene
+-,I-Gene
+I,I-Gene
+,,I-Gene
+the,O
+CASPR2,B-Gene
+ortholog,O
+Nrx,B-Gene
+-,I-Gene
+IV,I-Gene
+might,O
+also,O
+localize,O
+to,O
+synapses,O
+.,O
+ , 
+Overexpression,O
+of,O
+either,O
+protein,O
+can,O
+reorganize,O
+synaptic,O
+morphology,O
+and,O
+induce,O
+increased,O
+density,O
+of,O
+active,O
+zones,O
+,,O
+the,O
+synaptic,O
+domains,O
+of,O
+neurotransmitter,O
+release,O
+.,O
+ , 
+Moreover,O
+,,O
+both,O
+Nrx,B-Gene
+-,I-Gene
+I,I-Gene
+and,O
+Nrx,B-Gene
+-,I-Gene
+IV,I-Gene
+determine,O
+the,O
+level,O
+of,O
+the,O
+presynaptic,O
+active,O
+-,O
+zone,O
+protein,O
+bruchpilot,O
+,,O
+indicating,O
+a,O
+possible,O
+common,O
+molecular,O
+mechanism,O
+in,O
+Nrx,B-Gene
+-,I-Gene
+I,I-Gene
+and,O
+Nrx,B-Gene
+-,I-Gene
+IV,I-Gene
+mutant,O
+conditions,O
+.,O
+ , 
+We,O
+therefore,O
+propose,O
+that,O
+an,O
+analogous,O
+shared,O
+synaptic,O
+mechanism,O
+contributes,O
+to,O
+the,O
+similar,O
+clinical,O
+phenotypes,O
+resulting,O
+from,O
+defects,O
+in,O
+human,O
+NRXN1,B-Gene
+and,O
+CNTNAP2,B-Gene
+.,I-Gene
+ , 
+#8199594
+Identification,O
+of,O
+a,O
+point,O
+mutation,O
+and,O
+germinal,O
+mosaicism,O
+in,O
+a,O
+Duchenne,O
+muscular,O
+dystrophy,O
+family,O
+.,O
+ , 
+Duchenne,O
+and,O
+Becker,O
+muscular,O
+dystrophies,O
+(,O
+DMD,O
+and,O
+BMD,O
+),O
+are,O
+allelic,O
+X,O
+-,O
+linked,O
+disorders,O
+arising,O
+from,O
+mutations,O
+in,O
+the,O
+(,O
+2.4,O
+Mb,O
+),O
+dystrophin,B-Gene
+gene,O
+at,O
+Xp21,O
+.,O
+ , 
+We,O
+have,O
+applied,O
+the,O
+reverse,O
+transcriptase,O
+-,O
+polymerase,O
+chain,O
+reaction,O
+(,O
+RT,O
+-,O
+PCR,O
+),O
+to,O
+identify,O
+a,O
+larger,O
+than,O
+normal,O
+dystrophin,B-Gene
+mRNA,O
+from,O
+a,O
+male,O
+with,O
+Duchenne,O
+muscular,O
+dystrophy,O
+and,O
+his,O
+younger,O
+affected,O
+brother,O
+.,O
+ , 
+The,O
+increased,O
+size,O
+of,O
+the,O
+dystrophin,B-Gene
+mRNA,O
+was,O
+due,O
+to,O
+a,O
+splice,O
+-,O
+site,O
+mutation,O
+at,O
+the,O
+exon,O
+26,O
+:,O
+intron,O
+26,O
+junction,O
+where,O
+a,O
+T,O
+to,O
+G,O
+substitution,O
+prevented,O
+normal,O
+RNA,O
+processing,O
+.,O
+ , 
+A,O
+cryptic,O
+splice,O
+-,O
+site,O
+,,O
+downstream,O
+of,O
+the,O
+mutation,O
+,,O
+was,O
+activated,O
+during,O
+processing,O
+,,O
+resulting,O
+in,O
+the,O
+inclusion,O
+of,O
+117,O
+bases,O
+of,O
+intron,O
+26,O
+.,O
+ , 
+This,O
+insertion,O
+introduced,O
+an,O
+in,O
+-,O
+frame,O
+stop,O
+codon,O
+into,O
+the,O
+mature,O
+dystrophin,O
+mRNA,O
+.,O
+ , 
+An,O
+allele,O
+-,O
+specific,O
+test,O
+was,O
+developed,O
+to,O
+identify,O
+the,O
+mutation,O
+and,O
+was,O
+applied,O
+to,O
+this,O
+family,O
+.,O
+ , 
+Interestingly,O
+,,O
+the,O
+mother,O
+of,O
+the,O
+two,O
+affected,O
+boys,O
+did,O
+not,O
+carry,O
+the,O
+mutation,O
+,,O
+as,O
+determined,O
+by,O
+allele,O
+-,O
+specific,O
+amplification,O
+and,O
+direct,O
+DNA,O
+sequence,O
+analysis,O
+,,O
+indicating,O
+gonadal,O
+mosaicism,O
+.,O
+ , 
+Her,O
+eldest,O
+daughter,O
+,,O
+designated,O
+as,O
+a,O
+carrier,O
+based,O
+upon,O
+conventional,O
+testing,O
+and,O
+haplotype,O
+analysis,O
+,,O
+also,O
+did,O
+not,O
+carry,O
+the,O
+family,O
+mutation,O
+.,O
+ , 
+Initial,O
+haplotyping,O
+of,O
+the,O
+family,O
+appeared,O
+to,O
+be,O
+straightforward,O
+with,O
+gonadal,O
+mosaicism,O
+becoming,O
+evident,O
+only,O
+after,O
+allele,O
+-,O
+specific,O
+analysis,O
+.,O
+ , 
+The,O
+application,O
+of,O
+linked,O
+markers,O
+to,O
+identify,O
+the,O
+disease,O
+allele,O
+for,O
+conventional,O
+genetic,O
+counselling,O
+would,O
+have,O
+been,O
+erroneous,O
+in,O
+this,O
+family,O
+and,O
+highlights,O
+the,O
+diagnostic,O
+power,O
+of,O
+precise,O
+identification,O
+of,O
+the,O
+disease,O
+-,O
+causing,O
+mutation,O
+.,O
+ , 
+#19118813
+Fine,O
+mapping,O
+on,O
+chromosome,O
+10q22,O
+-,O
+q23,O
+implicates,O
+Neuregulin,B-Gene
+3,I-Gene
+in,O
+schizophrenia,O
+.,O
+ , 
+Linkage,O
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+implicated,O
+10q22,O
+-,O
+q23,O
+as,O
+a,O
+schizophrenia,O
+(,O
+SZ,O
+),O
+susceptibility,O
+locus,O
+in,O
+Ashkenazi,O
+Jewish,O
+(,O
+AJ,O
+),O
+and,O
+Han,O
+Chinese,O
+from,O
+Taiwan,O
+populations,O
+.,O
+ , 
+To,O
+further,O
+explore,O
+our,O
+previous,O
+linkage,O
+signal,O
+in,O
+the,O
+AJ,O
+population,O
+(,O
+NPL,O
+score,O
+:,O
+4.27,O
+,,O
+empirical,O
+p,O
+=,O
+2,O
+x,O
+10(-5,O
+),O
+),O
+,,O
+we,O
+performed,O
+a,O
+peakwide,O
+association,O
+fine,O
+mapping,O
+study,O
+by,O
+using,O
+1414,O
+SNPs,O
+across,O
+approximately,O
+12.5,O
+Mb,O
+in,O
+10q22,O
+-,O
+q23,O
+.,O
+ , 
+We,O
+genotyped,O
+1515,O
+AJ,O
+individuals,O
+,,O
+including,O
+285,O
+parent,O
+-,O
+child,O
+trios,O
+,,O
+173,O
+unrelated,O
+cases,O
+,,O
+and,O
+487,O
+unrelated,O
+controls,O
+.,O
+ , 
+We,O
+analyzed,O
+the,O
+binary,O
+diagnostic,O
+phenotype,O
+of,O
+SZ,O
+and,O
+9,O
+heritable,O
+quantitative,O
+traits,O
+derived,O
+from,O
+a,O
+principal,O
+components,O
+factor,O
+analysis,O
+of,O
+73,O
+items,O
+from,O
+our,O
+consensus,O
+diagnostic,O
+ratings,O
+and,O
+direct,O
+assessment,O
+interviews,O
+.,O
+ , 
+Although,O
+no,O
+marker,O
+withstood,O
+multiple,O
+test,O
+correction,O
+for,O
+association,O
+with,O
+the,O
+binary,O
+SZ,O
+phenotype,O
+,,O
+we,O
+found,O
+strong,O
+evidence,O
+of,O
+association,O
+by,O
+using,O
+the,O
+",O
+delusion,O
+",O
+factor,O
+as,O
+the,O
+quantitative,O
+trait,O
+at,O
+three,O
+SNPs,O
+(,O
+rs10883866,O
+,,O
+rs10748842,O
+,,O
+and,O
+rs6584400,O
+),O
+located,O
+in,O
+a,O
+13,O
+kb,O
+interval,O
+in,O
+intron,O
+1,O
+of,O
+Neuregulin,B-Gene
+3,I-Gene
+(,B-Gene
+NRG3,I-Gene
+),I-Gene
+.,O
+ , 
+Our,O
+best,O
+p,O
+value,O
+from,O
+family,O
+-,O
+based,O
+association,O
+analysis,O
+was,O
+7.26,O
+x,O
+10(-7,O
+),O
+.,O
+ , 
+We,O
+replicated,O
+this,O
+association,O
+in,O
+the,O
+collection,O
+of,O
+173,O
+unrelated,O
+AJ,O
+cases,O
+(,O
+p,O
+=,O
+1.55,O
+x,O
+10(-2,O
+),O
+),O
+,,O
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+a,O
+combined,O
+p,O
+value,O
+of,O
+2.30,O
+x,O
+10(-7,O
+),O
+.,O
+ , 
+After,O
+performing,O
+10,000,O
+permutations,O
+of,O
+each,O
+of,O
+the,O
+phenotypes,O
+,,O
+we,O
+estimated,O
+the,O
+empirical,O
+study,O
+-,O
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+significance,O
+across,O
+all,O
+9,O
+factors,O
+(,O
+90,000,O
+permutations,O
+),O
+to,O
+be,O
+p,O
+=,O
+2.7,O
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+),O
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+NRG3,B-Gene
+is,O
+primarily,O
+expressed,O
+in,O
+the,O
+central,O
+nervous,O
+system,O
+and,O
+is,O
+one,O
+of,O
+three,O
+paralogs,O
+of,O
+NRG1,B-Gene
+,,I-Gene
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+SZ,O
+.,O
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+These,O
+biological,O
+properties,O
+together,O
+with,O
+our,O
+linkage,O
+and,O
+association,O
+results,O
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+support,O
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+gene,O
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+SZ,O
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+#21376301
+Estimating,O
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+Genome,O
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+designed,O
+to,O
+discover,O
+SNPs,O
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+with,O
+a,O
+complex,O
+trait,O
+.,O
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+Employing,O
+strict,O
+significance,O
+thresholds,O
+when,O
+testing,O
+individual,O
+SNPs,O
+avoids,O
+false,O
+positives,O
+at,O
+the,O
+expense,O
+of,O
+increasing,O
+false,O
+negatives,O
+.,O
+ , 
+Recently,O
+,,O
+we,O
+developed,O
+a,O
+method,O
+for,O
+quantitative,O
+traits,O
+that,O
+estimates,O
+the,O
+variation,O
+accounted,O
+for,O
+when,O
+fitting,O
+all,O
+SNPs,O
+simultaneously,O
+.,O
+ , 
+Here,O
+we,O
+develop,O
+this,O
+method,O
+further,O
+for,O
+case,O
+-,O
+control,O
+studies,O
+.,O
+ , 
+We,O
+use,O
+a,O
+linear,O
+mixed,O
+model,O
+for,O
+analysis,O
+of,O
+binary,O
+traits,O
+and,O
+transform,O
+the,O
+estimates,O
+to,O
+a,O
+liability,O
+scale,O
+by,O
+adjusting,O
+both,O
+for,O
+scale,O
+and,O
+for,O
+ascertainment,O
+of,O
+the,O
+case,O
+samples,O
+.,O
+ , 
+We,O
+show,O
+by,O
+theory,O
+and,O
+simulation,O
+that,O
+the,O
+method,O
+is,O
+unbiased,O
+.,O
+ , 
+We,O
+apply,O
+the,O
+method,O
+to,O
+data,O
+from,O
+the,O
+Wellcome,O
+Trust,O
+Case,O
+Control,O
+Consortium,O
+and,O
+show,O
+that,O
+a,O
+substantial,O
+proportion,O
+of,O
+variation,O
+in,O
+liability,O
+for,O
+Crohn,O
+disease,O
+,,O
+bipolar,O
+disorder,O
+,,O
+and,O
+type,O
+I,O
+diabetes,O
+is,O
+tagged,O
+by,O
+common,O
+SNPs,O
+.,O
+ , 
+#22275001
+Nonsynonymous,O
+variants,O
+in,O
+the,O
+SMAD6,B-Gene
+gene,O
+predispose,O
+to,O
+congenital,O
+cardiovascular,O
+malformation,O
+.,O
+ , 
+Congenital,O
+cardiovascular,O
+malformation,O
+(,O
+CVM,O
+),O
+exhibits,O
+familial,O
+predisposition,O
+,,O
+but,O
+most,O
+of,O
+the,O
+specific,O
+genetic,O
+factors,O
+involved,O
+are,O
+unknown,O
+.,O
+ , 
+Postulating,O
+that,O
+rare,O
+variants,O
+in,O
+genes,O
+in,O
+critical,O
+cardiac,O
+developmental,O
+pathways,O
+predispose,O
+to,O
+CVM,O
+,,O
+we,O
+systematically,O
+surveyed,O
+three,O
+genes,O
+of,O
+the,O
+bone,O
+morphogenetic,O
+protein,O
+(,O
+BMP,O
+),O
+signaling,O
+pathway,O
+for,O
+novel,O
+variants,O
+.,O
+ , 
+Exonic,O
+,,O
+splice,O
+site,O
+,,O
+and,O
+untranslated,O
+regions,O
+of,O
+BMPR1A,B-Gene
+,,I-Gene
+BMPR2,B-Gene
+,,I-Gene
+and,O
+SMAD6,B-Gene
+genes,O
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+sequenced,O
+in,O
+90,O
+unrelated,O
+sporadic,O
+cases,O
+of,O
+CVM,O
+.,O
+ , 
+One,O
+nonsynonymous,O
+variant,O
+(,B-SNP
+p.,I-SNP
+C484F,I-SNP
+),I-SNP
+with,O
+predicted,O
+functional,O
+impact,O
+was,O
+found,O
+in,O
+the,O
+MAD,O
+homology,O
+2,O
+domain,O
+of,O
+SMAD6,B-Gene
+,,I-Gene
+an,O
+intracellular,O
+inhibitor,O
+of,O
+BMP,B-Gene
+signaling,O
+.,O
+ , 
+Sequencing,O
+this,O
+domain,O
+in,O
+an,O
+additional,O
+346,O
+cases,O
+of,O
+CVM,O
+yielded,O
+two,O
+further,O
+nonsynonymous,O
+variants,O
+(,B-SNP
+p.,I-SNP
+P415L,I-SNP
+and,O
+p.,B-SNP
+A325,I-SNP
+T,I-SNP
+),I-SNP
+.,O
+ , 
+Functional,O
+effects,O
+of,O
+all,O
+three,O
+SMAD6,B-Gene
+mutations,O
+were,O
+investigated,O
+using,O
+BMP,O
+signaling,O
+assays,O
+in,O
+vitro,O
+.,O
+ , 
+Two,O
+SMAD6,B-Gene
+variants,O
+(,B-SNP
+p.,I-SNP
+C484F,I-SNP
+and,O
+p.,B-SNP
+P415L,I-SNP
+),I-SNP
+had,O
+significantly,O
+(,O
+P,O
+<,O
+0.05,O
+),O
+lower,O
+activity,O
+than,O
+wild,O
+-,O
+type,O
+SMAD6,B-Gene
+in,O
+inhibiting,O
+BMP,O
+signaling,O
+in,O
+a,O
+transcriptional,O
+reporter,O
+assay,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+the,O
+p.,B-SNP
+C484F,I-SNP
+variant,O
+had,O
+a,O
+significantly,O
+(,O
+P,O
+<,O
+0.05,O
+),O
+lower,O
+capacity,O
+to,O
+inhibit,O
+an,O
+osteogenic,O
+response,O
+to,O
+BMP,O
+signaling,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+low,O
+-,O
+frequency,O
+deleterious,O
+variants,O
+in,O
+SMAD6,B-Gene
+predispose,O
+to,O
+CVM,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+report,O
+of,O
+a,O
+human,O
+disease,O
+phenotype,O
+related,O
+to,O
+genetic,O
+variation,O
+in,O
+SMAD6,B-Gene
+.,I-Gene
+ , 
+#15154114
+High,O
+prevalence,O
+of,O
+SLC6A8,B-Gene
+deficiency,O
+in,O
+X,O
+-,O
+linked,O
+mental,O
+retardation,O
+.,O
+ , 
+A,O
+novel,O
+X,O
+-,O
+linked,O
+mental,O
+retardation,O
+(,O
+XLMR,O
+),O
+syndrome,O
+was,O
+recently,O
+identified,O
+,,O
+resulting,O
+from,O
+creatine,O
+deficiency,O
+in,O
+the,O
+brain,O
+caused,O
+by,O
+mutations,O
+in,O
+the,O
+creatine,O
+transporter,O
+gene,O
+,,O
+SLC6A8,B-Gene
+.,I-Gene
+ , 
+We,O
+have,O
+studied,O
+the,O
+prevalence,O
+of,O
+SLC6A8,B-Gene
+mutations,O
+in,O
+a,O
+panel,O
+of,O
+290,O
+patients,O
+with,O
+nonsyndromic,O
+XLMR,O
+archived,O
+by,O
+the,O
+European,O
+XLMR,O
+Consortium,O
+.,O
+ , 
+The,O
+full,O
+-,O
+length,O
+open,O
+reading,O
+frame,O
+and,O
+splice,O
+sites,O
+of,O
+the,O
+SLC6A8,B-Gene
+gene,O
+were,O
+investigated,O
+by,O
+DNA,O
+sequence,O
+analysis,O
+.,O
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+Six,O
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+mutations,O
+,,O
+of,O
+which,O
+five,O
+were,O
+novel,O
+,,O
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+identified,O
+in,O
+a,O
+total,O
+of,O
+288,O
+patients,O
+with,O
+XLMR,O
+,,O
+showing,O
+a,O
+prevalence,O
+of,O
+at,O
+least,O
+2.1,O
+%,O
+(,O
+6/288,O
+),O
+.,O
+ , 
+The,O
+novel,O
+pathogenic,O
+mutations,O
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+nonsense,O
+mutation,O
+(,B-SNP
+p.,I-SNP
+Y317X,I-SNP
+),I-SNP
+and,O
+four,O
+missense,O
+mutations,O
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+Three,O
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+mutations,O
+(,B-SNP
+p.,I-SNP
+G87R,I-SNP
+,,I-SNP
+p.,B-SNP
+P390L,I-SNP
+,,I-SNP
+and,O
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+P554L,I-SNP
+),I-SNP
+were,O
+concluded,O
+to,O
+be,O
+pathogenic,O
+on,O
+the,O
+basis,O
+of,O
+conservation,O
+,,O
+segregation,O
+,,O
+chemical,O
+properties,O
+of,O
+the,O
+residues,O
+involved,O
+,,O
+as,O
+well,O
+as,O
+the,O
+absence,O
+of,O
+these,O
+and,O
+any,O
+other,O
+missense,O
+mutation,O
+in,O
+276,O
+controls,O
+.,O
+ , 
+For,O
+the,O
+p.,B-SNP
+C337W,I-SNP
+mutation,O
+,,O
+additional,O
+material,O
+was,O
+available,O
+to,O
+biochemically,O
+prove,O
+(,O
+i.e.,O
+,,O
+by,O
+increased,O
+urinary,O
+creatine,O
+:,O
+creatinine,O
+ratio,O
+),O
+pathogenicity,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+we,O
+found,O
+nine,O
+novel,O
+polymorphisms,O
+(,B-SNP
+IVS1,I-SNP
++,I-SNP
+26G-->A,I-SNP
+,,I-SNP
+IVS7,B-SNP
++,I-SNP
+37G-->A,I-SNP
+,,I-SNP
+IVS7,B-SNP
++,I-SNP
+87A-->G,I-SNP
+,,I-SNP
+IVS7,B-SNP
+-,I-SNP
+35G-->A,I-SNP
+,,I-SNP
+IVS12,B-SNP
+-,I-SNP
+3C-->T,I-SNP
+,,I-SNP
+IVS2,B-SNP
++,I-SNP
+88G-->C,I-SNP
+,,I-SNP
+IVS9,B-SNP
+-,I-SNP
+36G-->A,I-SNP
+,,I-SNP
+IVS12,B-SNP
+-,I-SNP
+82G-->C,I-SNP
+,,I-SNP
+and,O
+p.,B-SNP
+Y498,I-SNP
+),I-SNP
+that,O
+were,O
+present,O
+in,O
+the,O
+XLMR,O
+panel,O
+and/or,O
+in,O
+the,O
+control,O
+panel,O
+.,O
+ , 
+Two,O
+missense,O
+variants,O
+(,B-SNP
+p.,I-SNP
+V629I,I-SNP
+and,O
+p.,B-SNP
+M560V,I-SNP
+),I-SNP
+that,O
+were,O
+not,O
+highly,O
+conserved,O
+and,O
+were,O
+not,O
+associated,O
+with,O
+increased,O
+creatine,O
+:,O
+creatinine,O
+ratio,O
+,,O
+one,O
+translational,O
+silent,O
+variant,O
+(,O
+p.,O
+L472,O
+),O
+,,O
+and,O
+10,O
+intervening,O
+sequence,O
+variants,O
+or,O
+untranslated,O
+region,O
+variants,O
+(,B-SNP
+IVS6,I-SNP
++,I-SNP
+9C-->T,I-SNP
+,,I-SNP
+IVS7,B-SNP
+-,I-SNP
+151_152delGA,I-SNP
+,,I-SNP
+IVS7,B-SNP
+-,I-SNP
+99C-->A,I-SNP
+,,I-SNP
+IVS8,B-SNP
+-,I-SNP
+35G-->A,I-SNP
+,,I-SNP
+IVS8,B-SNP
++,I-SNP
+28C-->T,I-SNP
+,,I-SNP
+IVS10,B-SNP
+-,I-SNP
+18C-->T,I-SNP
+,,I-SNP
+IVS11,B-SNP
++,I-SNP
+21G-->A,I-SNP
+,,I-SNP
+IVS12,B-SNP
++,I-SNP
+15C-->T,I-SNP
+,,I-SNP
+*,B-SNP
+207G-->C,I-SNP
+,,I-SNP
+IVS12,B-SNP
++,I-SNP
+32C-->A,I-SNP
+),I-SNP
+were,O
+found,O
+only,O
+in,O
+the,O
+XLMR,O
+panel,O
+but,O
+should,O
+be,O
+considered,O
+as,O
+unclassified,O
+variants,O
+or,O
+as,O
+a,O
+polymorphism,O
+(,B-SNP
+p.,I-SNP
+M560V,I-SNP
+),I-SNP
+.,O
+ , 
+Our,O
+data,O
+indicate,O
+that,O
+the,O
+frequency,O
+of,O
+SLC6A8,B-Gene
+mutations,O
+in,O
+the,O
+XLMR,O
+population,O
+is,O
+close,O
+to,O
+that,O
+of,O
+CGG,O
+expansions,O
+in,O
+FMR1,B-Gene
+,,I-Gene
+the,O
+gene,O
+responsible,O
+for,O
+fragile,O
+-,O
+X,O
+syndrome,O
+.,O
+ , 
+#19191333
+Functional,O
+characterization,O
+of,O
+ryanodine,B-Gene
+receptor,I-Gene
+(,B-Gene
+RYR1,I-Gene
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+B,O
+-,O
+lymphocytes,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+RYR1,B-Gene
+gene,O
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+to,O
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+(,O
+MH,O
+),O
+,,O
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+core,O
+disease,O
+and,O
+multi,O
+-,O
+minicore,O
+disease,O
+.,O
+ , 
+We,O
+screened,O
+by,O
+DHPLC,O
+the,O
+RYR1,B-Gene
+gene,O
+in,O
+24,O
+subjects,O
+for,O
+mutations,O
+,,O
+and,O
+characterized,O
+functional,O
+alterations,O
+caused,O
+by,O
+some,O
+RYR1,B-Gene
+variants,O
+.,O
+ , 
+Three,O
+novel,O
+sequence,O
+variants,O
+and,O
+twenty,O
+novel,O
+polymorphisms,O
+were,O
+identified,O
+.,O
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+Immortalized,O
+lymphoblastoid,O
+cell,O
+lines,O
+from,O
+patients,O
+with,O
+RYR1,B-Gene
+variants,O
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+from,O
+controls,O
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+stimulated,O
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+4,O
+-,O
+chloro,O
+-,O
+m,O
+-,O
+cresol,O
+(,O
+4,O
+-,O
+CmC,O
+),O
+and,O
+the,O
+rate,O
+of,O
+extracellular,O
+acidification,O
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+recorded,O
+.,O
+ , 
+We,O
+demonstrate,O
+that,O
+the,O
+increased,O
+acidification,O
+rate,O
+of,O
+lymphoblastoid,O
+cells,O
+in,O
+response,O
+to,O
+4,O
+-,O
+CmC,O
+is,O
+mainly,O
+due,O
+to,O
+RYR1,B-Gene
+activation,O
+.,O
+ , 
+Cells,O
+expressing,O
+RYR1,B-Gene
+variants,O
+in,O
+the,O
+N,O
+-,O
+terminal,O
+and,O
+in,O
+the,O
+central,O
+region,O
+of,O
+the,O
+protein,O
+(,B-SNP
+p.,I-SNP
+Arg530His,I-SNP
+,,I-SNP
+p.,B-SNP
+Arg2163Pro,I-SNP
+,,I-SNP
+p.,B-SNP
+Asn2342Ser,I-SNP
+,,I-SNP
+p.,B-SNP
+Glu2371Gly,I-SNP
+and,O
+p.,B-SNP
+Arg2454His,I-SNP
+),I-SNP
+displayed,O
+higher,O
+activity,O
+compared,O
+with,O
+controls,O
+;,O
+this,O
+could,O
+account,O
+for,O
+the,O
+MH,O
+-,O
+susceptible,O
+phenotype,O
+.,O
+ , 
+Cell,O
+lines,O
+harboring,O
+RYR1(Cys4664Arg,B-Gene
+),I-SNP
+were,O
+significantly,O
+less,O
+activated,O
+by,O
+4,O
+-,O
+CmC.,O
+This,O
+result,O
+indicates,O
+that,O
+the,O
+p.,B-SNP
+Cys4664Arg,I-SNP
+variant,O
+causes,O
+a,O
+leaky,O
+channel,O
+and,O
+depletion,O
+of,O
+intracellular,O
+stores,O
+.,O
+ , 
+The,O
+functional,O
+changes,O
+detected,O
+corroborate,O
+the,O
+variants,O
+analyzed,O
+as,O
+disease,O
+-,O
+causing,O
+alterations,O
+and,O
+the,O
+acidification,O
+rate,O
+measurements,O
+as,O
+a,O
+means,O
+to,O
+monitor,O
+Ca(2+)-induced,O
+metabolic,O
+changes,O
+in,O
+cells,O
+harboring,O
+mutant,O
+RYR1,B-Gene
+channels,O
+.,O
+ , 
+#12632327
+Homozygous,O
+mutations,O
+in,O
+IHH,B-Gene
+cause,O
+acrocapitofemoral,O
+dysplasia,O
+,,O
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+autosomal,O
+recessive,O
+disorder,O
+with,O
+cone,O
+-,O
+shaped,O
+epiphyses,O
+in,O
+hands,O
+and,O
+hips,O
+.,O
+ , 
+Acrocapitofemoral,O
+dysplasia,O
+is,O
+a,O
+recently,O
+delineated,O
+autosomal,O
+recessive,O
+skeletal,O
+dysplasia,O
+,,O
+characterized,O
+clinically,O
+by,O
+short,O
+stature,O
+with,O
+short,O
+limbs,O
+and,O
+radiographically,O
+by,O
+cone,O
+-,O
+shaped,O
+epiphyses,O
+,,O
+mainly,O
+in,O
+hands,O
+and,O
+hips,O
+.,O
+ , 
+Genomewide,O
+homozygosity,O
+mapping,O
+in,O
+two,O
+consanguineous,O
+families,O
+linked,O
+the,O
+locus,O
+to,O
+2q35,O
+-,O
+q36,O
+with,O
+a,O
+maximum,O
+two,O
+-,O
+point,O
+LOD,O
+score,O
+of,O
+8.02,O
+at,O
+marker,O
+D2S2248,O
+.,O
+ , 
+Two,O
+recombination,O
+events,O
+defined,O
+the,O
+minimal,O
+critical,O
+region,O
+between,O
+markers,O
+D2S2248,O
+and,O
+D2S2151,O
+(,O
+3.74,O
+cM,O
+),O
+.,O
+ , 
+Using,O
+a,O
+candidate,O
+-,O
+gene,O
+approach,O
+,,O
+we,O
+identified,O
+two,O
+missense,O
+mutations,O
+in,O
+the,O
+amino,O
+-,O
+terminal,O
+signaling,O
+domain,O
+of,O
+the,O
+gene,O
+encoding,O
+Indian,B-Gene
+hedgehog,I-Gene
+(,B-Gene
+IHH,I-Gene
+),I-Gene
+.,O
+ , 
+Both,O
+affected,O
+individuals,O
+of,O
+family,O
+1,O
+are,O
+homozygous,O
+for,O
+a,O
+137C-->T,B-SNP
+transition,O
+(,B-SNP
+P46L,I-SNP
+),I-SNP
+,,O
+and,O
+the,O
+three,O
+patients,O
+in,O
+family,O
+2,O
+are,O
+homozygous,O
+for,O
+a,O
+569T-->C,B-SNP
+transition,O
+(,B-SNP
+V190A,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+two,O
+mutant,O
+amino,O
+acids,O
+are,O
+strongly,O
+conserved,O
+and,O
+predicted,O
+to,O
+be,O
+located,O
+outside,O
+the,O
+region,O
+where,O
+brachydactyly,O
+type,O
+A-1,O
+mutations,O
+are,O
+clustered,O
+.,O
+ , 
+#19576569
+Diverse,O
+evolutionary,O
+histories,O
+for,O
+beta,O
+-,O
+adrenoreceptor,O
+genes,O
+in,O
+humans,O
+.,O
+ , 
+In,O
+humans,O
+,,O
+three,O
+genes,O
+--,B-Gene
+ADRB1,I-Gene
+,,I-Gene
+ADRB2,B-Gene
+and,O
+ADRB3,B-Gene
+-,I-Gene
+-encode,O
+beta,O
+-,O
+adrenoreceptors,O
+(,O
+ADRB,O
+),O
+;,O
+these,O
+molecules,O
+mediate,O
+the,O
+action,O
+of,O
+catecholamines,O
+in,O
+multiple,O
+tissues,O
+and,O
+play,O
+pivotal,O
+roles,O
+in,O
+cardiovascular,O
+,,O
+respiratory,O
+,,O
+metabolic,O
+,,O
+and,O
+immunological,O
+functions,O
+.,O
+ , 
+Genetic,O
+variants,O
+in,O
+ADRB,O
+genes,O
+have,O
+been,O
+associated,O
+with,O
+widespread,O
+diseases,O
+and,O
+conditions,O
+,,O
+but,O
+inconsistent,O
+results,O
+have,O
+often,O
+been,O
+obtained,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+addressed,O
+the,O
+recent,O
+evolutionary,O
+history,O
+of,O
+ADRB,O
+genes,O
+in,O
+human,O
+populations,O
+.,O
+ , 
+Although,O
+ADRB1,B-Gene
+is,O
+neutrally,O
+evolving,O
+,,O
+most,O
+tests,O
+rejected,O
+neutral,O
+evolution,O
+for,O
+ADRB2,B-Gene
+in,O
+European,O
+,,O
+African,O
+,,O
+and,O
+Asian,O
+population,O
+samples,O
+.,O
+ , 
+Analysis,O
+of,O
+inferred,O
+haplotypes,O
+for,O
+ADRB2,B-Gene
+revealed,O
+three,O
+major,O
+clades,O
+with,O
+a,O
+coalescence,O
+time,O
+of,O
+1,O
+-,O
+1.5,O
+million,O
+years,O
+,,O
+suggesting,O
+that,O
+the,O
+gene,O
+is,O
+either,O
+subjected,O
+to,O
+balancing,O
+selection,O
+or,O
+undergoing,O
+a,O
+selective,O
+sweep,O
+.,O
+ , 
+Haplotype,O
+analysis,O
+also,O
+revealed,O
+ethnicity,O
+-,O
+specific,O
+differences,O
+.,O
+ , 
+Additionally,O
+,,O
+we,O
+observed,O
+significant,O
+deviations,O
+from,O
+Hardy,O
+-,O
+Weinberg,O
+equilibrium,O
+(,O
+HWE,O
+),O
+for,O
+ADRB2,B-Gene
+genotypes,O
+in,O
+distinct,O
+European,O
+cohorts,O
+;,O
+HWE,O
+deviation,O
+depends,O
+on,O
+sex,O
+(,O
+only,O
+females,O
+are,O
+in,O
+disequilibrium,O
+),O
+,,O
+and,O
+genotypes,O
+displaying,O
+maximum,O
+and,O
+minimum,O
+relative,O
+fitness,O
+differ,O
+across,O
+population,O
+samples,O
+,,O
+suggesting,O
+a,O
+complex,O
+situation,O
+possibly,O
+involving,O
+epistasis,O
+or,O
+maternal,O
+selection,O
+.,O
+ , 
+Overall,O
+,,O
+our,O
+data,O
+indicate,O
+that,O
+future,O
+association,O
+studies,O
+involving,O
+ADRB2,B-Gene
+will,O
+benefit,O
+from,O
+taking,O
+into,O
+account,O
+ethnicity,O
+-,O
+specific,O
+haplotype,O
+distributions,O
+and,O
+sex,O
+-,O
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+effects,O
+.,O
+ , 
+With,O
+respect,O
+to,O
+ADRB3,B-Gene
+,,I-Gene
+our,O
+data,O
+indicate,O
+that,O
+the,O
+gene,O
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+been,O
+subjected,O
+to,O
+a,O
+selective,O
+sweep,O
+in,O
+African,O
+populations,O
+,,O
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+Trp64,O
+variant,O
+possibly,O
+representing,O
+the,O
+selection,O
+target,O
+.,O
+ , 
+Given,O
+the,O
+previous,O
+association,O
+of,O
+the,O
+ancestral,O
+ADRB3,B-Gene
+Arg64,O
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+obesity,O
+and,O
+type,O
+2,O
+diabetes,O
+,,O
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+adaptations,O
+might,O
+represent,O
+the,O
+underlying,O
+selective,O
+force,O
+.,O
+ , 
+#15712104
+Genetic,O
+association,O
+analysis,O
+using,O
+data,O
+from,O
+triads,O
+and,O
+unrelated,O
+subjects,O
+.,O
+ , 
+The,O
+selection,O
+of,O
+an,O
+appropriate,O
+control,O
+sample,O
+for,O
+use,O
+in,O
+association,O
+mapping,O
+requires,O
+serious,O
+deliberation,O
+.,O
+ , 
+Unrelated,O
+controls,O
+are,O
+generally,O
+easy,O
+to,O
+collect,O
+,,O
+but,O
+the,O
+resulting,O
+analyses,O
+are,O
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+to,O
+spurious,O
+association,O
+arising,O
+from,O
+population,O
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+.,O
+ , 
+Parental,O
+controls,O
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+popular,O
+,,O
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+triads,O
+comprising,O
+a,O
+case,O
+and,O
+two,O
+parents,O
+can,O
+be,O
+used,O
+in,O
+analyses,O
+that,O
+are,O
+robust,O
+to,O
+this,O
+stratification,O
+.,O
+ , 
+However,O
+,,O
+parental,O
+controls,O
+are,O
+often,O
+expensive,O
+and,O
+difficult,O
+to,O
+collect,O
+.,O
+ , 
+In,O
+some,O
+situations,O
+,,O
+studies,O
+may,O
+have,O
+both,O
+parental,O
+and,O
+unrelated,O
+controls,O
+available,O
+for,O
+analysis,O
+.,O
+ , 
+For,O
+example,O
+,,O
+a,O
+candidate,O
+-,O
+gene,O
+study,O
+may,O
+analyze,O
+triads,O
+but,O
+may,O
+have,O
+an,O
+additional,O
+sample,O
+of,O
+unrelated,O
+controls,O
+for,O
+examination,O
+of,O
+background,O
+linkage,O
+disequilibrium,O
+in,O
+genomic,O
+regions,O
+.,O
+ , 
+Also,O
+,,O
+studies,O
+may,O
+collect,O
+a,O
+sample,O
+of,O
+triads,O
+to,O
+confirm,O
+results,O
+initially,O
+found,O
+using,O
+a,O
+traditional,O
+case,O
+-,O
+control,O
+study,O
+.,O
+ , 
+Initial,O
+association,O
+studies,O
+also,O
+may,O
+collect,O
+each,O
+type,O
+of,O
+control,O
+,,O
+to,O
+provide,O
+insurance,O
+against,O
+the,O
+weaknesses,O
+of,O
+the,O
+other,O
+type,O
+.,O
+ , 
+In,O
+these,O
+situations,O
+,,O
+resulting,O
+samples,O
+will,O
+consist,O
+of,O
+some,O
+triads,O
+,,O
+some,O
+unrelated,O
+controls,O
+,,O
+and,O
+,,O
+possibly,O
+,,O
+some,O
+unrelated,O
+cases,O
+.,O
+ , 
+Rather,O
+than,O
+analyze,O
+the,O
+triads,O
+and,O
+unrelated,O
+subjects,O
+separately,O
+,,O
+we,O
+present,O
+a,O
+likelihood,O
+-,O
+based,O
+approach,O
+for,O
+combining,O
+their,O
+information,O
+in,O
+a,O
+single,O
+combined,O
+association,O
+analysis,O
+.,O
+ , 
+Our,O
+approach,O
+allows,O
+for,O
+joint,O
+analysis,O
+of,O
+data,O
+from,O
+both,O
+triad,O
+and,O
+case,O
+-,O
+control,O
+study,O
+designs,O
+.,O
+ , 
+Simulations,O
+indicate,O
+that,O
+our,O
+proposed,O
+approach,O
+is,O
+more,O
+powerful,O
+than,O
+association,O
+tests,O
+that,O
+are,O
+based,O
+on,O
+each,O
+separate,O
+sample,O
+.,O
+ , 
+Our,O
+approach,O
+also,O
+allows,O
+for,O
+flexible,O
+modeling,O
+and,O
+estimation,O
+of,O
+allele,O
+effects,O
+,,O
+as,O
+well,O
+as,O
+for,O
+missing,O
+parental,O
+data,O
+.,O
+ , 
+We,O
+illustrate,O
+the,O
+usefulness,O
+of,O
+our,O
+approach,O
+using,O
+SNP,O
+data,O
+from,O
+a,O
+candidate,O
+-,O
+gene,O
+study,O
+of,O
+psoriasis,O
+.,O
+ , 
+#17186465
+Exact,O
+tests,O
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+Hardy,O
+-,O
+Weinberg,O
+equilibrium,O
+and,O
+homogeneity,O
+of,O
+disequilibrium,O
+across,O
+strata,O
+.,O
+ , 
+Detecting,O
+departures,O
+from,O
+Hardy,O
+-,O
+Weinberg,O
+equilibrium,O
+(,O
+HWE,O
+),O
+of,O
+marker,O
+-,O
+genotype,O
+frequencies,O
+is,O
+a,O
+crucial,O
+first,O
+step,O
+in,O
+almost,O
+all,O
+human,O
+genetic,O
+analyses,O
+.,O
+ , 
+When,O
+a,O
+sample,O
+is,O
+stratified,O
+by,O
+multiple,O
+ethnic,O
+groups,O
+,,O
+it,O
+is,O
+important,O
+to,O
+allow,O
+the,O
+marker,O
+-,O
+allele,O
+frequencies,O
+to,O
+differ,O
+over,O
+the,O
+strata,O
+.,O
+ , 
+In,O
+this,O
+situation,O
+,,O
+it,O
+is,O
+common,O
+to,O
+test,O
+for,O
+HWE,O
+by,O
+using,O
+an,O
+exact,O
+test,O
+within,O
+each,O
+stratum,O
+and,O
+then,O
+using,O
+the,O
+minimum,O
+P,O
+value,O
+as,O
+a,O
+global,O
+test,O
+.,O
+ , 
+This,O
+approach,O
+does,O
+not,O
+account,O
+for,O
+multiple,O
+testing,O
+,,O
+and,O
+,,O
+because,O
+it,O
+does,O
+not,O
+combine,O
+information,O
+over,O
+strata,O
+,,O
+it,O
+does,O
+not,O
+have,O
+optimal,O
+power,O
+.,O
+ , 
+Several,O
+approximate,O
+methods,O
+to,O
+combine,O
+information,O
+over,O
+strata,O
+have,O
+been,O
+proposed,O
+,,O
+but,O
+most,O
+of,O
+them,O
+sum,O
+over,O
+strata,O
+a,O
+measure,O
+of,O
+departure,O
+from,O
+HWE,O
+;,O
+if,O
+the,O
+departures,O
+are,O
+in,O
+different,O
+directions,O
+,,O
+then,O
+summing,O
+can,O
+diminish,O
+the,O
+overall,O
+evidence,O
+of,O
+departure,O
+from,O
+HWE,O
+.,O
+ , 
+An,O
+exact,O
+stratified,O
+test,O
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+more,O
+appealing,O
+because,O
+it,O
+uses,O
+the,O
+probability,O
+of,O
+genotype,O
+configurations,O
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+the,O
+strata,O
+as,O
+evidence,O
+for,O
+global,O
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+HWE,O
+.,O
+ , 
+We,O
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+an,O
+exact,O
+stratified,O
+test,O
+for,O
+HWE,O
+for,O
+diallelic,O
+markers,O
+,,O
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+as,O
+single,O
+-,O
+nucleotide,O
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+(,O
+SNPs,O
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+,,O
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+an,O
+exact,O
+test,O
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+Hardy,O
+-,O
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+.,O
+ , 
+By,O
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+our,O
+methods,O
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+data,O
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+Perlegen,O
+and,O
+HapMap,O
+--,O
+a,O
+combined,O
+total,O
+of,O
+more,O
+than,O
+five,O
+million,O
+SNP,O
+genotypes,O
+,,O
+with,O
+three,O
+to,O
+four,O
+strata,O
+and,O
+strata,O
+sizes,O
+ranging,O
+from,O
+23,O
+to,O
+60,O
+subjects,O
+--,O
+we,O
+illustrate,O
+that,O
+the,O
+exact,O
+stratified,O
+test,O
+provides,O
+more,O
+-,O
+robust,O
+and,O
+more,O
+-,O
+powerful,O
+results,O
+than,O
+those,O
+obtained,O
+by,O
+either,O
+the,O
+minimum,O
+of,O
+exact,O
+test,O
+P,O
+values,O
+over,O
+strata,O
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+approximate,O
+stratified,O
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+that,O
+sum,O
+measures,O
+of,O
+departure,O
+from,O
+HWE,O
+.,O
+ , 
+Hence,O
+,,O
+our,O
+new,O
+methods,O
+should,O
+be,O
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+samples,O
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+multiple,O
+ethnic,O
+groups,O
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+ , 
+#16532395
+Spread,O
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+inactive,O
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+caspase-12,B-Gene
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+The,O
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+a,O
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+codon,O
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+results,O
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+both,O
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+),O
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+(,O
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+gene,O
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+.,O
+ , 
+It,O
+has,O
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+elsewhere,O
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+carriers,O
+of,O
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+inactive,O
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+resistant,O
+to,O
+severe,O
+sepsis,O
+.,O
+ , 
+We,O
+have,O
+now,O
+investigated,O
+whether,O
+the,O
+inactive,O
+form,O
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+spread,O
+because,O
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+neutral,O
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+We,O
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+in,O
+a,O
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+52,O
+populations,O
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+resequenced,O
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+gene,O
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+77,O
+individuals,O
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+the,O
+HapMap,O
+Yoruba,O
+,,O
+Han,O
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+,,O
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+European,O
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+.,O
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+There,O
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+positive,O
+selection,O
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+low,O
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+,,O
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+allele,O
+-,O
+frequency,O
+spectra,O
+,,O
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+the,O
+predominance,O
+of,O
+a,O
+single,O
+haplotype,O
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+We,O
+suggest,O
+that,O
+the,O
+inactive,O
+form,O
+of,O
+the,O
+gene,O
+arose,O
+in,O
+Africa,O
+approximately,O
+100,O
+-,O
+500,O
+thousand,O
+years,O
+ago,O
+(,O
+KYA,O
+),O
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+initially,O
+neutral,O
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+almost,O
+neutral,O
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+that,O
+positive,O
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+approximately,O
+60,O
+-,O
+100,O
+KYA,O
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+it,O
+to,O
+near,O
+fixation,O
+.,O
+ , 
+We,O
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+propose,O
+that,O
+its,O
+selective,O
+advantage,O
+was,O
+sepsis,O
+resistance,O
+in,O
+populations,O
+that,O
+experienced,O
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+infectious,O
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+.,O
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+#7728151
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+Hippel,O
+-,O
+Lindau,O
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+(,O
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+by,O
+a,O
+predisposition,O
+to,O
+develop,O
+retinal,O
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+,,O
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+,,O
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+,,O
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+The,O
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+.,O
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+The,O
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+Clinical,O
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+VHL,O
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+VHL,O
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+classified,O
+into,O
+2,O
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+absence,O
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+pheochromocytoma,O
+.,O
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+The,O
+types,O
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+mutations,O
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+VHL,O
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+pheochromocytoma,O
+(,O
+VHL,O
+type,O
+1,O
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+differed,O
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+those,O
+responsible,O
+for,O
+VHL,O
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+pheochromocytoma,O
+(,O
+VHL,O
+type,O
+2,O
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+.,O
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+Fifty,O
+-,O
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+%,O
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+mutations,O
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+for,O
+VHL,O
+type,O
+1,O
+were,O
+microdeletions,O
+/,O
+insertions,O
+,,O
+nonsense,O
+mutations,O
+,,O
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+deletions,O
+;,O
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+mutations,O
+responsible,O
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+VHL,O
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+missense,O
+mutations,O
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+Specific,O
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+codon,O
+238,O
+accounted,O
+for,O
+43,O
+%,O
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+mutations,O
+responsible,O
+for,O
+VHL,O
+type,O
+2,O
+.,O
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+The,O
+mutations,O
+identified,O
+in,O
+these,O
+families,O
+will,O
+be,O
+useful,O
+in,O
+presymptomatic,O
+diagnosis,O
+.,O
+ , 
+The,O
+identification,O
+of,O
+mutations,O
+associated,O
+with,O
+phenotypes,O
+contributes,O
+to,O
+the,O
+understanding,O
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+fundamental,O
+genetic,O
+mechanisms,O
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+VHL,O
+disease,O
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+#19853236
+Sequence,O
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+Blood,O
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+numbers,O
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+homeostasis,O
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+.,O
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+Disruption,O
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+key,O
+regulatory,O
+mechanisms,O
+underlies,O
+many,O
+blood,O
+-,O
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+Mendelian,O
+diseases,O
+but,O
+also,O
+contributes,O
+to,O
+more,O
+common,O
+disorders,O
+,,O
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+atherosclerosis,O
+.,O
+ , 
+We,O
+searched,O
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+quantitative,O
+trait,O
+loci,O
+(,O
+QTL,O
+),O
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+hematology,O
+traits,O
+through,O
+a,O
+whole,O
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+genome,O
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+study,O
+,,O
+because,O
+these,O
+could,O
+provide,O
+new,O
+insights,O
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+hemopoeitic,O
+and,O
+disease,O
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+We,O
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+1.8,O
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+13,O
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+6015,O
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+These,O
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+knowledge,O
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+literature,O
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+The,O
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+LPAR1,B-Gene
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+mean,O
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+region,O
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+spanned,O
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+genes,O
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+CCND3,B-Gene
+,,I-Gene
+a,O
+member,O
+of,O
+the,O
+D,O
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+gene,O
+family,O
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+is,O
+involved,O
+in,O
+hematopoietic,O
+stem,O
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+.,O
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+The,O
+third,O
+region,O
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+with,O
+erythrocyte,O
+volume,O
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+was,O
+located,O
+in,O
+an,O
+intergenic,O
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+(,O
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+),O
+.,O
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+All,O
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+independent,O
+panel,O
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+(,O
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+9.9x10(-5,O
+),O
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+),O
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+ , 
+The,O
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+new,O
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+furthering,O
+our,O
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+#16116623
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+Array,O
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+DNA,O
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+from,O
+formalin,O
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+,,O
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+(,O
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+),O
+tissues,O
+has,O
+not,O
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+tested,O
+.,O
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+Therefore,O
+,,O
+we,O
+analyzed,O
+DNA,O
+derived,O
+from,O
+five,O
+matching,O
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+and,O
+FFPE,O
+ovarian,O
+tumors,O
+for,O
+gene,O
+copy,O
+number,O
+changes,O
+and,O
+loss,O
+of,O
+heterozygosity,O
+using,O
+the,O
+Affymetrix,O
+GeneChip,O
+Human,O
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+10,O
+K,O
+Array,O
+Xba,O
+131,O
+.,O
+ , 
+The,O
+data,O
+was,O
+analyzed,O
+using,O
+Affymetrix,O
+proprietary,O
+software,O
+,,O
+GeneChip,O
+DNA,O
+Analysis,O
+Software,O
+,,O
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+Chromosome,O
+Copy,O
+Number,O
+Tool,O
+.,O
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+The,O
+average,O
+SNP,O
+call,O
+rate,O
+(,O
+rate,O
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+successful,O
+genotype,O
+identification,O
+),O
+of,O
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+fresh,O
+samples,O
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+89.44,O
+%,O
+(,O
+range,O
+78.72,O
+-,O
+96.22,O
+%,O
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+92.72,O
+%,O
+),O
+and,O
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+only,O
+slightly,O
+lower,O
+for,O
+the,O
+matching,O
+FFPE,O
+samples,O
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+83.48,O
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+(,O
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+76.93,O
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+%,O
+,,O
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+82.60,O
+%,O
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+.,O
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+The,O
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+(,O
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+agreement,O
+between,O
+successful,O
+genotype,O
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+between,O
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+fresh,O
+and,O
+matching,O
+FFPE,O
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+97.06,O
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+(,O
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+92.70,O
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+99.41,O
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+97.52,O
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+ , 
+Loss,O
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+(,O
+LOH,O
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+profiles,O
+of,O
+the,O
+fresh,O
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+FFPE,O
+samples,O
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+all,O
+chromosomes,O
+.,O
+ , 
+Copy,O
+number,O
+data,O
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+also,O
+comparable,O
+,,O
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+quantification,O
+of,O
+copy,O
+number,O
+changes,O
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+overstated,O
+in,O
+the,O
+FFPE,O
+samples,O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+we,O
+have,O
+shown,O
+that,O
+it,O
+is,O
+possible,O
+to,O
+achieve,O
+high,O
+-,O
+performance,O
+outcomes,O
+using,O
+FFPE,O
+-,O
+derived,O
+DNA,O
+in,O
+the,O
+Affymetrix,O
+10,O
+K,O
+mapping,O
+array,O
+.,O
+ , 
+This,O
+advance,O
+will,O
+open,O
+up,O
+vast,O
+archival,O
+tissue,O
+resources,O
+to,O
+high,O
+-,O
+resolution,O
+genetic,O
+analysis,O
+and,O
+unlock,O
+a,O
+wealth,O
+of,O
+biological,O
+information,O
+.,O
+ , 
+#10738001
+A,O
+novel,O
+polymorphism,O
+(,B-SNP
+219G,I-SNP
+>,I-SNP
+A,I-SNP
+),I-SNP
+in,O
+the,O
+transferrin,B-Gene
+receptor,I-Gene
+gene,O
+.,O
+ , 
+#16110494
+Rare,O
+missense,O
+variants,O
+in,O
+ATP1A2,B-Gene
+in,O
+families,O
+with,O
+clustering,O
+of,O
+common,O
+forms,O
+of,O
+migraine,O
+.,O
+ , 
+Migraine,O
+is,O
+a,O
+recurrent,O
+neurovascular,O
+disease,O
+.,O
+ , 
+Its,O
+two,O
+most,O
+common,O
+forms,O
+-,O
+migraine,O
+without,O
+aura,O
+(,O
+MO,O
+),O
+and,O
+migraine,O
+with,O
+aura,O
+(,O
+MA)-both,O
+show,O
+familial,O
+clustering,O
+and,O
+a,O
+complex,O
+pattern,O
+of,O
+inheritance,O
+.,O
+ , 
+Familial,O
+hemiplegic,O
+migraine,O
+(,O
+FHM,O
+),O
+is,O
+a,O
+rare,O
+monogenic,O
+subform,O
+caused,O
+by,O
+mutations,O
+in,O
+the,O
+calcium,O
+channel,O
+gene,O
+CACNA1A,O
+or,O
+the,O
+Na(+)/K(+)-ATPase,O
+gene,O
+ATP1A2,O
+.,O
+ , 
+An,O
+involvement,O
+of,O
+FHM,O
+genes,O
+in,O
+the,O
+pathogenesis,O
+of,O
+common,O
+forms,O
+of,O
+migraine,O
+is,O
+not,O
+proven,O
+.,O
+ , 
+We,O
+therefore,O
+systematically,O
+screened,O
+ATP1A2,B-Gene
+in,O
+families,O
+with,O
+several,O
+members,O
+affected,O
+by,O
+MA,O
+and/or,O
+MO,O
+.,O
+ , 
+We,O
+identified,O
+two,O
+novel,O
+missense,O
+alterations,O
+[,B-SNP
+c.520G,I-SNP
+>,I-SNP
+A,I-SNP
+(,B-SNP
+p.,I-SNP
+E174,I-SNP
+K,I-SNP
+),I-SNP
+and,O
+c.1544G,B-SNP
+>,I-SNP
+ , 
+A,B-SNP
+(,B-SNP
+p.,I-SNP
+C515Y,I-SNP
+),I-SNP
+],O
+in,O
+two,O
+out,O
+of,O
+45,O
+families,O
+,,O
+which,O
+were,O
+not,O
+found,O
+in,O
+520,O
+control,O
+chromosomes,O
+.,O
+ , 
+Functional,O
+studies,O
+of,O
+these,O
+variants,O
+in,O
+Xenopus,O
+oocytes,O
+by,O
+two,O
+-,O
+electrode,O
+voltage,O
+clamp,O
+measurements,O
+and,O
+radiochemical,O
+determination,O
+of,O
+ATPase,O
+activity,O
+showed,O
+that,O
+C515Y,B-SNP
+leads,O
+to,O
+a,O
+complete,O
+loss,O
+of,O
+function,O
+comparable,O
+with,O
+the,O
+effect,O
+of,O
+FHM,B-Gene
+-,I-Gene
+mutations,O
+whereas,O
+for,O
+E174,B-SNP
+K,I-SNP
+no,O
+functional,O
+alteration,O
+could,O
+be,O
+found,O
+in,O
+the,O
+in,O
+vitro,O
+assays,O
+.,O
+ , 
+In,O
+conclusion,O
+we,O
+propose,O
+that,O
+rare,O
+variants,O
+in,O
+ATP1A2,B-Gene
+are,O
+involved,O
+in,O
+the,O
+susceptibility,O
+to,O
+common,O
+forms,O
+of,O
+migraine,O
+,,O
+because,O
+of,O
+1,O
+),O
+the,O
+absence,O
+of,O
+alterations,O
+in,O
+controls,O
+,,O
+2,O
+),O
+the,O
+particular,O
+pattern,O
+of,O
+segregation,O
+in,O
+both,O
+families,O
+,,O
+3,O
+),O
+the,O
+high,O
+conservation,O
+of,O
+mutated,O
+residues,O
+in,O
+Na(+)/K(+)-ATPases,O
+,,O
+4,O
+),O
+the,O
+functional,O
+effect,O
+of,O
+C515Y,B-SNP
+,,I-SNP
+and,O
+5,O
+),O
+the,O
+involvement,O
+of,O
+ATP1A2,B-Gene
+in,O
+a,O
+monogenic,O
+form,O
+of,O
+migraine,O
+.,O
+ , 
+#11139269
+A,O
+novel,O
+polymorphism,O
+(,B-SNP
+-88,I-SNP
+C,I-SNP
+>,I-SNP
+A,I-SNP
+),I-SNP
+in,O
+the,O
+5,O
+',O
+UTR,O
+of,O
+the,O
+p53R2,B-Gene
+gene,O
+.,O
+ , 
+#1346482
+Isolation,O
+and,O
+characterization,O
+of,O
+new,O
+highly,O
+polymorphic,O
+DNA,O
+markers,O
+from,O
+the,O
+Huntington,O
+disease,O
+region,O
+.,O
+ , 
+The,O
+defect,O
+causing,O
+Huntington,O
+disease,O
+(,O
+HD,O
+),O
+has,O
+been,O
+mapped,O
+to,O
+4p16.3,O
+,,O
+distal,O
+to,O
+the,O
+DNA,O
+marker,O
+D4S10,O
+.,O
+ , 
+Subsequently,O
+,,O
+additional,O
+polymorphic,O
+markers,O
+closer,O
+to,O
+the,O
+HD,O
+gene,O
+have,O
+been,O
+isolated,O
+,,O
+which,O
+has,O
+led,O
+to,O
+the,O
+establishment,O
+of,O
+predictive,O
+testing,O
+programs,O
+for,O
+individuals,O
+at,O
+risk,O
+for,O
+HD,O
+.,O
+ , 
+Approximately,O
+17,O
+%,O
+of,O
+persons,O
+presenting,O
+to,O
+the,O
+Canadian,O
+collaborative,O
+study,O
+for,O
+predictive,O
+testing,O
+for,O
+HD,O
+have,O
+not,O
+received,O
+any,O
+modification,O
+of,O
+risk,O
+,,O
+in,O
+part,O
+because,O
+of,O
+limited,O
+informativeness,O
+of,O
+currently,O
+available,O
+DNA,O
+markers,O
+.,O
+ , 
+Therefore,O
+,,O
+more,O
+highly,O
+polymorphic,O
+DNA,O
+markers,O
+are,O
+needed,O
+,,O
+which,O
+will,O
+further,O
+increase,O
+the,O
+accuracy,O
+and,O
+availability,O
+of,O
+predictive,O
+testing,O
+,,O
+specifically,O
+for,O
+families,O
+with,O
+complex,O
+or,O
+incomplete,O
+pedigree,O
+structures,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+new,O
+markers,O
+are,O
+urgently,O
+needed,O
+in,O
+order,O
+to,O
+refine,O
+the,O
+breakpoints,O
+in,O
+the,O
+few,O
+known,O
+recombinant,O
+HD,O
+chromosomes,O
+,,O
+which,O
+could,O
+allow,O
+a,O
+more,O
+accurate,O
+localization,O
+of,O
+the,O
+HD,O
+gene,O
+within,O
+4p16.3,O
+and,O
+,,O
+therefore,O
+,,O
+accelerate,O
+the,O
+cloning,O
+of,O
+the,O
+disease,O
+gene,O
+.,O
+ , 
+In,O
+this,O
+study,O
+we,O
+present,O
+the,O
+identification,O
+and,O
+characterization,O
+of,O
+nine,O
+new,O
+polymorphic,O
+DNA,O
+markers,O
+,,O
+including,O
+three,O
+markers,O
+which,O
+detect,O
+highly,O
+informative,O
+multiallelic,O
+VNTR,O
+-,O
+like,O
+polymorphisms,O
+with,O
+PIC,O
+values,O
+of,O
+up,O
+to,O
+.84,O
+.,O
+ , 
+These,O
+markers,O
+have,O
+been,O
+isolated,O
+from,O
+a,O
+cloned,O
+region,O
+of,O
+DNA,O
+which,O
+has,O
+been,O
+previously,O
+mapped,O
+approximately,O
+1,000,O
+kb,O
+from,O
+the,O
+4p,O
+telomere,O
+.,O
+ , 
+#20127982
+Disruption,O
+of,O
+OTC,B-Gene
+promoter,O
+-,O
+enhancer,O
+interaction,O
+in,O
+a,O
+patient,O
+with,O
+symptoms,O
+of,O
+ornithine,O
+carbamoyltransferase,O
+deficiency,O
+.,O
+ , 
+In,O
+a,O
+female,O
+patient,O
+with,O
+signs,O
+of,O
+ornithine,O
+carbamoyltransferase,O
+deficiency,O
+(,O
+OTCD,O
+),O
+,,O
+the,O
+only,O
+variation,O
+found,O
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+a,O
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+single,O
+nucleotide,O
+substitution,O
+c.-366A,B-SNP
+>,I-SNP
+G.,I-SNP
+Determination,O
+of,O
+transcription,O
+start,O
+sites,O
+of,O
+human,O
+OTC,B-Gene
+95,O
+,,O
+119,O
+and,O
+169,O
+bp,O
+upstream,O
+of,O
+the,O
+initiation,O
+codon,O
+located,O
+the,O
+variation,O
+upstream,O
+of,O
+the,O
+5'-untranslated,O
+region,O
+.,O
+ , 
+We,O
+predicted,O
+the,O
+human,O
+promoter,O
+and,O
+enhancer,O
+elements,O
+from,O
+homology,O
+with,O
+rat,O
+and,O
+mouse,O
+,,O
+performed,O
+function,O
+analysis,O
+of,O
+both,O
+regulatory,O
+regions,O
+and,O
+assessed,O
+the,O
+impact,O
+of,O
+the,O
+promoter,O
+variation,O
+in,O
+functional,O
+studies,O
+using,O
+dual,O
+luciferase,O
+reporter,O
+assay,O
+.,O
+ , 
+Our,O
+data,O
+indicate,O
+that,O
+:,O
+(,O
+i,O
+),O
+Full,O
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+activity,O
+of,O
+human,O
+OTC,B-Gene
+promoter,O
+depends,O
+on,O
+an,O
+upstream,O
+enhancer,O
+,,O
+as,O
+do,O
+the,O
+rodent,O
+promoters,O
+.,O
+ , 
+(,O
+ii,O
+),O
+ , 
+The,O
+promoter,O
+variation,O
+c.-366A,B-SNP
+>,I-SNP
+G,I-SNP
+does,O
+not,O
+affect,O
+the,O
+function,O
+of,O
+the,O
+promoter,O
+alone,O
+but,O
+it,O
+disrupts,O
+the,O
+interaction,O
+of,O
+the,O
+promoter,O
+with,O
+the,O
+enhancer,O
+.,O
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+(,O
+iii,O
+),O
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+The,O
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+tissue,O
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+OTC,B-Gene
+in,O
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+liver,O
+.,O
+ , 
+We,O
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+that,O
+mutations,O
+in,O
+the,O
+regulatory,O
+regions,O
+of,O
+OTC,B-Gene
+can,O
+lead,O
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+OTCD,O
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+included,O
+in,O
+genetic,O
+testing,O
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+#7599640
+Mutations,O
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+the,O
+iduronate-2,O
+-,O
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+a,O
+T146,O
+T,O
+background,O
+in,O
+three,O
+patients,O
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+Hunter,O
+syndrome,O
+.,O
+ , 
+#15372378
+A,O
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+in,O
+the,O
+vesicle,B-Gene
+-,I-Gene
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+protein,I-Gene
+VAPB,B-Gene
+causes,O
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+-,O
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+spinal,O
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+amyotrophic,O
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+Motor,O
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+(,O
+MNDs,O
+),O
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+disorders,O
+with,O
+involvement,O
+of,O
+upper,O
+and/or,O
+lower,O
+motor,O
+neurons,O
+,,O
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+as,O
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+(,O
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+),O
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+atrophy,O
+(,O
+SMA,O
+),O
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+,,O
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+sclerosis,O
+.,O
+ , 
+Recently,O
+,,O
+we,O
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+mapped,O
+a,O
+new,O
+locus,O
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+of,O
+ALS,O
+/,O
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+(,O
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+amyotrophic,O
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+sclerosis,O
+[,O
+ALS8,O
+],O
+),O
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+20q13.3,O
+in,O
+a,O
+large,O
+white,O
+Brazilian,O
+family,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+the,O
+finding,O
+of,O
+a,O
+novel,O
+missense,O
+mutation,O
+in,O
+the,O
+vesicle,B-Gene
+-,I-Gene
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+(,B-Gene
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+patients,O
+from,O
+this,O
+family,O
+.,O
+ , 
+Subsequently,O
+,,O
+the,O
+same,O
+mutation,O
+was,O
+identified,O
+in,O
+patients,O
+from,O
+six,O
+additional,O
+kindreds,O
+but,O
+with,O
+different,O
+clinical,O
+courses,O
+,,O
+such,O
+as,O
+ALS8,O
+,,O
+late,O
+-,O
+onset,O
+SMA,O
+,,O
+and,O
+typical,O
+severe,O
+ALS,O
+with,O
+rapid,O
+progression,O
+.,O
+ , 
+Although,O
+it,O
+was,O
+not,O
+possible,O
+to,O
+link,O
+all,O
+these,O
+families,O
+,,O
+haplotype,O
+analysis,O
+suggests,O
+a,O
+founder,O
+effect,O
+.,O
+ , 
+Members,O
+of,O
+the,O
+vesicle,O
+-,O
+associated,O
+proteins,O
+are,O
+intracellular,O
+membrane,O
+proteins,O
+that,O
+can,O
+associate,O
+with,O
+microtubules,O
+and,O
+that,O
+have,O
+been,O
+shown,O
+to,O
+have,O
+a,O
+function,O
+in,O
+membrane,O
+transport,O
+.,O
+ , 
+These,O
+data,O
+suggest,O
+that,O
+clinically,O
+variable,O
+MNDs,O
+may,O
+be,O
+caused,O
+by,O
+a,O
+dysfunction,O
+in,O
+intracellular,O
+membrane,O
+trafficking,O
+.,O
+ , 
+#8279475
+Refining,O
+the,O
+locus,O
+for,O
+Best,O
+vitelliform,O
+macular,O
+dystrophy,O
+and,O
+mutation,O
+analysis,O
+of,O
+the,O
+candidate,O
+gene,O
+ROM1,B-Gene
+.,I-Gene
+ , 
+Vitelliform,O
+macular,O
+dystrophy,O
+(,O
+Best,O
+disease,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+macular,O
+dystrophy,O
+which,O
+shares,O
+important,O
+clinical,O
+features,O
+with,O
+age,O
+-,O
+related,O
+macular,O
+degeneration,O
+,,O
+the,O
+most,O
+common,O
+cause,O
+of,O
+legal,O
+blindness,O
+in,O
+the,O
+elderly,O
+.,O
+ , 
+Unfortunately,O
+,,O
+our,O
+understanding,O
+and,O
+treatment,O
+for,O
+this,O
+common,O
+age,O
+-,O
+related,O
+disorder,O
+is,O
+limited,O
+.,O
+ , 
+Discovery,O
+of,O
+the,O
+gene,O
+which,O
+causes,O
+Best,O
+disease,O
+has,O
+the,O
+potential,O
+to,O
+increase,O
+our,O
+understanding,O
+of,O
+the,O
+pathogenesis,O
+of,O
+all,O
+types,O
+of,O
+macular,O
+degeneration,O
+,,O
+including,O
+the,O
+common,O
+age,O
+-,O
+related,O
+form,O
+.,O
+ , 
+Best,O
+disease,O
+has,O
+recently,O
+been,O
+mapped,O
+to,O
+chromosome,O
+11q13,O
+.,O
+ , 
+The,O
+photoreceptor,O
+-,O
+specific,O
+protein,O
+ROM1,B-Gene
+has,O
+also,O
+been,O
+recently,O
+mapped,O
+to,O
+this,O
+location,O
+,,O
+and,O
+the,O
+ROM1,B-Gene
+gene,O
+is,O
+a,O
+candidate,O
+gene,O
+for,O
+Best,O
+disease,O
+.,O
+ , 
+Using,O
+highly,O
+polymorphic,O
+markers,O
+,,O
+we,O
+have,O
+narrowed,O
+the,O
+genetic,O
+region,O
+which,O
+contains,O
+the,O
+Best,O
+disease,O
+gene,O
+to,O
+the,O
+10,O
+-,O
+cM,O
+region,O
+between,O
+markers,O
+D11S871,O
+and,O
+PYGM,B-Gene
+.,I-Gene
+ , 
+Marker,O
+D11S956,O
+demonstrated,O
+no,O
+recombinants,O
+with,O
+Best,O
+disease,O
+in,O
+three,O
+large,O
+families,O
+and,O
+resulted,O
+in,O
+a,O
+lod,O
+score,O
+of,O
+18.2,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+a,O
+polymorphism,O
+within,O
+the,O
+ROM1,B-Gene
+gene,O
+also,O
+demonstrated,O
+no,O
+recombinants,O
+and,O
+resulted,O
+in,O
+a,O
+lod,O
+score,O
+of,O
+10.0,O
+in,O
+these,O
+same,O
+three,O
+families,O
+.,O
+ , 
+We,O
+used,O
+a,O
+combination,O
+of,O
+SSCP,O
+analysis,O
+,,O
+denaturing,O
+gradient,O
+gel,O
+electrophoresis,O
+,,O
+and,O
+DNA,O
+sequencing,O
+to,O
+screen,O
+the,O
+entire,O
+coding,O
+region,O
+of,O
+the,O
+ROM1,B-Gene
+gene,O
+in,O
+11,O
+different,O
+unrelated,O
+patients,O
+affected,O
+with,O
+Best,O
+disease,O
+.,O
+ , 
+No,O
+nucleotide,O
+changes,O
+were,O
+found,O
+in,O
+the,O
+coding,O
+sequence,O
+of,O
+any,O
+affected,O
+patient,O
+,,O
+indicating,O
+that,O
+mutations,O
+within,O
+the,O
+coding,O
+sequence,O
+are,O
+unlikely,O
+to,O
+cause,O
+Best,O
+disease,O
+.,O
+ , 
+#9683604
+From,O
+amplification,O
+to,O
+gene,O
+in,O
+thyroid,O
+cancer,O
+:,O
+a,O
+high,O
+-,O
+resolution,O
+mapped,O
+bacterial,O
+-,O
+artificial,O
+-,O
+chromosome,O
+resource,O
+for,O
+cancer,O
+chromosome,O
+aberrations,O
+guides,O
+gene,O
+discovery,O
+after,O
+comparative,O
+genome,O
+hybridization,O
+.,O
+ , 
+Chromosome,O
+rearrangements,O
+associated,O
+with,O
+neoplasms,O
+provide,O
+a,O
+rich,O
+resource,O
+for,O
+definition,O
+of,O
+the,O
+pathways,O
+of,O
+tumorigenesis,O
+.,O
+ , 
+The,O
+power,O
+of,O
+comparative,O
+genome,O
+hybridization,O
+(,O
+CGH,O
+),O
+to,O
+identify,O
+novel,O
+genes,O
+depends,O
+on,O
+the,O
+existence,O
+of,O
+suitable,O
+markers,O
+,,O
+which,O
+are,O
+lacking,O
+throughout,O
+most,O
+of,O
+the,O
+genome,O
+.,O
+ , 
+We,O
+now,O
+report,O
+a,O
+general,O
+approach,O
+that,O
+translates,O
+CGH,O
+data,O
+into,O
+higher,O
+-,O
+resolution,O
+genomic,O
+-,O
+clone,O
+data,O
+that,O
+are,O
+then,O
+used,O
+to,O
+define,O
+the,O
+genes,O
+located,O
+in,O
+aneuploid,O
+regions,O
+.,O
+ , 
+We,O
+used,O
+CGH,O
+to,O
+study,O
+33,O
+thyroid,O
+-,O
+tumor,O
+DNAs,O
+and,O
+two,O
+tumor,O
+-,O
+cell,O
+-,O
+line,O
+DNAs,O
+.,O
+ , 
+The,O
+results,O
+revealed,O
+amplifications,O
+of,O
+chromosome,O
+band,O
+2p21,O
+,,O
+with,O
+less,O
+-,O
+intense,O
+amplification,O
+on,O
+2p13,O
+,,O
+19q13.1,O
+,,O
+and,O
+1p36,O
+and,O
+with,O
+least,O
+-,O
+intense,O
+amplification,O
+on,O
+1p34,O
+,,O
+1q42,O
+,,O
+5q31,O
+,,O
+5q33,O
+-,O
+34,O
+,,O
+9q32,O
+-,O
+34,O
+,,O
+and,O
+14q32,O
+.,O
+ , 
+To,O
+define,O
+the,O
+2p21,O
+region,O
+amplified,O
+,,O
+a,O
+dense,O
+array,O
+of,O
+373,O
+FISH,O
+-,O
+mapped,O
+chromosome,O
+2,O
+bacterial,O
+artificial,O
+chromosomes,O
+(,O
+BACs,O
+),O
+was,O
+constructed,O
+,,O
+and,O
+87,O
+of,O
+these,O
+were,O
+hybridized,O
+to,O
+a,O
+tumor,O
+-,O
+cell,O
+line,O
+.,O
+ , 
+Four,O
+BACs,O
+carried,O
+genomic,O
+DNA,O
+that,O
+was,O
+amplified,O
+in,O
+these,O
+cells,O
+.,O
+ , 
+The,O
+maximum,O
+amplified,O
+region,O
+was,O
+narrowed,O
+to,O
+3,O
+-,O
+6,O
+Mb,O
+by,O
+multicolor,O
+FISH,O
+with,O
+the,O
+flanking,O
+BACs,O
+,,O
+and,O
+the,O
+minimum,O
+amplicon,O
+size,O
+was,O
+defined,O
+by,O
+a,O
+contig,O
+of,O
+420,O
+kb,O
+.,O
+ , 
+Sequence,O
+analysis,O
+of,O
+the,O
+amplified,O
+BAC,O
+1D9,O
+revealed,O
+a,O
+fragment,O
+of,O
+the,O
+gene,O
+,,O
+encoding,O
+protein,B-Gene
+kinase,I-Gene
+C,I-Gene
+epsilon,I-Gene
+(,B-Gene
+PKCepsilon,I-Gene
+),I-Gene
+,,I-Gene
+that,O
+was,O
+then,O
+shown,O
+to,O
+be,O
+amplified,O
+and,O
+rearranged,O
+in,O
+tumor,O
+cells,O
+.,O
+ , 
+In,O
+summary,O
+,,O
+CGH,O
+combined,O
+with,O
+a,O
+dense,O
+mapped,O
+resource,O
+of,O
+BACs,O
+and,O
+large,O
+-,O
+scale,O
+sequencing,O
+has,O
+led,O
+directly,O
+to,O
+the,O
+definition,O
+of,O
+PKCepsilon,B-Gene
+as,O
+a,O
+previously,O
+unmapped,O
+candidate,O
+gene,O
+involved,O
+in,O
+thyroid,O
+tumorigenesis,O
+.,O
+ , 
+#14695532
+Twenty,O
+-,O
+two,O
+novel,O
+mutations,O
+in,O
+the,O
+lysosomal,B-Gene
+alpha,I-Gene
+-,I-Gene
+glucosidase,I-Gene
+gene,O
+(,B-Gene
+GAA,I-Gene
+),I-Gene
+underscore,O
+the,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+in,O
+glycogen,O
+storage,O
+disease,O
+type,O
+II,O
+.,O
+ , 
+Patients,O
+with,O
+glycogen,O
+storage,O
+disease,O
+type,O
+II,O
+(,O
+GSDII,O
+,,O
+Pompe,O
+disease,O
+),O
+suffer,O
+from,O
+progressive,O
+muscle,O
+weakness,O
+due,O
+to,O
+acid,B-Gene
+alpha,I-Gene
+-,I-Gene
+glucosidase,I-Gene
+deficiency,O
+.,O
+ , 
+The,O
+disease,O
+is,O
+inherited,O
+as,O
+an,O
+autosomal,O
+recessive,O
+trait,O
+with,O
+a,O
+spectrum,O
+of,O
+clinical,O
+phenotypes,O
+.,O
+ , 
+We,O
+have,O
+investigated,O
+29,O
+cases,O
+of,O
+GSDII,O
+and,O
+thereby,O
+identified,O
+55,O
+pathogenic,O
+mutations,O
+of,O
+the,O
+acid,B-Gene
+alpha,I-Gene
+-,I-Gene
+glucosidase,I-Gene
+gene,O
+(,B-Gene
+GAA,I-Gene
+),I-Gene
+encoding,O
+acid,O
+maltase,O
+.,O
+ , 
+There,O
+were,O
+34,O
+different,O
+mutations,O
+identified,O
+,,O
+22,O
+of,O
+which,O
+were,O
+novel,O
+.,O
+ , 
+All,O
+of,O
+the,O
+missense,O
+mutations,O
+and,O
+two,O
+other,O
+mutations,O
+with,O
+an,O
+unpredictable,O
+effect,O
+on,O
+acid,O
+alpha,O
+-,O
+glucosidase,O
+synthesis,O
+and,O
+function,O
+were,O
+transiently,O
+expressed,O
+in,O
+COS,O
+cells,O
+.,O
+ , 
+The,O
+effect,O
+of,O
+a,O
+novel,O
+splice,O
+-,O
+site,O
+mutation,O
+was,O
+investigated,O
+by,O
+real,O
+-,O
+time,O
+PCR,O
+analysis,O
+.,O
+ , 
+The,O
+outcome,O
+of,O
+our,O
+analysis,O
+underscores,O
+the,O
+notion,O
+that,O
+the,O
+clinical,O
+phenotype,O
+of,O
+GSDII,O
+is,O
+largely,O
+dictated,O
+by,O
+the,O
+nature,O
+of,O
+the,O
+mutations,O
+in,O
+the,O
+GAA,O
+alleles,O
+.,O
+ , 
+This,O
+genotype,O
+-,O
+phenotype,O
+correlation,O
+makes,O
+DNA,O
+analysis,O
+a,O
+valuable,O
+tool,O
+to,O
+help,O
+predict,O
+the,O
+clinical,O
+course,O
+of,O
+the,O
+disease,O
+.,O
+ , 
+#11078473
+The,O
+peopling,O
+of,O
+Europe,O
+from,O
+the,O
+maternal,O
+and,O
+paternal,O
+perspectives,O
+.,O
+ , 
+#16671095
+A,O
+homozygous,O
+ZMPSTE24,B-Gene
+null,O
+mutation,O
+in,O
+combination,O
+with,O
+a,O
+heterozygous,O
+mutation,O
+in,O
+the,O
+LMNA,B-Gene
+gene,O
+causes,O
+Hutchinson,O
+-,O
+Gilford,O
+progeria,O
+syndrome,O
+(,O
+HGPS,O
+):,O
+insights,O
+into,O
+the,O
+pathophysiology,O
+of,O
+HGPS,O
+.,O
+ , 
+Hutchinson,O
+-,O
+Gilford,O
+progeria,O
+syndrome,O
+(,O
+HGPS,O
+),O
+is,O
+a,O
+rare,O
+premature,O
+aging,O
+disorder,O
+normally,O
+caused,O
+by,O
+a,O
+spontaneous,O
+heterozygous,O
+mutation,O
+in,O
+the,O
+LMNA,B-Gene
+gene,O
+that,O
+codes,O
+for,O
+the,O
+nuclear,B-Gene
+lamina,I-Gene
+protein,I-Gene
+lamin,I-Gene
+A.,I-Gene
+Several,O
+enzymes,O
+are,O
+involved,O
+in,O
+the,O
+processing,O
+of,O
+its,O
+precursor,O
+,,O
+prelamin,O
+A,O
+,,O
+to,O
+the,O
+mature,O
+lamin,O
+A.,O
+A,O
+functional,O
+knockout,O
+of,O
+one,O
+of,O
+the,O
+enzymes,O
+involved,O
+in,O
+prelamin,O
+A,O
+processing,O
+,,O
+the,O
+zinc,O
+metalloprotease,O
+ZMPSTE24,B-Gene
+,,I-Gene
+causes,O
+an,O
+even,O
+more,O
+severe,O
+disorder,O
+with,O
+early,O
+neonatal,O
+death,O
+described,O
+as,O
+restrictive,O
+dermatopathy,O
+(,O
+RD,O
+),O
+.,O
+ , 
+This,O
+work,O
+describes,O
+a,O
+HGPS,O
+patient,O
+with,O
+a,O
+combined,O
+defect,O
+of,O
+a,O
+homozygous,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mutation,O
+in,O
+the,O
+ZMPSTE24,B-Gene
+gene,O
+and,O
+a,O
+heterozygous,O
+mutation,O
+in,O
+the,O
+LMNA,B-Gene
+gene,O
+that,O
+results,O
+in,O
+a,O
+C,O
+-,O
+terminal,O
+elongation,O
+of,O
+the,O
+final,O
+lamin,B-Gene
+A.,I-Gene
+Whereas,O
+the,O
+loss,O
+of,O
+function,O
+mutation,O
+of,O
+ZMPSTE24,B-Gene
+normally,O
+results,O
+in,O
+lethal,O
+RD,O
+,,O
+the,O
+truncation,O
+of,O
+LMNA,B-Gene
+seems,O
+to,O
+be,O
+a,O
+salvage,O
+alteration,O
+alleviating,O
+the,O
+clinical,O
+picture,O
+to,O
+the,O
+HGPS,O
+phenotype,O
+.,O
+ , 
+The,O
+mutations,O
+of,O
+our,O
+patient,O
+indicate,O
+that,O
+farnesylated,O
+prelamin,O
+ , 
+A,O
+is,O
+the,O
+deleterious,O
+agent,O
+leading,O
+to,O
+the,O
+HGPS,O
+phenotype,O
+,,O
+which,O
+gives,O
+further,O
+insights,O
+into,O
+the,O
+pathophysiology,O
+of,O
+the,O
+disorder,O
+.,O
+ , 
+#10790218
+Analysis,O
+of,O
+the,O
+human,O
+KCNH2(HERG,B-Gene
+),I-Gene
+gene,O
+:,O
+identification,O
+and,O
+characterization,O
+of,O
+a,O
+novel,O
+mutation,O
+Y667X,B-SNP
+associated,O
+with,O
+long,O
+QT,O
+syndrome,O
+and,O
+a,O
+non,O
+-,O
+pathological,O
+9,O
+bp,O
+insertion,O
+.,O
+ , 
+Long,O
+QT,O
+(,O
+LQT,O
+),O
+syndrome,O
+is,O
+a,O
+potentially,O
+life,O
+-,O
+threatening,O
+disorder,O
+,,O
+characterized,O
+by,O
+a,O
+distinct,O
+cardiac,O
+arrhythmia,O
+known,O
+as,O
+torsades,O
+de,O
+pointes,O
+.,O
+ , 
+Mutations,O
+within,O
+a,O
+number,O
+of,O
+genes,O
+linked,O
+to,O
+the,O
+familial,O
+form,O
+,,O
+including,O
+that,O
+coding,O
+for,O
+a,O
+cardiac,O
+potassium,O
+channel,O
+called,O
+KCNH2,B-Gene
+(,B-Gene
+HERG,I-Gene
+),I-Gene
+,,O
+have,O
+been,O
+described,O
+based,O
+on,O
+the,O
+characterized,O
+genomic,O
+organization,O
+.,O
+ , 
+A,O
+standardized,O
+method,O
+was,O
+developed,O
+to,O
+screen,O
+the,O
+entire,O
+gene,O
+for,O
+gene,O
+variants,O
+.,O
+ , 
+We,O
+report,O
+a,O
+single,O
+base,O
+pair,O
+substitution,O
+,,O
+introducing,O
+a,O
+premature,O
+STOP,O
+codon,O
+at,O
+codon,O
+667,O
+of,O
+the,O
+gene,O
+in,O
+a,O
+healthy,O
+individual,O
+with,O
+an,O
+extended,O
+QTc,O
+interval,O
+(,O
+460,O
+msec,O
+),O
+.,O
+ , 
+In,O
+vitro,O
+expression,O
+of,O
+the,O
+codon,O
+Y667X,B-SNP
+variant,O
+in,O
+Xenopus,O
+oocyte,O
+suggests,O
+that,O
+the,O
+autosomal,O
+dominant,O
+variant,O
+does,O
+not,O
+function,O
+in,O
+a,O
+dominant,O
+/,O
+negative,O
+manner,O
+and,O
+can,O
+not,O
+co,O
+-,O
+assemble,O
+to,O
+form,O
+a,O
+channel,O
+,,O
+resulting,O
+in,O
+a,O
+reduction,O
+of,O
+the,O
+KCNH2,B-Gene
+current,O
+,,O
+and,O
+an,O
+extension,O
+of,O
+the,O
+QT,O
+interval,O
+.,O
+ , 
+This,O
+indicates,O
+that,O
+pathogenic,O
+LQT,O
+gene,O
+variants,O
+exist,O
+in,O
+the,O
+apparently,O
+normal,O
+population,O
+,,O
+the,O
+prognosis,O
+and,O
+clinical,O
+consequences,O
+of,O
+which,O
+remain,O
+to,O
+be,O
+determined,O
+.,O
+ , 
+The,O
+assays,O
+described,O
+should,O
+facilitate,O
+future,O
+studies,O
+into,O
+this,O
+area,O
+.,O
+ , 
+#20970104
+Mutations,O
+in,O
+NEXN,B-Gene
+,,I-Gene
+a,O
+Z,O
+-,O
+disc,O
+gene,O
+,,O
+are,O
+associated,O
+with,O
+hypertrophic,O
+cardiomyopathy,O
+.,O
+ , 
+Hypertrophic,O
+cardiomyopathy,O
+(,O
+HCM,O
+),O
+,,O
+the,O
+most,O
+common,O
+inherited,O
+cardiac,O
+disorder,O
+,,O
+is,O
+characterized,O
+by,O
+increased,O
+ventricular,O
+wall,O
+thickness,O
+that,O
+can,O
+not,O
+be,O
+explained,O
+by,O
+underlying,O
+conditions,O
+,,O
+cadiomyocyte,O
+hypertrophy,O
+and,O
+disarray,O
+,,O
+and,O
+increased,O
+myocardial,O
+fibrosis,O
+.,O
+ , 
+In,O
+as,O
+many,O
+as,O
+50,O
+%,O
+of,O
+HCM,O
+cases,O
+,,O
+the,O
+genetic,O
+cause,O
+remains,O
+unknown,O
+,,O
+suggesting,O
+that,O
+more,O
+genes,O
+may,O
+be,O
+involved,O
+.,O
+ , 
+Nexilin,O
+,,O
+encoded,O
+by,O
+NEXN,B-Gene
+,,I-Gene
+is,O
+a,O
+cardiac,O
+Z,O
+-,O
+disc,O
+protein,O
+recently,O
+identified,O
+as,O
+a,O
+crucial,O
+protein,O
+that,O
+functions,O
+to,O
+protect,O
+cardiac,O
+Z,O
+-,O
+discs,O
+from,O
+forces,O
+generated,O
+within,O
+the,O
+sarcomere,O
+.,O
+ , 
+We,O
+screened,O
+NEXN,B-Gene
+in,O
+121,O
+unrelated,O
+HCM,O
+patients,O
+who,O
+did,O
+not,O
+carry,O
+any,O
+mutation,O
+in,O
+eight,O
+genes,O
+commonly,O
+mutated,O
+in,O
+myofilament,O
+disease,O
+.,O
+ , 
+Two,O
+missense,O
+mutations,O
+,,O
+c.391C,B-SNP
+>,I-SNP
+G,I-SNP
+(,B-SNP
+p.,I-SNP
+Q131E,I-SNP
+),I-SNP
+and,O
+c.835C,B-SNP
+>,I-SNP
+T,I-SNP
+(,B-SNP
+p.,I-SNP
+R279C,I-SNP
+),I-SNP
+,,O
+were,O
+identified,O
+in,O
+exons,O
+5,O
+and,O
+8,O
+of,O
+NEXN,B-Gene
+,,I-Gene
+respectively,O
+,,O
+in,O
+two,O
+probands,O
+.,O
+ , 
+Each,O
+of,O
+the,O
+two,O
+mutations,O
+segregated,O
+with,O
+the,O
+HCM,O
+phenotype,O
+in,O
+the,O
+family,O
+and,O
+was,O
+absent,O
+in,O
+384,O
+control,O
+chromosomes,O
+.,O
+ , 
+In,O
+silico,O
+analysis,O
+revealed,O
+that,O
+both,O
+of,O
+the,O
+mutations,O
+affect,O
+highly,O
+conserved,O
+amino,O
+acid,O
+residues,O
+,,O
+which,O
+are,O
+predicted,O
+to,O
+be,O
+functionally,O
+deleterious,O
+.,O
+ , 
+Cellular,O
+transfection,O
+studies,O
+showed,O
+that,O
+the,O
+two,O
+mutations,O
+resulted,O
+in,O
+local,O
+accumulations,O
+of,O
+nexilin,O
+and,O
+that,O
+the,O
+expressed,O
+fragment,O
+of,O
+actin,O
+-,O
+binding,O
+domain,O
+containing,O
+p.,B-SNP
+Q131E,I-SNP
+completely,O
+lost,O
+the,O
+ability,O
+to,O
+bind,O
+F,O
+-,O
+actin,O
+in,O
+C2C12,O
+cells,O
+.,O
+ , 
+Coimmunoprecipitation,O
+assay,O
+indicated,O
+that,O
+the,O
+p.,B-SNP
+Q131E,I-SNP
+mutation,O
+decreased,O
+the,O
+binding,O
+of,O
+full,O
+-,O
+length,O
+NEXN,B-Gene
+to,O
+α,O
+-,O
+actin,O
+and,O
+abolished,O
+the,O
+interaction,O
+between,O
+the,O
+fragment,O
+of,O
+actin,O
+-,O
+binding,O
+domain,O
+and,O
+α,O
+-,O
+actin,O
+.,O
+ , 
+Therefore,O
+,,O
+the,O
+mutations,O
+in,O
+NEXN,B-Gene
+that,O
+we,O
+describe,O
+here,O
+may,O
+further,O
+expand,O
+the,O
+knowledge,O
+of,O
+Z,O
+-,O
+disc,O
+genes,O
+in,O
+the,O
+pathogenesis,O
+of,O
+HCM,O
+.,O
+ , 
+#9452040
+Novel,O
+nonsense,O
+mutation,O
+in,O
+exon,O
+15,O
+of,O
+the,O
+APC,B-Gene
+gene,O
+in,O
+one,O
+Jewish,O
+family,O
+.,O
+ , 
+#11731936
+Human,O
+-,O
+specific,O
+duplication,O
+and,O
+mosaic,O
+transcripts,O
+:,O
+the,O
+recent,O
+paralogous,O
+structure,O
+of,O
+chromosome,O
+22,O
+.,O
+ , 
+In,O
+recent,O
+decades,O
+,,O
+comparative,O
+chromosomal,O
+banding,O
+,,O
+chromosome,O
+painting,O
+,,O
+and,O
+gene,O
+-,O
+order,O
+studies,O
+have,O
+shown,O
+strong,O
+conservation,O
+of,O
+gross,O
+chromosome,O
+structure,O
+and,O
+gene,O
+order,O
+in,O
+mammals,O
+.,O
+ , 
+However,O
+,,O
+findings,O
+from,O
+the,O
+human,O
+genome,O
+sequence,O
+suggest,O
+an,O
+unprecedented,O
+degree,O
+of,O
+recent,O
+(,O
+<,O
+35,O
+million,O
+years,O
+ago,O
+),O
+segmental,O
+duplication,O
+.,O
+ , 
+This,O
+dynamism,O
+of,O
+segmental,O
+duplications,O
+has,O
+important,O
+implications,O
+in,O
+disease,O
+and,O
+evolution,O
+.,O
+ , 
+Here,O
+we,O
+present,O
+a,O
+chromosome,O
+-,O
+wide,O
+view,O
+of,O
+the,O
+structure,O
+and,O
+evolution,O
+of,O
+the,O
+most,O
+highly,O
+homologous,O
+duplications,O
+(,O
+>,O
+or,O
+=,O
+1,O
+kb,O
+and,O
+>,O
+or,O
+=,O
+90,O
+%,O
+),O
+on,O
+chromosome,O
+22,O
+.,O
+ , 
+Overall,O
+,,O
+10.8,O
+%,O
+(,O
+3.7/33.8,O
+Mb,O
+),O
+of,O
+chromosome,O
+22,O
+is,O
+duplicated,O
+,,O
+with,O
+an,O
+average,O
+sequence,O
+identity,O
+of,O
+95.4,O
+%,O
+.,O
+ , 
+To,O
+organize,O
+the,O
+duplications,O
+into,O
+tractable,O
+units,O
+,,O
+intron,O
+-,O
+exon,O
+structure,O
+and,O
+well,O
+-,O
+defined,O
+duplication,O
+boundaries,O
+were,O
+used,O
+to,O
+define,O
+78,O
+duplicated,O
+modules,O
+(,O
+minimally,O
+shared,O
+evolutionary,O
+segments,O
+),O
+with,O
+157,O
+copies,O
+on,O
+chromosome,O
+22,O
+.,O
+ , 
+Analysis,O
+of,O
+these,O
+modules,O
+provides,O
+evidence,O
+for,O
+the,O
+creation,O
+or,O
+modification,O
+of,O
+11,O
+novel,O
+transcripts,O
+.,O
+ , 
+Comparative,O
+FISH,O
+analyses,O
+of,O
+human,O
+,,O
+chimpanzee,O
+,,O
+gorilla,O
+,,O
+orangutan,O
+,,O
+and,O
+macaque,O
+reveal,O
+qualitative,O
+and,O
+quantitative,O
+differences,O
+in,O
+the,O
+distribution,O
+of,O
+these,O
+duplications,O
+--,O
+consistent,O
+with,O
+their,O
+recent,O
+origin,O
+.,O
+ , 
+Several,O
+duplications,O
+appear,O
+to,O
+be,O
+human,O
+specific,O
+,,O
+including,O
+a,O
+approximately,O
+400,O
+-,O
+kb,O
+duplication,O
+(,O
+99.4%-99.8,O
+%,O
+sequence,O
+identity,O
+),O
+that,O
+transposed,O
+from,O
+chromosome,O
+14,O
+to,O
+the,O
+most,O
+proximal,O
+pericentromeric,O
+region,O
+of,O
+chromosome,O
+22,O
+.,O
+ , 
+Experimental,O
+and,O
+in,O
+silico,O
+data,O
+further,O
+support,O
+a,O
+pericentromeric,O
+gradient,O
+of,O
+duplications,O
+where,O
+the,O
+most,O
+recent,O
+duplications,O
+transpose,O
+adjacent,O
+to,O
+the,O
+centromere,O
+.,O
+ , 
+Taken,O
+together,O
+,,O
+these,O
+data,O
+suggest,O
+that,O
+segmental,O
+duplications,O
+have,O
+been,O
+an,O
+ongoing,O
+process,O
+of,O
+primate,O
+genome,O
+evolution,O
+,,O
+contributing,O
+to,O
+recent,O
+gene,O
+innovation,O
+and,O
+the,O
+dynamic,O
+transformation,O
+of,O
+genome,O
+architecture,O
+within,O
+and,O
+among,O
+closely,O
+related,O
+species,O
+.,O
+ , 
+#11083947
+Extent,O
+and,O
+distribution,O
+of,O
+linkage,O
+disequilibrium,O
+in,O
+three,O
+genomic,O
+regions,O
+.,O
+ , 
+The,O
+positional,O
+cloning,O
+of,O
+genes,O
+underlying,O
+common,O
+complex,O
+diseases,O
+relies,O
+on,O
+the,O
+identification,O
+of,O
+linkage,O
+disequilibrium,O
+(,O
+LD,O
+),O
+between,O
+genetic,O
+markers,O
+and,O
+disease,O
+.,O
+ , 
+We,O
+have,O
+examined,O
+127,O
+polymorphisms,O
+in,O
+three,O
+genomic,O
+regions,O
+in,O
+a,O
+sample,O
+of,O
+575,O
+chromosomes,O
+from,O
+unrelated,O
+individuals,O
+of,O
+British,O
+ancestry,O
+.,O
+ , 
+To,O
+establish,O
+phase,O
+,,O
+800,O
+individuals,O
+were,O
+genotyped,O
+in,O
+160,O
+families,O
+.,O
+ , 
+The,O
+fine,O
+structure,O
+of,O
+LD,O
+was,O
+found,O
+to,O
+be,O
+highly,O
+irregular,O
+.,O
+ , 
+Forty,O
+-,O
+five,O
+percent,O
+of,O
+the,O
+variation,O
+in,O
+disequilibrium,O
+measures,O
+could,O
+be,O
+explained,O
+by,O
+physical,O
+distance,O
+.,O
+ , 
+Additional,O
+factors,O
+,,O
+such,O
+as,O
+allele,O
+frequency,O
+,,O
+type,O
+of,O
+polymorphism,O
+,,O
+and,O
+genomic,O
+location,O
+,,O
+explained,O
+<,O
+5,O
+%,O
+of,O
+the,O
+variation,O
+.,O
+ , 
+Nevertheless,O
+,,O
+disequilibrium,O
+was,O
+occasionally,O
+detectable,O
+at,O
+500,O
+kb,O
+and,O
+was,O
+present,O
+for,O
+over,O
+one,O
+-,O
+half,O
+of,O
+marker,O
+pairs,O
+separated,O
+by,O
+<,O
+50,O
+kb,O
+.,O
+ , 
+Although,O
+these,O
+findings,O
+are,O
+encouraging,O
+for,O
+the,O
+prospects,O
+of,O
+a,O
+genomewide,O
+LD,O
+map,O
+,,O
+they,O
+suggest,O
+caution,O
+in,O
+interpreting,O
+localization,O
+due,O
+to,O
+allelic,O
+association,O
+.,O
+ , 
+#22052681
+A,O
+novel,O
+mutation,O
+impairing,O
+the,O
+tertiary,O
+structure,O
+and,O
+stability,O
+of,O
+γC,B-Gene
+-,I-Gene
+crystallin,I-Gene
+(,B-Gene
+CRYGC,I-Gene
+),I-Gene
+leads,O
+to,O
+cataract,O
+formation,O
+in,O
+humans,O
+and,O
+zebrafish,O
+lens,O
+.,O
+ , 
+Congenital,O
+cataract,O
+is,O
+one,O
+of,O
+the,O
+leading,O
+causes,O
+of,O
+human,O
+blindness,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+identified,O
+a,O
+novel,O
+,,O
+heterozygous,O
+c.385G,B-SNP
+<,I-SNP
+T,I-SNP
+mutation,O
+in,O
+CRYGC,B-Gene
+that,O
+resulted,O
+in,O
+the,O
+substitution,O
+of,O
+a,O
+highly,O
+conserved,O
+glycine,B-SNP
+by,I-SNP
+cysteine,I-SNP
+at,I-SNP
+codon,I-SNP
+129,I-SNP
+(,B-SNP
+p.,I-SNP
+Gly129Cys,I-SNP
+),I-SNP
+in,O
+a,O
+three,O
+-,O
+generation,O
+Chinese,O
+family,O
+with,O
+autosomal,O
+dominant,O
+congenital,O
+nuclear,O
+cataract,O
+by,O
+sequencing,O
+candidate,O
+genes,O
+.,O
+ , 
+Using,O
+zebrafish,O
+as,O
+a,O
+model,O
+,,O
+we,O
+demonstrated,O
+that,O
+γC,B-Gene
+-,I-Gene
+crystallin,I-Gene
+p.,B-SNP
+Gly129Cys,I-SNP
+mutant,O
+caused,O
+the,O
+vacuole,O
+and,O
+the,O
+incomplete,O
+denucleation,O
+of,O
+lens,O
+,,O
+recapitulating,O
+the,O
+cataract,O
+phenotype,O
+in,O
+human,O
+beings,O
+.,O
+ , 
+Molecular,O
+modeling,O
+and,O
+spectroscopic,O
+studies,O
+indicated,O
+that,O
+the,O
+mutation,O
+impaired,O
+the,O
+tertiary,O
+structure,O
+of,O
+the,O
+protein,O
+by,O
+modifying,O
+the,O
+H,O
+-,O
+bonding,O
+network,O
+in,O
+the,O
+C,O
+-,O
+terminal,O
+domain,O
+.,O
+ , 
+The,O
+mutation,O
+led,O
+to,O
+a,O
+dramatic,O
+decrease,O
+in,O
+the,O
+thermal,O
+stability,O
+of,O
+γC,B-Gene
+-,I-Gene
+crystallin,I-Gene
+,,I-Gene
+and,O
+a,O
+significant,O
+increase,O
+in,O
+the,O
+propensity,O
+of,O
+aggregation,O
+when,O
+subject,O
+to,O
+storage,O
+at,O
+high,O
+concentrations,O
+,,O
+heat,O
+,,O
+and,O
+UV-,O
+irradiation,O
+stresses,O
+.,O
+ , 
+Taken,O
+together,O
+,,O
+these,O
+results,O
+indicate,O
+that,O
+a,O
+novel,O
+γC,B-Gene
+-,I-Gene
+crystallin,I-Gene
+p.,B-SNP
+Gly129Cys,I-SNP
+mutation,O
+impaired,O
+the,O
+tertiary,O
+structure,O
+of,O
+the,O
+protein,O
+and,O
+caused,O
+cataract,O
+formation,O
+,,O
+which,O
+provides,O
+a,O
+new,O
+insight,O
+into,O
+how,O
+the,O
+mutation,O
+may,O
+affect,O
+the,O
+γC,B-Gene
+-,I-Gene
+crystallin,I-Gene
+structure,O
+,,O
+stability,O
+,,O
+and,O
+function,O
+.,O
+ , 
+Our,O
+study,O
+also,O
+highlighted,O
+zebrafish,O
+as,O
+a,O
+valuable,O
+model,O
+tool,O
+for,O
+studying,O
+congenital,O
+inherited,O
+cataract,O
+.,O
+ , 
+#11179004
+Connexin,B-Gene
+mutations,O
+in,O
+skin,O
+disease,O
+and,O
+hearing,O
+loss,O
+.,O
+ , 
+#21376300
+Excess,O
+of,O
+de,O
+novo,O
+deleterious,O
+mutations,O
+in,O
+genes,O
+associated,O
+with,O
+glutamatergic,O
+systems,O
+in,O
+nonsyndromic,O
+intellectual,O
+disability,O
+.,O
+ , 
+Little,O
+is,O
+known,O
+about,O
+the,O
+genetics,O
+of,O
+nonsyndromic,O
+intellectual,O
+disability,O
+(,O
+NSID,O
+),O
+.,O
+ , 
+We,O
+hypothesized,O
+that,O
+de,O
+novo,O
+mutations,O
+(,O
+DNMs,O
+),O
+in,O
+synaptic,O
+genes,O
+explain,O
+an,O
+important,O
+fraction,O
+of,O
+sporadic,O
+NSID,O
+cases,O
+.,O
+ , 
+In,O
+order,O
+to,O
+investigate,O
+this,O
+possibility,O
+,,O
+we,O
+sequenced,O
+197,O
+genes,O
+encoding,O
+glutamate,O
+receptors,O
+and,O
+a,O
+large,O
+subset,O
+of,O
+their,O
+known,O
+interacting,O
+proteins,O
+in,O
+95,O
+sporadic,O
+cases,O
+of,O
+NSID,O
+.,O
+ , 
+We,O
+found,O
+11,O
+DNMs,O
+,,O
+including,O
+ten,O
+potentially,O
+deleterious,O
+mutations,O
+(,O
+three,O
+nonsense,O
+,,O
+two,O
+splicing,O
+,,O
+one,O
+frameshift,O
+,,O
+four,O
+missense,O
+),O
+and,O
+one,O
+neutral,O
+mutation,O
+(,O
+silent,O
+),O
+in,O
+eight,O
+different,O
+genes,O
+.,O
+ , 
+Calculation,O
+of,O
+point,O
+-,O
+substitution,O
+DNM,O
+rates,O
+per,O
+functional,O
+and,O
+neutral,O
+site,O
+showed,O
+significant,O
+excess,O
+of,O
+functional,O
+DNMs,O
+compared,O
+to,O
+neutral,O
+ones,O
+.,O
+ , 
+De,O
+novo,O
+truncating,O
+and/or,O
+splicing,O
+mutations,O
+in,O
+SYNGAP1,B-Gene
+,,I-Gene
+STXBP1,B-Gene
+,,I-Gene
+and,O
+SHANK3,B-Gene
+were,O
+found,O
+in,O
+six,O
+patients,O
+and,O
+are,O
+likely,O
+to,O
+be,O
+pathogenic,O
+.,O
+ , 
+De,O
+novo,O
+missense,O
+mutations,O
+were,O
+found,O
+in,O
+KIF1A,B-Gene
+,,I-Gene
+GRIN1,B-Gene
+,,I-Gene
+CACNG2,B-Gene
+,,I-Gene
+and,O
+EPB41L1,B-Gene
+.,I-Gene
+ , 
+Functional,O
+studies,O
+showed,O
+that,O
+all,O
+these,O
+missense,O
+mutations,O
+affect,O
+protein,O
+function,O
+in,O
+cell,O
+culture,O
+systems,O
+,,O
+suggesting,O
+that,O
+they,O
+may,O
+be,O
+pathogenic,O
+.,O
+ , 
+Sequencing,O
+these,O
+four,O
+genes,O
+in,O
+50,O
+additional,O
+sporadic,O
+cases,O
+of,O
+NSID,O
+identified,O
+a,O
+second,O
+DNM,O
+in,O
+GRIN1,B-Gene
+(,B-SNP
+c.1679_1681dup,I-SNP
+/,B-SNP
+p.,I-SNP
+Ser560dup,I-SNP
+),I-SNP
+.,O
+ , 
+This,O
+mutation,O
+also,O
+affects,O
+protein,O
+function,O
+,,O
+consistent,O
+with,O
+structural,O
+predictions,O
+.,O
+ , 
+None,O
+of,O
+these,O
+mutations,O
+or,O
+any,O
+other,O
+DNMs,O
+were,O
+identified,O
+in,O
+these,O
+genes,O
+in,O
+285,O
+healthy,O
+controls,O
+.,O
+ , 
+This,O
+study,O
+highlights,O
+the,O
+importance,O
+of,O
+the,O
+glutamate,O
+receptor,O
+complexes,O
+in,O
+NSID,O
+and,O
+further,O
+supports,O
+the,O
+role,O
+of,O
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+disorder,O
+.,O
+ , 
+#9973288
+Hyperparathyroidism,O
+-,O
+jaw,O
+tumor,O
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+:,O
+the,O
+HRPT2,B-Gene
+locus,O
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+within,O
+a,O
+0.7,O
+-,O
+cM,O
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+on,O
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+1q,O
+.,O
+ , 
+Hyperparathyroidism,O
+-,O
+jaw,O
+tumor,O
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+(,O
+HPT,O
+-,O
+JT,O
+),O
+is,O
+an,O
+autosomal,O
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+development,O
+of,O
+multiple,O
+parathyroid,O
+adenomas,O
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+multiple,O
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+-,O
+osseous,O
+tumors,O
+of,O
+the,O
+maxilla,O
+and,O
+mandible,O
+.,O
+ , 
+Some,O
+families,O
+have,O
+had,O
+affected,O
+members,O
+with,O
+involvement,O
+of,O
+the,O
+kidneys,O
+,,O
+variously,O
+reported,O
+as,O
+Wilms,O
+tumors,O
+,,O
+nephroblastomas,O
+,,O
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+hamartomas,O
+.,O
+ , 
+The,O
+HPT,O
+-,O
+JT,O
+gene,O
+(,B-Gene
+HRPT2,I-Gene
+),I-Gene
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+chromosome,O
+1q25,O
+-,O
+q31,O
+.,O
+ , 
+We,O
+describe,O
+further,O
+investigation,O
+of,O
+two,O
+HPT,O
+-,O
+JT,O
+families,O
+(,O
+K3304,O
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+K3349,O
+),O
+identified,O
+through,O
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+literature,O
+.,O
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+These,O
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+.,O
+ , 
+Multipoint,O
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+LOD,O
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+7.83,O
+(,O
+at,O
+recombination,O
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+0,O
+),O
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+markers,O
+D1S2848,O
+-,O
+D1S191,O
+.,O
+ , 
+Recombination,O
+events,O
+in,O
+these,O
+families,O
+reduced,O
+the,O
+HRPT2,B-Gene
+region,O
+to,O
+approximately,O
+14.7,O
+cM.,O
+ , 
+In,O
+addition,O
+,,O
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+these,O
+four,O
+study,O
+families,O
+(,O
+i.e.,O
+,,O
+K3304,O
+and,O
+K11687,O
+),O
+share,O
+a,O
+2.2,O
+-,O
+cM,O
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+of,O
+their,O
+(,O
+expanded,O
+),O
+affected,O
+haplotype,O
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+a,O
+possible,O
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+.,O
+ , 
+Combining,O
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+linkage,O
+data,O
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+-,O
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+,,O
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+a,O
+0.7,O
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+region,O
+for,O
+HRPT2,B-Gene
+.,I-Gene
+ , 
+#7825598
+Evidence,O
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+an,O
+association,O
+between,O
+RFLPs,O
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+transforming,O
+growth,O
+factor,O
+alpha,O
+(,O
+locus,O
+),O
+and,O
+nonsyndromic,O
+cleft,O
+lip,O
+/,O
+palate,O
+in,O
+a,O
+South,O
+American,O
+population,O
+.,O
+ , 
+#9401011
+Mutation,O
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+hMSH3,B-Gene
+and,O
+hMSH6,B-Gene
+mismatch,O
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+genes,O
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+genetically,O
+unstable,O
+human,O
+colorectal,O
+and,O
+gastric,O
+carcinomas,O
+.,O
+ , 
+Mutations,O
+within,O
+microsatellite,O
+sequences,O
+,,O
+consisting,O
+of,O
+additions,O
+or,O
+deletions,O
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+repeat,O
+units,O
+,,O
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+known,O
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+the,O
+replication,O
+/,O
+repair,O
+error,O
+positive,O
+(,O
+RER+,O
+),O
+phenotype,O
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+(,O
+MI,O
+),O
+.,O
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+Microsatellite,O
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+and,O
+sporadic,O
+colorectal,O
+carcinomas,O
+and,O
+is,O
+usually,O
+observed,O
+in,O
+noncoding,O
+regions,O
+of,O
+genomic,O
+DNA,O
+.,O
+ , 
+However,O
+,,O
+relatively,O
+few,O
+coding,O
+region,O
+targets,O
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+MI,O
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+been,O
+identified,O
+thus,O
+far,O
+.,O
+ , 
+Using,O
+PCR,O
+,,O
+we,O
+amplified,O
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+(,O
+A)8,O
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+(,O
+C)8,O
+microsatellite,O
+tracts,O
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+hMSH3,B-Gene
+and,O
+hMSH6,B-Gene
+from,O
+31,O
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+23,O
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+32,O
+RER-,O
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+.,O
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+Mutations,O
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+found,O
+in,O
+11,O
+(,O
+36,O
+%,O
+),O
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+31,O
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+colon,O
+carcinomas,O
+,,O
+4,O
+(,O
+50,O
+%,O
+),O
+of,O
+8,O
+hereditary,O
+colorectal,O
+cancers,O
+,,O
+and,O
+5,O
+(,O
+22,O
+%,O
+),O
+of,O
+23,O
+RER+,O
+gastric,O
+carcinomas,O
+,,O
+but,O
+in,O
+only,O
+2,O
+(,O
+6,O
+%,O
+),O
+of,O
+32,O
+RER-,O
+gastric,O
+carcinomas,O
+.,O
+ , 
+These,O
+frameshift,O
+mutations,O
+cause,O
+premature,O
+stop,O
+codons,O
+downstream,O
+that,O
+are,O
+predicted,O
+to,O
+abolish,O
+normal,O
+protein,O
+function,O
+.,O
+ , 
+Our,O
+results,O
+and,O
+those,O
+of,O
+others,O
+suggest,O
+that,O
+DNA,O
+mismatch,O
+repair,O
+genes,O
+,,O
+such,O
+as,O
+hMSH3,B-Gene
+and,O
+hMSH6,B-Gene
+,,I-Gene
+are,O
+targets,O
+for,O
+the,O
+mutagenic,O
+activity,O
+of,O
+upstream,O
+mismatch,O
+repair,O
+gene,O
+mutations,O
+and,O
+that,O
+this,O
+enhanced,O
+genomic,O
+instability,O
+may,O
+accelerate,O
+the,O
+accumulation,O
+of,O
+mutations,O
+in,O
+RER+,O
+tumors,O
+.,O
+ , 
+#8019568
+Phenylketonuria,O
+in,O
+China,O
+:,O
+identification,O
+and,O
+characterization,O
+of,O
+three,O
+novel,O
+nucleotide,O
+substitutions,O
+in,O
+the,O
+human,O
+phenylalanine,B-Gene
+hydroxylase,I-Gene
+gene,O
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+ , 
+#7981721
+A,O
+tandem,O
+CC-->TT,O
+transition,O
+in,O
+the,O
+p53,B-Gene
+gene,O
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+a,O
+breast,O
+cancer,O
+.,O
+ , 
+#19718767
+NR2E3,B-Gene
+mutations,O
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+S,O
+-,O
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+(,O
+ESCS,O
+),O
+,,O
+Goldmann,O
+-,O
+Favre,O
+syndrome,O
+(,O
+GFS,O
+),O
+,,O
+clumped,O
+pigmentary,O
+retinal,O
+degeneration,O
+(,O
+CPRD,O
+),O
+,,O
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+retinitis,O
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+(,O
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+),O
+.,O
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+NR2E3,B-Gene
+,,I-Gene
+also,O
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+photoreceptor,B-Gene
+-,I-Gene
+specific,I-Gene
+nuclear,I-Gene
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+(,B-Gene
+PNR,I-Gene
+),I-Gene
+,,O
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+a,O
+transcription,O
+factor,O
+of,O
+the,O
+nuclear,O
+hormone,O
+receptor,O
+superfamily,O
+whose,O
+expression,O
+is,O
+uniquely,O
+restricted,O
+to,O
+photoreceptors,O
+.,O
+ , 
+There,O
+,,O
+its,O
+physiological,O
+activity,O
+is,O
+essential,O
+for,O
+proper,O
+rod,O
+and,O
+cone,O
+photoreceptor,O
+development,O
+and,O
+maintenance,O
+.,O
+ , 
+Thirty,O
+-,O
+two,O
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+mutations,O
+in,O
+NR2E3,B-Gene
+have,O
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+identified,O
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+homozygous,O
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+heterozygous,O
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+recessively,O
+inherited,O
+enhanced,O
+S,O
+-,O
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+(,O
+ESCS,O
+),O
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+(,O
+GFS,O
+),O
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+pigmentary,O
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+(,O
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+),O
+.,O
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+The,O
+clinical,O
+phenotype,O
+common,O
+to,O
+all,O
+these,O
+patients,O
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+night,O
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+,,O
+rudimental,O
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+absent,O
+rod,O
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+,,O
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+S,O
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+ , 
+A,O
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+G56R,I-SNP
+mutation,O
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+in,O
+a,O
+dominant,O
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+pigmentosa,O
+(,O
+RP,O
+),O
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+We,O
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+established,O
+a,O
+new,O
+locus,O
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+specific,O
+database,O
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+NR2E3,B-Gene
+(,O
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+),O
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+A,O
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+proportion,O
+of,O
+mutations,O
+are,O
+located,O
+in,O
+the,O
+evolutionarily,O
+-,O
+conserved,O
+DNA,O
+-,O
+binding,O
+domains,O
+(,O
+DBDs,O
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+ligand,O
+-,O
+binding,O
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+(,O
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+),O
+of,O
+NR2E3,B-Gene
+.,I-Gene
+ , 
+Based,O
+on,O
+homology,O
+modeling,O
+of,O
+these,O
+NR2E3,B-Gene
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+,,O
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+propose,O
+a,O
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+localization,O
+of,O
+mutated,O
+residues,O
+.,O
+ , 
+The,O
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+variability,O
+of,O
+clinical,O
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+by,O
+NR2E3,B-Gene
+-,I-Gene
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+,,O
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+of,O
+DNA,O
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+,,O
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+activity,O
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+modifier,O
+genes,O
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+#15272417
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+locus,O
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+chromosome,O
+6q23,O
+-,O
+25,O
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+Lung,O
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+a,O
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+United,O
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+countries,O
+.,O
+ , 
+The,O
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+certain,O
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+,,O
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+familial,O
+factors,O
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+clearly,O
+play,O
+a,O
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+role,O
+.,O
+ , 
+To,O
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+susceptibility,O
+genes,O
+for,O
+familial,O
+lung,O
+cancer,O
+,,O
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+conducted,O
+a,O
+genomewide,O
+linkage,O
+analysis,O
+of,O
+52,O
+extended,O
+pedigrees,O
+ascertained,O
+through,O
+probands,O
+with,O
+lung,O
+cancer,O
+who,O
+had,O
+several,O
+first,O
+-,O
+degree,O
+relatives,O
+with,O
+the,O
+same,O
+disease,O
+.,O
+ , 
+Multipoint,O
+linkage,O
+analysis,O
+,,O
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+a,O
+simple,O
+autosomal,O
+dominant,O
+model,O
+,,O
+of,O
+all,O
+52,O
+families,O
+with,O
+three,O
+or,O
+more,O
+individuals,O
+affected,O
+by,O
+lung,O
+,,O
+throat,O
+,,O
+or,O
+laryngeal,O
+cancer,O
+,,O
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+a,O
+maximum,O
+heterogeneity,O
+LOD,O
+score,O
+(,O
+HLOD,O
+),O
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+2.79,O
+at,O
+155,O
+cM,O
+on,O
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+6q,O
+(,O
+marker,O
+D6S2436,O
+),O
+.,O
+ , 
+A,O
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+four,O
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+more,O
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+a,O
+multipoint,O
+HLOD,O
+of,O
+3.47,O
+at,O
+155,O
+cM.,O
+ , 
+Analysis,O
+of,O
+a,O
+further,O
+subset,O
+of,O
+23,O
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+pedigrees,O
+with,O
+five,O
+or,O
+more,O
+affected,O
+individuals,O
+yielded,O
+a,O
+multipoint,O
+HLOD,O
+score,O
+of,O
+4.26,O
+at,O
+the,O
+same,O
+position,O
+.,O
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+The,O
+14,O
+families,O
+with,O
+only,O
+three,O
+affected,O
+relatives,O
+yielded,O
+negative,O
+LOD,O
+scores,O
+in,O
+this,O
+region,O
+.,O
+ , 
+A,O
+predivided,O
+samples,O
+test,O
+for,O
+heterogeneity,O
+comparing,O
+the,O
+LOD,O
+scores,O
+from,O
+the,O
+23,O
+multigenerational,O
+families,O
+with,O
+those,O
+from,O
+the,O
+remaining,O
+families,O
+was,O
+significant,O
+(,O
+P=.007,O
+),O
+.,O
+ , 
+The,O
+1,O
+-,O
+HLOD,O
+multipoint,O
+support,O
+interval,O
+from,O
+the,O
+multigenerational,O
+families,O
+extends,O
+from,O
+C6S1848,O
+at,O
+146,O
+cM,O
+to,O
+164,O
+cM,O
+near,O
+D6S1035,O
+,,O
+overlapping,O
+a,O
+genomic,O
+region,O
+that,O
+is,O
+deleted,O
+in,O
+sporadic,O
+lung,O
+cancers,O
+as,O
+well,O
+as,O
+numerous,O
+other,O
+cancer,O
+types,O
+.,O
+ , 
+Parametric,O
+linkage,O
+and,O
+variance,O
+-,O
+components,O
+analysis,O
+that,O
+incorporated,O
+effects,O
+of,O
+age,O
+and,O
+personal,O
+smoking,O
+also,O
+supported,O
+linkage,O
+in,O
+this,O
+region,O
+,,O
+but,O
+with,O
+somewhat,O
+diminished,O
+support,O
+.,O
+ , 
+These,O
+results,O
+localize,O
+a,O
+major,O
+susceptibility,O
+locus,O
+influencing,O
+lung,O
+cancer,O
+risk,O
+to,O
+6q23,O
+-,O
+25,O
+.,O
+ , 
+#7762554
+Frequent,O
+intragenic,O
+deletion,O
+of,O
+the,O
+P,B-Gene
+gene,I-Gene
+in,O
+Tanzanian,O
+patients,O
+with,O
+type,O
+II,O
+oculocutaneous,O
+albinism,O
+(,O
+OCA2,O
+),O
+.,O
+ , 
+Type,O
+II,O
+oculocutaneous,O
+albinism,O
+(,O
+OCA2,O
+),O
+is,O
+an,O
+autosomal,O
+recessive,O
+disorder,O
+in,O
+which,O
+the,O
+biosynthesis,O
+of,O
+melanin,O
+pigment,O
+is,O
+reduced,O
+in,O
+the,O
+skin,O
+,,O
+hair,O
+,,O
+and,O
+eyes,O
+.,O
+ , 
+OCA2,O
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+P,B-Gene
+gene,I-Gene
+,,I-Gene
+is,O
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+type,O
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+in,O
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+African,O
+-,O
+American,O
+patients,O
+.,O
+ , 
+OCA2,O
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+frequent,O
+in,O
+Tanzania,O
+,,O
+where,O
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+approximately,O
+1/1,400,O
+.,O
+ , 
+We,O
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+identified,O
+abnormalities,O
+of,O
+the,O
+P,B-Gene
+gene,I-Gene
+in,O
+each,O
+of,O
+13,O
+unrelated,O
+patients,O
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+OCA2,O
+from,O
+Tanzania,O
+.,O
+ , 
+One,O
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+these,O
+,,O
+a,O
+deletion,O
+of,O
+exon,O
+7,O
+,,O
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+predominant,O
+,,O
+accounting,O
+for,O
+approximately,O
+77,O
+%,O
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+mutant,O
+alleles,O
+in,O
+this,O
+group,O
+of,O
+patients,O
+.,O
+ , 
+#12515255
+The,O
+ABCA4,B-Gene
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+-,O
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+.,O
+ , 
+#12687497
+A,O
+family,O
+-,O
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+correlation,O
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+gene,O
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+trait,O
+values,O
+.,O
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+Advances,O
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+it,O
+attractive,O
+to,O
+combine,O
+information,O
+on,O
+clinical,O
+traits,O
+,,O
+marker,O
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+,,O
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+comprehensive,O
+gene,O
+expression,O
+from,O
+family,O
+studies,O
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+dissect,O
+complex,O
+disease,O
+genetics,O
+.,O
+ , 
+Without,O
+accounting,O
+for,O
+family,O
+structure,O
+,,O
+methods,O
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+test,O
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+association,O
+between,O
+a,O
+trait,O
+and,O
+gene,O
+-,O
+expression,O
+levels,O
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+be,O
+misleading,O
+.,O
+ , 
+We,O
+demonstrate,O
+that,O
+the,O
+standard,O
+unstratified,O
+test,O
+based,O
+on,O
+Pearson,O
+'s,O
+correlation,O
+coefficient,O
+can,O
+produce,O
+spurious,O
+results,O
+when,O
+applied,O
+to,O
+family,O
+data,O
+,,O
+and,O
+we,O
+present,O
+a,O
+stratified,O
+family,O
+expression,O
+association,O
+test,O
+(,O
+FEXAT,O
+),O
+.,O
+ , 
+We,O
+illustrate,O
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+utility,O
+of,O
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+FEXAT,O
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+an,O
+application,O
+to,O
+gene,O
+-,O
+expression,O
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+lymphoblastoid,O
+cell,O
+lines,O
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+four,O
+CEPH,O
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+The,O
+FEXAT,O
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+a,O
+smaller,O
+estimated,O
+false,O
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+than,O
+the,O
+standard,O
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+within,O
+-,O
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+correlations,O
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+interest,O
+,,O
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+it,O
+detects,O
+biologically,O
+plausible,O
+correlations,O
+between,O
+beta,O
+catenin,O
+and,O
+genes,O
+in,O
+the,O
+WNT,O
+-,O
+activation,O
+pathway,O
+in,O
+humans,O
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+the,O
+standard,O
+test,O
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+#15759212
+Identifying,O
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+Patients,O
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+5,O
+',O
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+RET,B-Gene
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+RET,B-Gene
+mutation,O
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+ , 
+In,O
+a,O
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+study,O
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+a,O
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+%,O
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+the,O
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+.,O
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+Among,O
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+patients,O
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+that,O
+haplotype,O
+,,O
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+%,O
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+it,O
+on,O
+both,O
+chromosomes,O
+,,O
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+led,O
+to,O
+a,O
+much,O
+higher,O
+risk,O
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+developing,O
+HSCR,O
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+the,O
+haplotype,O
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+heterozygously,O
+.,O
+ , 
+To,O
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+disease,O
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+variant(s,O
+),O
+,,O
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+shared,O
+common,O
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+region,O
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+10,O
+kb,O
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+of,O
+the,O
+RET,B-Gene
+gene,O
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+1,O
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+exon,O
+2,O
+(,O
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+33,O
+kb,O
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+the,O
+common,O
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+and,O
+in,O
+a,O
+control,O
+individual,O
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+the,O
+most,O
+common,O
+nonrisk,O
+haplotype,O
+.,O
+ , 
+A,O
+comparison,O
+of,O
+these,O
+sequences,O
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+86,O
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+differences,O
+.,O
+ , 
+Of,O
+these,O
+86,O
+variations,O
+,,O
+8,O
+proved,O
+to,O
+be,O
+in,O
+regions,O
+highly,O
+conserved,O
+among,O
+different,O
+vertebrates,O
+and,O
+within,O
+putative,O
+transcription,O
+factor,O
+binding,O
+sites,O
+.,O
+ , 
+We,O
+therefore,O
+considered,O
+these,O
+as,O
+candidate,O
+disease,O
+-,O
+associated,O
+variants,O
+.,O
+ , 
+Subsequent,O
+genotyping,O
+of,O
+these,O
+eight,O
+variants,O
+revealed,O
+a,O
+strong,O
+disease,O
+association,O
+for,O
+six,O
+of,O
+the,O
+eight,O
+markers,O
+.,O
+ , 
+These,O
+six,O
+markers,O
+also,O
+showed,O
+the,O
+largest,O
+distortions,O
+in,O
+allele,O
+transmission,O
+.,O
+ , 
+Interspecies,O
+comparison,O
+showed,O
+that,O
+only,O
+one,O
+of,O
+the,O
+six,O
+variations,O
+was,O
+located,O
+in,O
+a,O
+region,O
+also,O
+conserved,O
+in,O
+a,O
+nonmammalian,O
+species,O
+,,O
+making,O
+it,O
+the,O
+most,O
+likely,O
+candidate,O
+HSCR,O
+-,O
+associated,O
+variant,O
+.,O
+ , 
+#16642431
+Fine,O
+-,O
+mapping,O
+chromosome,O
+20,O
+in,O
+230,O
+systemic,O
+lupus,O
+erythematosus,O
+sib,O
+pair,O
+and,O
+multiplex,O
+families,O
+:,O
+evidence,O
+for,O
+genetic,O
+epistasis,O
+with,O
+chromosome,O
+16q12,O
+.,O
+ , 
+The,O
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+of,O
+systemic,O
+lupus,O
+erythematosus,O
+(,O
+SLE,O
+),O
+susceptibility,O
+genes,O
+on,O
+chromosome,O
+20,O
+is,O
+suggested,O
+by,O
+the,O
+observation,O
+of,O
+genetic,O
+linkage,O
+in,O
+several,O
+independent,O
+SLE,O
+family,O
+collections,O
+.,O
+ , 
+To,O
+further,O
+localize,O
+the,O
+genetic,O
+effects,O
+,,O
+we,O
+typed,O
+59,O
+microsatellites,O
+in,O
+the,O
+two,O
+best,O
+regions,O
+,,O
+as,O
+defined,O
+by,O
+genome,O
+screens,O
+.,O
+ , 
+Genotypes,O
+were,O
+analyzed,O
+for,O
+statistical,O
+linkage,O
+and/or,O
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+SLE,O
+,,O
+by,O
+use,O
+of,O
+a,O
+combination,O
+of,O
+nonparametric,O
+linkage,O
+methods,O
+,,O
+family,O
+-,O
+based,O
+tests,O
+of,O
+association,O
+(,O
+transmission,O
+/,O
+disequilibrium,O
+and,O
+pedigree,O
+disequilibrium,O
+tests,O
+),O
+,,O
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+haplotype,O
+-,O
+sharing,O
+statistics,O
+(,O
+haplotype,O
+runs,O
+test,O
+),O
+,,O
+in,O
+a,O
+set,O
+of,O
+230,O
+SLE,O
+pedigrees,O
+.,O
+ , 
+Maximal,O
+evidence,O
+for,O
+linkage,O
+to,O
+SLE,O
+was,O
+to,O
+20p12,O
+(,O
+LOD,O
+=,O
+2.84,O
+),O
+and,O
+20q13.1,O
+(,O
+LOD,O
+=,O
+1.64,O
+),O
+in,O
+the,O
+white,O
+pedigrees,O
+.,O
+ , 
+Subsetting,O
+families,O
+on,O
+the,O
+basis,O
+of,O
+evidence,O
+for,O
+linkage,O
+to,O
+16q12,O
+significantly,O
+improved,O
+the,O
+LOD,O
+scores,O
+at,O
+both,O
+chromosome,O
+20,O
+locations,O
+(,O
+20p12,O
+LOD,O
+=,O
+5.06,O
+and,O
+20q13,O
+LOD,O
+=,O
+3.65,O
+),O
+,,O
+consistent,O
+with,O
+epistasis,O
+.,O
+ , 
+We,O
+then,O
+typed,O
+162,O
+single,O
+-,O
+nucleotide,O
+polymorphism,O
+markers,O
+across,O
+a,O
+1.3,O
+-,O
+Mb,O
+candidate,O
+region,O
+on,O
+20q13.1,O
+and,O
+identified,O
+several,O
+SNPs,O
+that,O
+demonstrated,O
+significant,O
+evidence,O
+for,O
+association,O
+.,O
+ , 
+These,O
+data,O
+provide,O
+additional,O
+support,O
+for,O
+linkage,O
+and,O
+association,O
+to,O
+20p12,O
+and,O
+20q13.1,O
+in,O
+SLE,O
+and,O
+further,O
+refine,O
+the,O
+intervals,O
+of,O
+interest,O
+.,O
+ , 
+These,O
+data,O
+further,O
+suggest,O
+the,O
+possibility,O
+of,O
+epistatic,O
+relationships,O
+among,O
+loci,O
+within,O
+the,O
+20q12,O
+,,O
+20q13,O
+,,O
+and,O
+16q12,O
+regions,O
+in,O
+SLE,O
+families,O
+.,O
+ , 
+#21129725
+Replication,O
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+rare,O
+variant,O
+complex,O
+trait,O
+association,O
+studies,O
+via,O
+next,O
+-,O
+generation,O
+sequencing,O
+.,O
+ , 
+There,O
+is,O
+solid,O
+evidence,O
+that,O
+complex,O
+traits,O
+can,O
+be,O
+caused,O
+by,O
+rare,O
+variants,O
+.,O
+ , 
+Next,O
+-,O
+generation,O
+sequencing,O
+technologies,O
+are,O
+powerful,O
+tools,O
+for,O
+mapping,O
+rare,O
+variants,O
+.,O
+ , 
+Confirmation,O
+of,O
+significant,O
+findings,O
+in,O
+stage,O
+1,O
+through,O
+replication,O
+in,O
+an,O
+independent,O
+stage,O
+2,O
+sample,O
+is,O
+necessary,O
+for,O
+association,O
+studies,O
+.,O
+ , 
+For,O
+gene,O
+-,O
+based,O
+mapping,O
+of,O
+rare,O
+variants,O
+,,O
+two,O
+replication,O
+strategies,O
+are,O
+possible,O
+:,O
+(,O
+1,O
+),O
+variant,O
+-,O
+based,O
+replication,O
+,,O
+wherein,O
+only,O
+variants,O
+from,O
+nucleotide,O
+sites,O
+uncovered,O
+in,O
+stage,O
+1,O
+are,O
+genotyped,O
+and,O
+followed,O
+-,O
+up,O
+and,O
+(,O
+2,O
+),O
+sequence,O
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+replication,O
+,,O
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+the,O
+gene,O
+region,O
+is,O
+sequenced,O
+in,O
+the,O
+replication,O
+sample,O
+and,O
+both,O
+known,O
+and,O
+novel,O
+variants,O
+are,O
+tested,O
+.,O
+ , 
+The,O
+efficiency,O
+of,O
+the,O
+two,O
+strategies,O
+is,O
+dependent,O
+on,O
+the,O
+proportions,O
+of,O
+causative,O
+variants,O
+discovered,O
+in,O
+stage,O
+1,O
+and,O
+sequencing,O
+/,O
+genotyping,O
+errors,O
+.,O
+ , 
+With,O
+rigorous,O
+population,O
+genetic,O
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+phenotypic,O
+models,O
+,,O
+it,O
+is,O
+demonstrated,O
+that,O
+sequence,O
+-,O
+based,O
+replication,O
+is,O
+consistently,O
+more,O
+powerful,O
+.,O
+ , 
+However,O
+,,O
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+gain,O
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+small,O
+(,O
+1,O
+),O
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+large,O
+-,O
+scale,O
+studies,O
+with,O
+thousands,O
+of,O
+individuals,O
+,,O
+because,O
+a,O
+large,O
+fraction,O
+of,O
+causative,O
+variant,O
+sites,O
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+and,O
+(,O
+2,O
+),O
+for,O
+small-,O
+to,O
+medium,O
+-,O
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+Therefore,O
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+a,O
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+if,O
+stage,O
+1,O
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+2,O
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+same,O
+population,O
+.,O
+ , 
+However,O
+,,O
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+if,O
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+stage,O
+1,O
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+is,O
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+It,O
+is,O
+shown,O
+that,O
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+attainable,O
+levels,O
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+sequencing,O
+error,O
+only,O
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+affect,O
+the,O
+comparison,O
+,,O
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+advantage,O
+of,O
+sequence,O
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+.,O
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+#8488834
+Insurance,O
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+genetic,O
+discrimination,O
+.,O
+ , 
+#8081391
+Mutations,O
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+steroid,B-Gene
+21,I-Gene
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+CYP21,I-Gene
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+.,O
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+The,O
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+More,O
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+This,O
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+Steroid,B-Gene
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+(,B-Gene
+P450c21,I-Gene
+),I-Gene
+is,O
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+conversion,O
+of,O
+17,B-Gene
+-,I-Gene
+hydroxyprogesterone,I-Gene
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+11,B-Gene
+-,I-Gene
+deoxycortisol,I-Gene
+and,I-Gene
+deoxycorticosterone,I-Gene
+respectively,O
+.,O
+ , 
+In,O
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+,,O
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+CYP21,B-Gene
+(,B-Gene
+CYP21B,I-Gene
+),I-Gene
+gene,O
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+in,O
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+HLA,O
+major,O
+histocompatibility,O
+complex,O
+along,O
+with,O
+a,O
+pseudogene,O
+,,O
+CYP21P,B-Gene
+(,B-Gene
+CYP21A,I-Gene
+),I-Gene
+.,O
+ , 
+Mutations,O
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+causing,O
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+generated,O
+by,O
+recombinations,O
+between,O
+CYP21,B-Gene
+and,O
+CYP21P.,B-Gene
+These,O
+recombinations,O
+either,O
+delete,O
+CYP21,B-Gene
+or,O
+transfer,O
+deleterious,O
+mutations,O
+from,O
+CYP21P,B-Gene
+to,O
+CYP21,B-Gene
+,,I-Gene
+a,O
+process,O
+termed,O
+apparent,O
+gene,O
+conversion,O
+.,O
+ , 
+The,O
+degree,O
+of,O
+enzymatic,O
+compromise,O
+caused,O
+by,O
+each,O
+mutation,O
+is,O
+correlated,O
+with,O
+the,O
+clinical,O
+severity,O
+of,O
+the,O
+deficiency,O
+observed,O
+in,O
+patients,O
+carrying,O
+that,O
+mutation,O
+.,O
+ , 
+#16773567
+Intra-,O
+and,O
+interindividual,O
+epigenetic,O
+variation,O
+in,O
+human,O
+germ,O
+cells,O
+.,O
+ , 
+Epigenetics,O
+represents,O
+a,O
+secondary,O
+inheritance,O
+system,O
+that,O
+has,O
+been,O
+poorly,O
+investigated,O
+in,O
+human,O
+biology,O
+.,O
+ , 
+The,O
+objective,O
+of,O
+this,O
+study,O
+was,O
+to,O
+perform,O
+a,O
+comprehensive,O
+analysis,O
+of,O
+DNA,O
+methylation,O
+variation,O
+between,O
+and,O
+within,O
+the,O
+germlines,O
+of,O
+normal,O
+males,O
+.,O
+ , 
+First,O
+,,O
+methylated,O
+cytosines,O
+were,O
+mapped,O
+using,O
+bisulphite,O
+modification,O
+-,O
+based,O
+sequencing,O
+in,O
+the,O
+promoter,O
+regions,O
+of,O
+the,O
+following,O
+disease,O
+genes,O
+:,O
+presenilins,O
+(,B-Gene
+PSEN1,I-Gene
+and,O
+PSEN2,B-Gene
+),I-Gene
+,,O
+breast,O
+cancer,O
+(,B-Gene
+BRCA1,I-Gene
+and,O
+BRCA2,B-Gene
+),I-Gene
+,,O
+myotonic,O
+dystrophy,O
+(,B-Gene
+DM1,I-Gene
+),I-Gene
+,,O
+and,O
+Huntington,O
+disease,O
+(,B-Gene
+HD,I-Gene
+),I-Gene
+.,O
+ , 
+Major,O
+epigenetic,O
+variation,O
+was,O
+detected,O
+within,O
+samples,O
+,,O
+since,O
+the,O
+majority,O
+of,O
+sperm,O
+cells,O
+of,O
+the,O
+same,O
+individual,O
+exhibited,O
+unique,O
+DNA,O
+methylation,O
+profiles,O
+.,O
+ , 
+In,O
+the,O
+interindividual,O
+analysis,O
+,,O
+41,O
+of,O
+61,O
+pairwise,O
+comparisons,O
+revealed,O
+distinct,O
+DNA,O
+methylation,O
+profiles,O
+(,O
+P=.036,O
+to,O
+6.8,O
+x,O
+10(-14,O
+),O
+),O
+.,O
+ , 
+Second,O
+,,O
+a,O
+microarray,O
+-,O
+based,O
+epigenetic,O
+profiling,O
+of,O
+the,O
+same,O
+sperm,O
+samples,O
+was,O
+performed,O
+using,O
+a,O
+12,198,O
+-,O
+feature,O
+CpG,O
+island,O
+microarray,O
+.,O
+ , 
+The,O
+microarray,O
+analysis,O
+has,O
+identified,O
+numerous,O
+DNA,O
+methylation,O
+-,O
+variable,O
+positions,O
+in,O
+the,O
+germ,O
+cell,O
+genome,O
+.,O
+ , 
+The,O
+largest,O
+degree,O
+of,O
+variation,O
+was,O
+detected,O
+within,O
+the,O
+promoter,O
+CpG,O
+islands,O
+and,O
+pericentromeric,O
+satellites,O
+among,O
+the,O
+single,O
+-,O
+copy,O
+DNA,O
+fragments,O
+and,O
+repetitive,O
+elements,O
+,,O
+respectively,O
+.,O
+ , 
+A,O
+number,O
+of,O
+genes,O
+,,O
+such,O
+as,O
+EED,B-Gene
+,,I-Gene
+CTNNA2,B-Gene
+,,I-Gene
+CALM1,B-Gene
+,,I-Gene
+CDH13,B-Gene
+,,I-Gene
+and,O
+STMN2,B-Gene
+,,I-Gene
+exhibited,O
+age,O
+-,O
+related,O
+DNA,O
+methylation,O
+changes,O
+.,O
+ , 
+Finally,O
+,,O
+allele,O
+-,O
+specific,O
+methylation,O
+patterns,O
+in,O
+CDH13,B-Gene
+were,O
+detected,O
+.,O
+ , 
+This,O
+study,O
+provides,O
+evidence,O
+for,O
+significant,O
+epigenetic,O
+variability,O
+in,O
+human,O
+germ,O
+cells,O
+,,O
+which,O
+warrants,O
+further,O
+research,O
+to,O
+determine,O
+whether,O
+such,O
+epigenetic,O
+patterns,O
+can,O
+be,O
+efficiently,O
+transmitted,O
+across,O
+generations,O
+and,O
+what,O
+impact,O
+inherited,O
+epigenetic,O
+individuality,O
+may,O
+have,O
+on,O
+phenotypic,O
+outcomes,O
+in,O
+health,O
+and,O
+disease,O
+.,O
+ , 
+#9452055
+De,O
+novo,O
+mutation,O
+of,O
+the,O
+myelin,B-Gene
+Po,I-Gene
+gene,O
+in,O
+Déjérine,O
+-,O
+Sottas,O
+disease,O
+(,O
+hereditary,O
+motor,O
+and,O
+sensory,O
+neuropathy,O
+type,O
+III,O
+):,O
+two,O
+amino,O
+acid,O
+insertion,O
+after,O
+Asp,O
+118,O
+.,O
+ , 
+#16642442
+Breakpoint,O
+cloning,O
+and,O
+haplotype,O
+analysis,O
+indicate,O
+a,O
+single,O
+origin,O
+of,O
+the,O
+common,O
+Inv(10)(p11.2q21.2,O
+),O
+mutation,O
+among,O
+northern,O
+Europeans,O
+.,O
+ , 
+The,O
+pericentric,O
+inv(10)(p11.2q21.2,O
+),O
+mutation,O
+has,O
+been,O
+frequently,O
+identified,O
+in,O
+cytogenetic,O
+laboratories,O
+,,O
+is,O
+phenotypically,O
+silent,O
+,,O
+and,O
+is,O
+considered,O
+to,O
+be,O
+a,O
+polymorphic,O
+variant,O
+.,O
+ , 
+Cloning,O
+and,O
+sequencing,O
+of,O
+the,O
+junction,O
+fragments,O
+on,O
+10p11,O
+and,O
+10q21,O
+revealed,O
+that,O
+neither,O
+inversion,O
+breakpoint,O
+directly,O
+involved,O
+any,O
+genes,O
+or,O
+repetitive,O
+sequences,O
+,,O
+although,O
+both,O
+breakpoint,O
+regions,O
+contain,O
+a,O
+number,O
+of,O
+repeats,O
+.,O
+ , 
+All,O
+20,O
+apparently,O
+unrelated,O
+inv(10,O
+),O
+families,O
+in,O
+our,O
+study,O
+had,O
+identical,O
+breakpoints,O
+,,O
+and,O
+detailed,O
+haplotype,O
+analysis,O
+showed,O
+that,O
+the,O
+inversions,O
+were,O
+identical,O
+by,O
+descent,O
+.,O
+ , 
+Thus,O
+,,O
+although,O
+considered,O
+a,O
+common,O
+variant,O
+,,O
+inv(10)(p11.2q21.2,O
+),O
+has,O
+a,O
+single,O
+ancestral,O
+founder,O
+among,O
+northern,O
+Europeans,O
+.,O
+ , 
+#19716112
+Mutations,O
+of,O
+the,O
+FHL1,B-Gene
+gene,O
+cause,O
+Emery,O
+-,O
+Dreifuss,O
+muscular,O
+dystrophy,O
+.,O
+ , 
+Emery,O
+-,O
+Dreifuss,O
+muscular,O
+dystrophy,O
+(,O
+EDMD,O
+),O
+is,O
+a,O
+rare,O
+disorder,O
+characterized,O
+by,O
+early,O
+joint,O
+contractures,O
+,,O
+muscular,O
+dystrophy,O
+,,O
+and,O
+cardiac,O
+involvement,O
+with,O
+conduction,O
+defects,O
+and,O
+arrhythmias,O
+.,O
+ , 
+So,O
+far,O
+,,O
+only,O
+35,O
+%,O
+of,O
+EDMD,O
+cases,O
+are,O
+genetically,O
+elucidated,O
+and,O
+associated,O
+with,O
+EMD,B-Gene
+or,O
+LMNA,B-Gene
+gene,O
+mutations,O
+,,O
+suggesting,O
+the,O
+existence,O
+of,O
+additional,O
+major,O
+genes,O
+.,O
+ , 
+By,O
+whole,O
+-,O
+genome,O
+scan,O
+,,O
+we,O
+identified,O
+linkage,O
+to,O
+the,O
+Xq26.3,O
+locus,O
+containing,O
+the,O
+FHL1,B-Gene
+gene,O
+in,O
+three,O
+informative,O
+families,O
+belonging,O
+to,O
+our,O
+EMD-,B-Gene
+and,O
+LMNA,B-Gene
+-,I-Gene
+negative,O
+cohort,O
+.,O
+ , 
+Analysis,O
+of,O
+the,O
+FHL1,B-Gene
+gene,O
+identified,O
+seven,O
+mutations,O
+,,O
+in,O
+the,O
+distal,O
+exons,O
+of,O
+FHL1,B-Gene
+in,O
+these,O
+families,O
+,,O
+three,O
+additional,O
+families,O
+,,O
+and,O
+one,O
+isolated,O
+case,O
+,,O
+which,O
+differently,O
+affect,O
+the,O
+three,O
+FHL1,B-Gene
+protein,O
+isoforms,O
+:,O
+two,O
+missense,O
+mutations,O
+affecting,O
+highly,O
+conserved,O
+cysteines,O
+,,O
+one,O
+abolishing,O
+the,O
+termination,O
+codon,O
+,,O
+and,O
+four,O
+out,O
+-,O
+of,O
+-,O
+frame,O
+insertions,O
+or,O
+deletions,O
+.,O
+ , 
+The,O
+predominant,O
+phenotype,O
+was,O
+characterized,O
+by,O
+myopathy,O
+with,O
+scapulo,O
+-,O
+peroneal,O
+and/or,O
+axial,O
+distribution,O
+,,O
+as,O
+well,O
+as,O
+joint,O
+contractures,O
+,,O
+and,O
+associated,O
+with,O
+a,O
+peculiar,O
+cardiac,O
+disease,O
+characterized,O
+by,O
+conduction,O
+defects,O
+,,O
+arrhythmias,O
+,,O
+and,O
+hypertrophic,O
+cardiomyopathy,O
+in,O
+all,O
+index,O
+cases,O
+of,O
+the,O
+seven,O
+families,O
+.,O
+ , 
+Heterozygous,O
+female,O
+carriers,O
+were,O
+either,O
+asymptomatic,O
+or,O
+had,O
+cardiac,O
+disease,O
+and/or,O
+mild,O
+myopathy,O
+.,O
+ , 
+Interestingly,O
+,,O
+four,O
+of,O
+the,O
+FHL1,O
+-,O
+mutated,O
+male,O
+relatives,O
+had,O
+isolated,O
+cardiac,O
+disease,O
+,,O
+and,O
+an,O
+overt,O
+hypertrophic,O
+cardiomyopathy,O
+was,O
+present,O
+in,O
+two,O
+.,O
+ , 
+Expression,O
+and,O
+functional,O
+studies,O
+demonstrated,O
+that,O
+the,O
+FHL1,B-Gene
+proteins,O
+were,O
+severely,O
+reduced,O
+in,O
+all,O
+tested,O
+patients,O
+and,O
+that,O
+this,O
+was,O
+associated,O
+with,O
+a,O
+severe,O
+delay,O
+in,O
+myotube,O
+formation,O
+in,O
+the,O
+two,O
+patients,O
+for,O
+whom,O
+myoblasts,O
+were,O
+available,O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+FHL1,B-Gene
+should,O
+be,O
+considered,O
+as,O
+a,O
+gene,O
+associated,O
+with,O
+the,O
+X,O
+-,O
+linked,O
+EDMD,O
+phenotype,O
+,,O
+as,O
+well,O
+as,O
+with,O
+hypertrophic,O
+cardiomyopathy,O
+.,O
+ , 
+#16395665
+Prioritizing,O
+regions,O
+of,O
+candidate,O
+genes,O
+for,O
+efficient,O
+mutation,O
+screening,O
+.,O
+ , 
+The,O
+availability,O
+of,O
+the,O
+complete,O
+sequence,O
+of,O
+the,O
+human,O
+genome,O
+has,O
+dramatically,O
+facilitated,O
+the,O
+search,O
+for,O
+disease,O
+-,O
+causing,O
+sequence,O
+variations,O
+.,O
+ , 
+In,O
+fact,O
+,,O
+the,O
+rate,O
+-,O
+limiting,O
+step,O
+has,O
+shifted,O
+from,O
+the,O
+discovery,O
+and,O
+characterization,O
+of,O
+candidate,O
+genes,O
+to,O
+the,O
+actual,O
+screening,O
+of,O
+human,O
+populations,O
+and,O
+the,O
+subsequent,O
+interpretation,O
+of,O
+observed,O
+variations,O
+.,O
+ , 
+In,O
+this,O
+study,O
+we,O
+tested,O
+the,O
+hypothesis,O
+that,O
+some,O
+segments,O
+of,O
+candidate,O
+genes,O
+are,O
+more,O
+likely,O
+than,O
+others,O
+to,O
+contain,O
+disease,O
+-,O
+causing,O
+variations,O
+and,O
+that,O
+these,O
+segments,O
+can,O
+be,O
+predicted,O
+bioinformatically,O
+.,O
+ , 
+A,O
+bioinformatic,O
+technique,O
+,,O
+prioritization,O
+of,O
+annotated,O
+regions,O
+(,O
+PAR,O
+),O
+,,O
+was,O
+developed,O
+to,O
+predict,O
+the,O
+likelihood,O
+that,O
+a,O
+specific,O
+coding,O
+region,O
+of,O
+a,O
+gene,O
+will,O
+harbor,O
+a,O
+disease,O
+-,O
+causing,O
+mutation,O
+based,O
+on,O
+conserved,O
+protein,O
+functional,O
+domains,O
+and,O
+protein,O
+secondary,O
+structures,O
+.,O
+ , 
+This,O
+method,O
+was,O
+evaluated,O
+by,O
+using,O
+it,O
+to,O
+analyze,O
+710,O
+genes,O
+that,O
+collectively,O
+harbor,O
+4,498,O
+previously,O
+identified,O
+mutations,O
+.,O
+ , 
+Nearly,O
+50,O
+%,O
+of,O
+the,O
+genes,O
+were,O
+recognized,O
+as,O
+disease,O
+-,O
+associated,O
+after,O
+screening,O
+only,O
+9,O
+%,O
+of,O
+the,O
+complete,O
+coding,O
+sequence,O
+.,O
+ , 
+The,O
+PAR,O
+technique,O
+identified,O
+90,O
+%,O
+of,O
+the,O
+genes,O
+as,O
+containing,O
+at,O
+least,O
+one,O
+mutation,O
+,,O
+with,O
+less,O
+than,O
+40,O
+%,O
+of,O
+the,O
+screening,O
+resources,O
+that,O
+traditional,O
+approaches,O
+would,O
+require,O
+.,O
+ , 
+These,O
+results,O
+suggest,O
+that,O
+prioritization,O
+strategies,O
+such,O
+as,O
+PAR,O
+can,O
+accelerate,O
+disease,O
+-,O
+gene,O
+identification,O
+through,O
+more,O
+efficient,O
+use,O
+of,O
+screening,O
+resources,O
+.,O
+ , 
+#11793480
+BRCA1,B-Gene
+and,O
+BRCA2,B-Gene
+mutations,O
+in,O
+Russian,O
+familial,O
+breast,O
+cancer,O
+.,O
+ , 
+We,O
+have,O
+screened,O
+index,O
+cases,O
+from,O
+25,O
+Russian,O
+breast,O
+/,O
+ovarian,O
+cancer,O
+families,O
+for,O
+germ,O
+-,O
+line,O
+mutations,O
+in,O
+all,O
+coding,O
+exons,O
+of,O
+the,O
+BRCA1,B-Gene
+and,O
+BRCA2,B-Gene
+genes,O
+,,O
+using,O
+multiplex,O
+heteroduplex,O
+analysis,O
+.,O
+ , 
+In,O
+addition,O
+we,O
+tested,O
+22,O
+patients,O
+with,O
+breast,O
+cancer,O
+diagnosed,O
+before,O
+age,O
+40,O
+without,O
+family,O
+history,O
+and,O
+6,O
+patients,O
+with,O
+bilateral,O
+breast,O
+cancer,O
+.,O
+ , 
+The,O
+frequency,O
+of,O
+families,O
+with,O
+germline,O
+mutations,O
+in,O
+BRCA,O
+was,O
+16,O
+%,O
+(,O
+4/25,O
+),O
+.,O
+ , 
+One,O
+BRCA1,B-Gene
+mutation,O
+,,O
+5382insC,B-SNP
+,,I-SNP
+was,O
+found,O
+in,O
+three,O
+families,O
+.,O
+ , 
+The,O
+results,O
+of,O
+present,O
+study,O
+,,O
+and,O
+those,O
+of,O
+a,O
+separate,O
+study,O
+of,O
+19,O
+breast,O
+-,O
+ovarian,O
+cancer,O
+families,O
+,,O
+suggest,O
+that,O
+BRCA1,B-Gene
+5382insC,B-SNP
+is,O
+a,O
+founder,O
+mutation,O
+in,O
+the,O
+Russian,O
+population,O
+.,O
+ , 
+Three,O
+BRCA2,B-Gene
+mutations,O
+were,O
+found,O
+in,O
+patients,O
+with,O
+breast,O
+cancer,O
+without,O
+family,O
+history,O
+:,O
+two,O
+in,O
+young,O
+patients,O
+and,O
+one,O
+in,O
+patients,O
+with,O
+bilateral,O
+breast,O
+cancer,O
+.,O
+ , 
+Four,O
+novel,O
+BRCA2,B-Gene
+mutations,O
+were,O
+identified,O
+:,O
+three,O
+frameshift,O
+(,B-SNP
+695insT,I-SNP
+,,I-SNP
+1528del4,B-SNP
+,,I-SNP
+9318del4,B-SNP
+),I-SNP
+and,O
+one,O
+nonsense,O
+(,B-SNP
+S1099X,I-SNP
+),I-SNP
+.,O
+ , 
+#22623374
+Gaucher,O
+disease,O
+paradigm,O
+:,O
+From,O
+ERAD,O
+to,O
+comorbidity,O
+.,O
+ , 
+Mutations,O
+in,O
+the,O
+GBA,B-Gene
+gene,O
+,,O
+encoding,O
+the,O
+lysosomal,B-Gene
+acid,I-Gene
+beta,I-Gene
+-,I-Gene
+glucocerebrosidase,I-Gene
+(,B-Gene
+GCase,I-Gene
+),I-Gene
+,,O
+lead,O
+to,O
+deficient,O
+activity,O
+of,O
+the,O
+enzyme,O
+in,O
+the,O
+lysosomes,O
+,,O
+to,O
+glucosylceramide,O
+accumulation,O
+and,O
+to,O
+development,O
+of,O
+Gaucher,O
+disease,O
+(,O
+GD,O
+),O
+.,O
+ , 
+More,O
+than,O
+280,O
+mutations,O
+in,O
+the,O
+GBA,B-Gene
+gene,O
+have,O
+been,O
+directly,O
+associated,O
+with,O
+GD,O
+.,O
+ , 
+Mutant,O
+GCase,O
+variants,O
+present,O
+variable,O
+levels,O
+of,O
+endoplasmic,O
+reticulum,O
+(,O
+ER,O
+),O
+retention,O
+,,O
+due,O
+to,O
+their,O
+inability,O
+to,O
+correctly,O
+fold,O
+,,O
+and,O
+undergo,O
+ER,O
+-,O
+associated,O
+degradation,O
+(,O
+ERAD,O
+),O
+in,O
+the,O
+proteasomes,O
+.,O
+ , 
+The,O
+degree,O
+of,O
+ER,O
+retention,O
+and,O
+proteasomal,O
+degradation,O
+is,O
+one,O
+of,O
+the,O
+factors,O
+that,O
+determine,O
+GD,O
+severity,O
+.,O
+ , 
+In,O
+the,O
+present,O
+review,O
+,,O
+we,O
+discuss,O
+ERAD,O
+of,O
+mutant,O
+GCase,O
+variants,O
+and,O
+its,O
+possible,O
+consequences,O
+in,O
+GD,O
+patients,O
+and,O
+in,O
+carriers,O
+of,O
+GD,O
+mutations,O
+.,O
+ , 
+Hum,O
+Mutat,O
+33:1398,O
+-,O
+1407,O
+,,O
+2012,O
+.,O
+ , 
+©,O
+2012,O
+Wiley,O
+Periodicals,O
+,,O
+Inc.,O
+ , 
+#1347972
+Identification,O
+of,O
+heterogeneous,O
+PrP,B-Gene
+gene,O
+deletions,O
+in,O
+controls,O
+by,O
+detection,O
+of,O
+allele,O
+-,O
+specific,O
+heteroduplexes,O
+(,O
+DASH,O
+),O
+ , 
+#22503634
+Genetic,O
+adaptation,O
+of,O
+fatty,O
+-,O
+acid,O
+metabolism,O
+:,O
+a,O
+human,O
+-,O
+specific,O
+haplotype,O
+increasing,O
+the,O
+biosynthesis,O
+of,O
+long,O
+-,O
+chain,O
+omega-3,O
+and,O
+omega-6,O
+fatty,O
+acids,O
+.,O
+ , 
+Omega-3,O
+and,O
+omega-6,O
+long,O
+-,O
+chain,O
+polyunsaturated,O
+fatty,O
+acids,O
+(,O
+LC,O
+-,O
+PUFAs,O
+),O
+are,O
+essential,O
+for,O
+the,O
+development,O
+and,O
+function,O
+of,O
+the,O
+human,O
+brain,O
+.,O
+ , 
+They,O
+can,O
+be,O
+obtained,O
+directly,O
+from,O
+food,O
+,,O
+e.g.,O
+,,O
+fish,O
+,,O
+or,O
+synthesized,O
+from,O
+precursor,O
+molecules,O
+found,O
+in,O
+vegetable,O
+oils,O
+.,O
+ , 
+To,O
+determine,O
+the,O
+importance,O
+of,O
+genetic,O
+variability,O
+to,O
+fatty,O
+-,O
+acid,O
+biosynthesis,O
+,,O
+we,O
+studied,O
+FADS1,B-Gene
+and,O
+FADS2,B-Gene
+,,I-Gene
+which,O
+encode,O
+rate,O
+-,O
+limiting,O
+enzymes,O
+for,O
+fatty,O
+-,O
+acid,O
+conversion,O
+.,O
+ , 
+We,O
+performed,O
+genome,O
+-,O
+wide,O
+genotyping,O
+(,O
+n,O
+=,O
+5,652,O
+individuals,O
+),O
+and,O
+targeted,O
+resequencing,O
+(,O
+n,O
+=,O
+960,O
+individuals,O
+),O
+of,O
+the,O
+FADS,O
+region,O
+in,O
+five,O
+European,O
+population,O
+cohorts,O
+.,O
+ , 
+We,O
+also,O
+analyzed,O
+available,O
+genomic,O
+data,O
+from,O
+human,O
+populations,O
+,,O
+archaic,O
+hominins,O
+,,O
+and,O
+more,O
+distant,O
+primates,O
+.,O
+ , 
+Our,O
+results,O
+show,O
+that,O
+present,O
+-,O
+day,O
+humans,O
+have,O
+two,O
+common,O
+FADS,O
+haplotypes,O
+-,O
+defined,O
+by,O
+28,O
+closely,O
+linked,O
+SNPs,O
+across,O
+38.9,O
+kb,O
+-,O
+that,O
+differ,O
+dramatically,O
+in,O
+their,O
+ability,O
+to,O
+generate,O
+LC,O
+-,O
+PUFAs,O
+.,O
+ , 
+No,O
+independent,O
+effects,O
+on,O
+FADS,O
+activity,O
+were,O
+seen,O
+for,O
+rare,O
+SNPs,O
+detected,O
+by,O
+targeted,O
+resequencing,O
+.,O
+ , 
+The,O
+more,O
+efficient,O
+,,O
+evolutionarily,O
+derived,O
+haplotype,O
+appeared,O
+after,O
+the,O
+lineage,O
+split,O
+leading,O
+to,O
+modern,O
+humans,O
+and,O
+Neanderthals,O
+and,O
+shows,O
+evidence,O
+of,O
+positive,O
+selection,O
+.,O
+ , 
+This,O
+human,O
+-,O
+specific,O
+haplotype,O
+increases,O
+the,O
+efficiency,O
+of,O
+synthesizing,O
+essential,O
+long,O
+-,O
+chain,O
+fatty,O
+acids,O
+from,O
+precursors,O
+and,O
+thereby,O
+might,O
+have,O
+provided,O
+an,O
+advantage,O
+in,O
+environments,O
+with,O
+limited,O
+access,O
+to,O
+dietary,O
+LC,O
+-,O
+PUFAs,O
+.,O
+ , 
+In,O
+the,O
+modern,O
+world,O
+,,O
+this,O
+haplotype,O
+has,O
+been,O
+associated,O
+with,O
+lifestyle,O
+-,O
+related,O
+diseases,O
+,,O
+such,O
+as,O
+coronary,O
+artery,O
+disease,O
+.,O
+ , 
+#8352275
+Linkage,O
+analysis,O
+of,O
+idiopathic,O
+generalized,O
+epilepsy,O
+(,O
+IGE,O
+),O
+and,O
+marker,O
+loci,O
+on,O
+chromosome,O
+6p,O
+in,O
+families,O
+of,O
+patients,O
+with,O
+juvenile,O
+myoclonic,O
+epilepsy,O
+:,O
+no,O
+evidence,O
+for,O
+an,O
+epilepsy,O
+locus,O
+in,O
+the,O
+HLA,O
+region,O
+.,O
+ , 
+Evidence,O
+for,O
+a,O
+locus,O
+(,B-Gene
+EJM1,I-Gene
+),I-Gene
+in,O
+the,O
+HLA,O
+region,O
+of,O
+chromosome,O
+6p,O
+predisposing,O
+to,O
+idiopathic,O
+generalized,O
+epilepsy,O
+(,O
+IGE,O
+),O
+in,O
+the,O
+families,O
+of,O
+patients,O
+with,O
+juvenile,O
+myoclonic,O
+epilepsy,O
+(,O
+JME,O
+),O
+has,O
+been,O
+obtained,O
+in,O
+two,O
+previous,O
+studies,O
+of,O
+separately,O
+ascertained,O
+groups,O
+of,O
+kindreds,O
+.,O
+ , 
+Linkage,O
+analysis,O
+has,O
+been,O
+undertaken,O
+in,O
+a,O
+third,O
+set,O
+of,O
+25,O
+families,O
+including,O
+a,O
+patient,O
+with,O
+JME,O
+and,O
+at,O
+least,O
+one,O
+first,O
+-,O
+degree,O
+relative,O
+with,O
+IGE,O
+.,O
+ , 
+Family,O
+members,O
+were,O
+typed,O
+for,O
+eight,O
+polymorphic,O
+loci,O
+on,O
+chromosome,O
+6p,O
+:,O
+F13A,B-SNP
+,,I-SNP
+D6S89,B-SNP
+,,I-SNP
+D6S109,B-SNP
+,,I-SNP
+D6S105,B-SNP
+,,I-SNP
+D6S10,B-SNP
+,,I-SNP
+C4B,B-SNP
+,,I-SNP
+DQA1,B-SNP
+/,I-SNP
+A2,I-SNP
+,,I-SNP
+and,O
+TCTE1,B-Gene
+.,I-Gene
+ , 
+Pairwise,O
+and,O
+multipoint,O
+linkage,O
+analysis,O
+was,O
+carried,O
+out,O
+assuming,O
+autosomal,O
+dominant,O
+and,O
+autosomal,O
+recessive,O
+inheritance,O
+and,O
+age,O
+-,O
+dependent,O
+high,O
+or,O
+low,O
+penetrance,O
+.,O
+ , 
+No,O
+significant,O
+evidence,O
+in,O
+favor,O
+of,O
+linkage,O
+was,O
+obtained,O
+at,O
+any,O
+locus,O
+.,O
+ , 
+Multipoint,O
+linkage,O
+analysis,O
+generated,O
+significant,O
+exclusion,O
+data,O
+(,O
+lod,O
+score,O
+<,O
+-2.0,O
+),O
+at,O
+HLA,O
+and,O
+for,O
+a,O
+region,O
+10,O
+-,O
+30,O
+cM,O
+telomeric,O
+to,O
+HLA,O
+,,O
+the,O
+extent,O
+of,O
+which,O
+varied,O
+with,O
+the,O
+level,O
+of,O
+penetrance,O
+assumed,O
+.,O
+ , 
+These,O
+observations,O
+indicate,O
+that,O
+genetic,O
+heterogeneity,O
+exists,O
+within,O
+this,O
+epilepsy,O
+phenotype,O
+.,O
+ , 
+#7485151
+Mutations,O
+in,O
+SOX9,B-Gene
+,,I-Gene
+the,O
+gene,O
+responsible,O
+for,O
+Campomelic,O
+dysplasia,O
+and,O
+autosomal,O
+sex,O
+reversal,O
+.,O
+ , 
+Campomelic,O
+dysplasia,O
+(,O
+CD,O
+),O
+is,O
+a,O
+skeletal,O
+malformation,O
+syndrome,O
+frequently,O
+accompanied,O
+by,O
+46,XY,O
+sex,O
+reversal,O
+.,O
+ , 
+A,O
+mutation,O
+-,O
+screening,O
+strategy,O
+using,O
+SSCP,O
+was,O
+employed,O
+to,O
+identify,O
+mutations,O
+in,O
+SOX9,B-Gene
+,,I-Gene
+the,O
+chromosome,O
+17q24,O
+gene,O
+responsible,O
+for,O
+CD,O
+and,O
+autosomal,O
+sex,O
+reversal,O
+in,O
+man,O
+.,O
+ , 
+We,O
+have,O
+screened,O
+seven,O
+CD,O
+patients,O
+with,O
+no,O
+cytologically,O
+detectable,O
+chromosomal,O
+aberrations,O
+and,O
+two,O
+CD,O
+patients,O
+with,O
+chromosome,O
+17,O
+rearrangements,O
+for,O
+mutations,O
+in,O
+the,O
+entire,O
+open,O
+reading,O
+frame,O
+of,O
+SOX9,B-Gene
+.,I-Gene
+ , 
+Five,O
+different,O
+mutations,O
+have,O
+been,O
+identified,O
+in,O
+six,O
+CD,O
+patients,O
+:,O
+two,O
+missense,O
+mutations,O
+in,O
+the,O
+SOX9,B-Gene
+putative,O
+DNA,O
+binding,O
+domain,O
+(,O
+high,O
+mobility,O
+group,O
+,,O
+or,O
+HMG,O
+,,O
+box,O
+),O
+;,O
+three,O
+frameshift,O
+mutations,O
+and,O
+a,O
+splice,O
+-,O
+acceptor,O
+mutation,O
+.,O
+ , 
+An,O
+identical,O
+frameshift,O
+mutation,O
+is,O
+found,O
+in,O
+two,O
+unrelated,O
+46,XY,O
+patients,O
+,,O
+one,O
+exhibiting,O
+a,O
+male,O
+phenotype,O
+and,O
+the,O
+other,O
+displaying,O
+a,O
+female,O
+phenotype,O
+(,O
+XY,O
+sex,O
+reversal,O
+),O
+.,O
+ , 
+All,O
+mutations,O
+found,O
+affect,O
+a,O
+single,O
+allele,O
+,,O
+which,O
+is,O
+consistent,O
+with,O
+a,O
+dominant,O
+mode,O
+of,O
+inheritance,O
+.,O
+ , 
+No,O
+mutations,O
+were,O
+found,O
+in,O
+the,O
+SOX9,B-Gene
+open,O
+reading,O
+frame,O
+of,O
+two,O
+patients,O
+with,O
+chromosome,O
+17q,O
+rearrangements,O
+,,O
+suggesting,O
+that,O
+the,O
+translocations,O
+affect,O
+SOX9,B-Gene
+expression,O
+.,O
+ , 
+These,O
+findings,O
+are,O
+consistent,O
+with,O
+the,O
+hypothesis,O
+that,O
+CD,O
+results,O
+from,O
+haploinsufficiency,O
+of,O
+SOX9,B-Gene
+.,I-Gene
+ , 
+#11577372
+Alpha,B-Gene
+-,I-Gene
+B,I-Gene
+crystallin,I-Gene
+gene,I-Gene
+(,B-Gene
+CRYAB,I-Gene
+),I-Gene
+mutation,O
+causes,O
+dominant,O
+congenital,O
+posterior,O
+polar,O
+cataract,O
+in,O
+humans,O
+.,O
+ , 
+Congenital,O
+cataracts,O
+are,O
+an,O
+important,O
+cause,O
+of,O
+bilateral,O
+visual,O
+impairment,O
+in,O
+infants,O
+.,O
+ , 
+In,O
+a,O
+four,O
+-,O
+generation,O
+family,O
+of,O
+English,O
+descent,O
+,,O
+we,O
+mapped,O
+dominant,O
+congenital,O
+posterior,O
+polar,O
+cataract,O
+to,O
+chromosome,O
+11q22,O
+-,O
+q22.3,O
+.,O
+ , 
+The,O
+maximum,O
+LOD,O
+score,O
+,,O
+3.92,O
+at,O
+recombination,O
+fraction,O
+0,O
+,,O
+was,O
+obtained,O
+for,O
+marker,O
+D11S898,O
+,,O
+near,O
+the,O
+gene,O
+that,O
+encodes,O
+crystallin,O
+alpha,O
+-,O
+B,O
+protein,O
+(,B-Gene
+CRYAB,I-Gene
+),I-Gene
+.,O
+ , 
+By,O
+sequencing,O
+the,O
+coding,O
+regions,O
+of,O
+CRYAB,B-Gene
+,,I-Gene
+we,O
+found,O
+in,O
+exon,O
+3,O
+a,O
+deletion,O
+mutation,O
+,,O
+450delA,B-SNP
+,,I-SNP
+that,O
+is,O
+associated,O
+with,O
+cataract,O
+in,O
+this,O
+family,O
+.,O
+ , 
+The,O
+mutation,O
+resulted,O
+in,O
+a,O
+frameshift,O
+in,O
+codon,O
+150,O
+and,O
+produced,O
+an,O
+aberrant,O
+protein,O
+consisting,O
+of,O
+184,O
+residues,O
+.,O
+ , 
+This,O
+is,O
+the,O
+first,O
+report,O
+of,O
+a,O
+mutation,O
+,,O
+in,O
+this,O
+gene,O
+,,O
+resulting,O
+in,O
+isolated,O
+congenital,O
+cataract,O
+.,O
+ , 
+#11822023
+Evidence,O
+of,O
+genetic,O
+interaction,O
+between,O
+the,O
+beta,O
+-,O
+globin,O
+complex,O
+and,O
+chromosome,O
+8q,O
+in,O
+the,O
+expression,O
+of,O
+fetal,O
+hemoglobin,O
+.,O
+ , 
+During,O
+human,O
+development,O
+,,O
+the,O
+switch,O
+from,O
+fetal,O
+to,O
+adult,O
+hemoglobin,O
+(,O
+Hb,O
+),O
+is,O
+not,O
+complete,O
+with,O
+the,O
+residual,O
+gamma,O
+-,O
+globin,O
+expression,O
+being,O
+restricted,O
+to,O
+a,O
+subset,O
+of,O
+erythrocytes,O
+termed,O
+",O
+F,O
+cells,O
+",O
+(,O
+FC,O
+),O
+.,O
+ , 
+Statistical,O
+analyses,O
+have,O
+shown,O
+the,O
+FC,O
+trait,O
+to,O
+be,O
+influenced,O
+by,O
+a,O
+common,O
+sequence,O
+variant,O
+(,B-SNP
+C-->T,I-SNP
+),I-SNP
+at,I-SNP
+position,I-SNP
+-158,I-SNP
+upstream,I-SNP
+of,O
+the,O
+Ggamma,B-Gene
+-,I-Gene
+globin,I-Gene
+gene,O
+,,O
+termed,O
+the,O
+",O
+XmnI,O
+-,O
+Ggamma,O
+polymorphism,O
+.,O
+",O
+ , 
+The,O
+XmnI,O
+-,O
+Ggamma,O
+site,O
+is,O
+believed,O
+to,O
+be,O
+involved,O
+in,O
+the,O
+expression,O
+of,O
+the,O
+Ggamma,B-Gene
+-,I-Gene
+globin,I-Gene
+gene,O
+through,O
+interaction,O
+with,O
+transcription,O
+factors,O
+,,O
+and,O
+polymorphisms,O
+in,O
+the,O
+transcription,O
+factors,O
+could,O
+be,O
+influencing,O
+fetal,O
+Hb,O
+expression,O
+,,O
+conditional,O
+on,O
+the,O
+XmnI,O
+-,O
+Ggamma,O
+site,O
+.,O
+ , 
+Using,O
+a,O
+two,O
+-,O
+locus,O
+model,O
+,,O
+in,O
+which,O
+the,O
+second,O
+locus,O
+was,O
+the,O
+known,O
+quantitative,O
+-,O
+trait,O
+locus,O
+(,O
+QTL,O
+),O
+at,O
+the,O
+XmnI,O
+-,O
+Ggamma,O
+site,O
+,,O
+we,O
+showed,O
+suggestive,O
+linkage,O
+to,O
+chromosome,O
+8q,O
+.,O
+ , 
+A,O
+maximum,O
+single,O
+-,O
+point,O
+LOD,O
+score,O
+of,O
+4.33,O
+and,O
+a,O
+multipoint,O
+LOD,O
+score,O
+of,O
+4.75,O
+were,O
+found,O
+in,O
+a,O
+15,O
+-,O
+20,O
+cM,O
+region,O
+of,O
+chromosome,O
+8q,O
+.,O
+ , 
+A,O
+single,O
+-,O
+locus,O
+analysis,O
+failed,O
+to,O
+show,O
+linkage,O
+of,O
+FC,O
+to,O
+the,O
+region,O
+when,O
+the,O
+XmnI,O
+-,O
+Ggamma,O
+site,O
+was,O
+accounted,O
+for,O
+by,O
+removing,O
+its,O
+effects,O
+from,O
+the,O
+data,O
+or,O
+including,O
+it,O
+as,O
+a,O
+covariate,O
+.,O
+ , 
+Results,O
+of,O
+the,O
+single,O
+-,O
+locus,O
+analysis,O
+were,O
+significant,O
+when,O
+the,O
+effects,O
+of,O
+the,O
+XmnI,O
+-,O
+Ggamma,O
+site,O
+were,O
+not,O
+accounted,O
+for,O
+in,O
+any,O
+way,O
+.,O
+ , 
+The,O
+results,O
+of,O
+analysis,O
+in,O
+a,O
+large,O
+Indian,O
+kindred,O
+indicate,O
+that,O
+there,O
+is,O
+an,O
+interaction,O
+between,O
+the,O
+XmnI,O
+-,O
+Ggamma,O
+site,O
+and,O
+a,O
+QTL,O
+on,O
+chromosome,O
+8q,O
+that,O
+is,O
+influencing,O
+the,O
+production,O
+of,O
+fetal,O
+Hb,O
+.,O
+ , 
+#23122591
+Response,O
+to,O
+Zhu,O
+et,O
+ ,O
+al,O
+.,O
+ , 
+#17236129
+Complex,O
+inheritance,O
+pattern,O
+resembling,O
+autosomal,O
+recessive,O
+inheritance,O
+involving,O
+a,O
+microdeletion,O
+in,O
+thrombocytopenia,O
+-,O
+absent,O
+radius,O
+syndrome,O
+.,O
+ , 
+Thrombocytopenia,O
+-,O
+absent,O
+radius,O
+(,O
+TAR,O
+),O
+syndrome,O
+is,O
+characterized,O
+by,O
+hypomegakaryocytic,O
+thrombocytopenia,O
+and,O
+bilateral,O
+radial,O
+aplasia,O
+in,O
+the,O
+presence,O
+of,O
+both,O
+thumbs,O
+.,O
+ , 
+Other,O
+frequent,O
+associations,O
+are,O
+congenital,O
+heart,O
+disease,O
+and,O
+a,O
+high,O
+incidence,O
+of,O
+cow,O
+'s,O
+milk,O
+intolerance,O
+.,O
+ , 
+Evidence,O
+for,O
+autosomal,O
+recessive,O
+inheritance,O
+comes,O
+from,O
+families,O
+with,O
+several,O
+affected,O
+individuals,O
+born,O
+to,O
+unaffected,O
+parents,O
+,,O
+but,O
+several,O
+other,O
+observations,O
+argue,O
+for,O
+a,O
+more,O
+complex,O
+pattern,O
+of,O
+inheritance,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+describe,O
+a,O
+common,O
+interstitial,O
+microdeletion,O
+of,O
+200,O
+kb,O
+on,O
+chromosome,O
+1q21.1,O
+in,O
+all,O
+30,O
+investigated,O
+patients,O
+with,O
+TAR,O
+syndrome,O
+,,O
+detected,O
+by,O
+microarray,O
+-,O
+based,O
+comparative,O
+genomic,O
+hybridization,O
+.,O
+ , 
+Analysis,O
+of,O
+the,O
+parents,O
+revealed,O
+that,O
+this,O
+deletion,O
+occurred,O
+de,O
+novo,O
+in,O
+25,O
+%,O
+of,O
+affected,O
+individuals,O
+.,O
+ , 
+Intriguingly,O
+,,O
+inheritance,O
+of,O
+the,O
+deletion,O
+along,O
+the,O
+maternal,O
+line,O
+as,O
+well,O
+as,O
+the,O
+paternal,O
+line,O
+was,O
+observed,O
+.,O
+ , 
+The,O
+absence,O
+of,O
+this,O
+deletion,O
+in,O
+a,O
+cohort,O
+of,O
+control,O
+individuals,O
+argues,O
+for,O
+a,O
+specific,O
+role,O
+played,O
+by,O
+the,O
+microdeletion,O
+in,O
+the,O
+pathogenesis,O
+of,O
+TAR,O
+syndrome,O
+.,O
+ , 
+We,O
+hypothesize,O
+that,O
+TAR,O
+syndrome,O
+is,O
+associated,O
+with,O
+a,O
+deletion,O
+on,O
+chromosome,O
+1q21.1,O
+but,O
+that,O
+the,O
+phenotype,O
+develops,O
+only,O
+in,O
+the,O
+presence,O
+of,O
+an,O
+additional,O
+as,O
+-,O
+yet,O
+-,O
+unknown,O
+modifier,O
+(,O
+mTAR,O
+),O
+.,O
+ , 
+#16110485
+Intrachromosomal,O
+serial,O
+replication,O
+slippage,O
+in,O
+trans,O
+gives,O
+rise,O
+to,O
+diverse,O
+genomic,O
+rearrangements,O
+involving,O
+inversions,O
+.,O
+ , 
+Serial,O
+replication,O
+slippage,O
+in,O
+cis,O
+(,O
+SRScis,O
+),O
+provides,O
+a,O
+plausible,O
+explanation,O
+for,O
+many,O
+complex,O
+genomic,O
+rearrangements,O
+that,O
+underlie,O
+human,O
+genetic,O
+disease,O
+.,O
+ , 
+This,O
+concept,O
+,,O
+taken,O
+together,O
+with,O
+the,O
+intra-,O
+and,O
+intermolecular,O
+strand,O
+switch,O
+models,O
+that,O
+account,O
+for,O
+mutations,O
+that,O
+arise,O
+via,O
+quasipalindrome,O
+correction,O
+,,O
+suggest,O
+that,O
+intrachromosomal,O
+SRS,O
+in,O
+trans,O
+(,O
+SRStrans,O
+),O
+mediated,O
+by,O
+short,O
+inverted,O
+repeats,O
+may,O
+also,O
+give,O
+rise,O
+to,O
+a,O
+diverse,O
+series,O
+of,O
+complex,O
+genomic,O
+rearrangements,O
+.,O
+ , 
+If,O
+this,O
+were,O
+to,O
+be,O
+so,O
+,,O
+such,O
+rearrangements,O
+would,O
+invariably,O
+generate,O
+inversions,O
+.,O
+ , 
+To,O
+test,O
+this,O
+idea,O
+,,O
+we,O
+collated,O
+all,O
+informative,O
+mutations,O
+involving,O
+inversions,O
+of,O
+>,O
+or=5,O
+bp,O
+but,O
+<,O
+1,O
+kb,O
+by,O
+screening,O
+the,O
+Human,O
+Gene,O
+Mutation,O
+Database,O
+(,O
+HGMD,O
+;,O
+www.hgmd.org,O
+),O
+and,O
+conducting,O
+an,O
+extensive,O
+literature,O
+search,O
+.,O
+ , 
+Of,O
+the,O
+21,O
+resulting,O
+mutations,O
+,,O
+only,O
+two,O
+(,O
+both,O
+of,O
+which,O
+coincidentally,O
+contain,O
+untemplated,O
+additions,O
+),O
+were,O
+found,O
+to,O
+be,O
+incompatible,O
+with,O
+the,O
+SRStrans,O
+model,O
+.,O
+ , 
+Eighteen,O
+(,O
+one,O
+simple,O
+inversion,O
+,,O
+six,O
+inversions,O
+involving,O
+sequence,O
+replacement,O
+by,O
+upstream,O
+or,O
+downstream,O
+sequence,O
+,,O
+five,O
+inversions,O
+involving,O
+the,O
+partial,O
+reinsertion,O
+of,O
+removed,O
+sequence,O
+,,O
+and,O
+six,O
+inversions,O
+that,O
+occurred,O
+in,O
+a,O
+more,O
+complicated,O
+context,O
+),O
+of,O
+the,O
+remaining,O
+19,O
+mutations,O
+were,O
+found,O
+to,O
+be,O
+consistent,O
+with,O
+either,O
+two,O
+steps,O
+of,O
+intrachromosomal,O
+SRStrans,O
+or,O
+a,O
+combination,O
+of,O
+replication,O
+slippage,O
+in,O
+cis,O
+plus,O
+intrachromosomal,O
+SRStrans,O
+.,O
+ , 
+The,O
+remaining,O
+lesion,O
+,,O
+a,O
+31,O
+-,O
+kb,O
+segmental,O
+duplication,O
+associated,O
+with,O
+a,O
+small,O
+inversion,O
+in,O
+the,O
+SLC3A1,B-Gene
+gene,O
+,,O
+is,O
+explicable,O
+in,O
+terms,O
+of,O
+a,O
+modified,O
+SRS,O
+model,O
+that,O
+integrates,O
+the,O
+concept,O
+of,O
+",O
+break,O
+-,O
+induced,O
+replication,O
+.,O
+",O
+ , 
+This,O
+study,O
+therefore,O
+lends,O
+broad,O
+support,O
+to,O
+our,O
+postulate,O
+that,O
+intrachromosomal,O
+SRStrans,O
+can,O
+account,O
+for,O
+a,O
+variety,O
+of,O
+complex,O
+gene,O
+rearrangements,O
+that,O
+involve,O
+inversions,O
+.,O
+ , 
+#9452022
+Low,O
+basal,O
+transcripts,O
+of,O
+the,O
+COL2A1,B-Gene
+collagen,O
+gene,O
+from,O
+lymphoblasts,O
+show,O
+alternative,O
+splicing,O
+of,O
+exon,O
+12,O
+in,O
+the,O
+Kniest,O
+form,O
+of,O
+spondyloepiphyseal,O
+dysplasia,O
+.,O
+ , 
+#12442283
+Novel,O
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+in,O
+the,O
+MYOC,B-Gene
+/,I-Gene
+GLC1A,O
+gene,O
+in,O
+a,O
+large,O
+group,O
+of,O
+glaucoma,O
+patients,O
+.,O
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+Mutations,O
+at,O
+the,O
+myocilin,B-Gene
+(,B-Gene
+MYOC,I-Gene
+),I-Gene
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+GLC1A,O
+locus,O
+have,O
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+revealed,O
+in,O
+2,O
+-,O
+4,O
+%,O
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+patients,O
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+primary,O
+open,O
+angle,O
+glaucoma,O
+(,O
+POAG,O
+),O
+worldwide,O
+.,O
+ , 
+In,O
+our,O
+ongoing,O
+glaucoma,O
+study,O
+six,O
+hundred,O
+eighty,O
+two,O
+persons,O
+have,O
+been,O
+screened,O
+for,O
+MYOC,B-Gene
+mutations,O
+.,O
+ , 
+The,O
+first,O
+group,O
+consisted,O
+of,O
+453,O
+patients,O
+from,O
+a,O
+long,O
+-,O
+term,O
+clinical,O
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+either,O
+with,O
+juvenile,O
+OAG,O
+(,O
+JOAG,O
+),O
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+POAG,O
+,,O
+ocular,O
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+(,O
+OHT,O
+),O
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+normal,O
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+glaucoma,O
+(,O
+NTG,O
+),O
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+22,O
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+of,O
+secondary,O
+glaucoma,O
+.,O
+ , 
+This,O
+group,O
+,,O
+and,O
+additional,O
+83,O
+healthy,O
+controls,O
+,,O
+is,O
+part,O
+of,O
+a,O
+long,O
+term,O
+study,O
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+repeated,O
+clinical,O
+examinations,O
+at,O
+the,O
+University,O
+of,O
+Erlangen,O
+-,O
+Nurnberg,O
+.,O
+ , 
+An,O
+additional,O
+sample,O
+of,O
+124,O
+glaucoma,O
+patients,O
+or,O
+at,O
+risk,O
+persons,O
+referred,O
+from,O
+other,O
+sources,O
+were,O
+included,O
+in,O
+the,O
+mutation,O
+screening,O
+.,O
+ , 
+Five,O
+novel,O
+mutations,O
+,,O
+namely,O
+Gly434Ser,B-SNP
+,,I-SNP
+Asn450Asp,B-SNP
+,,I-SNP
+Val251Ala,B-SNP
+,,I-SNP
+Ile345Met,B-SNP
+and,O
+Ser393Asn,B-SNP
+,,I-SNP
+could,O
+be,O
+identified,O
+as,O
+cause,O
+of,O
+preperimetric,O
+POAG,O
+,,O
+JOAG,O
+,,O
+normal,O
+tension,O
+POAG,O
+and,O
+POAG,O
+.,O
+ , 
+Myocilin,B-Gene
+mutations,O
+were,O
+identified,O
+similar,O
+with,O
+previous,O
+reports,O
+with,O
+other,O
+ethnic,O
+populations,O
+at,O
+the,O
+rate,O
+of,O
+11/341,O
+(,O
+3.2,O
+%,O
+),O
+probands,O
+.,O
+ , 
+#8328456
+Anticipation,O
+in,O
+bipolar,O
+affective,O
+disorder,O
+.,O
+ , 
+Anticipation,O
+refers,O
+to,O
+the,O
+increase,O
+in,O
+disease,O
+severity,O
+or,O
+decrease,O
+in,O
+age,O
+at,O
+onset,O
+in,O
+succeeding,O
+generations,O
+.,O
+ , 
+This,O
+phenomenon,O
+,,O
+formerly,O
+ascribed,O
+to,O
+observation,O
+biases,O
+,,O
+correlates,O
+with,O
+the,O
+expansion,O
+of,O
+trinucleotide,O
+repeat,O
+sequences,O
+(,O
+TNRs,O
+),O
+in,O
+some,O
+disorders,O
+.,O
+ , 
+If,O
+present,O
+in,O
+bipolar,O
+affective,O
+disorder,O
+(,B-Gene
+BPAD,I-Gene
+),I-Gene
+,,O
+anticipation,O
+could,O
+provide,O
+clues,O
+to,O
+its,O
+genetic,O
+etiology,O
+.,O
+ , 
+We,O
+compared,O
+age,O
+at,O
+onset,O
+and,O
+disease,O
+severity,O
+between,O
+two,O
+generations,O
+of,O
+34,O
+unilineal,O
+families,O
+ascertained,O
+for,O
+a,O
+genetic,O
+linkage,O
+study,O
+of,O
+BPAD,B-Gene
+.,I-Gene
+ , 
+Life,O
+-,O
+table,O
+analyses,O
+showed,O
+a,O
+significant,O
+decrease,O
+in,O
+survival,O
+to,O
+first,O
+mania,O
+or,O
+depression,O
+from,O
+the,O
+first,O
+to,O
+the,O
+second,O
+generation,O
+(,O
+P,O
+<,O
+.001,O
+),O
+.,O
+ , 
+Intergenerational,O
+pairwise,O
+comparisons,O
+showed,O
+both,O
+a,O
+significantly,O
+earlier,O
+age,O
+at,O
+onset,O
+(,O
+P,O
+<,O
+.001,O
+),O
+and,O
+a,O
+significantly,O
+increased,O
+disease,O
+severity,O
+(,O
+P,O
+<,O
+.001,O
+),O
+in,O
+the,O
+second,O
+generation,O
+.,O
+ , 
+This,O
+difference,O
+was,O
+significant,O
+under,O
+each,O
+of,O
+four,O
+data,O
+-,O
+sampling,O
+schemes,O
+which,O
+excluded,O
+probands,O
+in,O
+the,O
+second,O
+generation,O
+.,O
+ , 
+The,O
+second,O
+generation,O
+experienced,O
+onset,O
+8.9,O
+-,O
+13.5,O
+years,O
+earlier,O
+and,O
+illness,O
+1.8,O
+-,O
+3.4,O
+times,O
+more,O
+severe,O
+than,O
+did,O
+the,O
+first,O
+generation,O
+.,O
+ , 
+In,O
+additional,O
+analyses,O
+,,O
+drug,O
+abuse,O
+,,O
+deaths,O
+of,O
+affected,O
+individuals,O
+prior,O
+to,O
+interview,O
+,,O
+decreased,O
+fertility,O
+,,O
+censoring,O
+of,O
+age,O
+at,O
+onset,O
+,,O
+and,O
+the,O
+cohort,O
+effect,O
+did,O
+not,O
+affect,O
+our,O
+results,O
+.,O
+ , 
+We,O
+conclude,O
+that,O
+genetic,O
+anticipation,O
+occurs,O
+in,O
+this,O
+sample,O
+of,O
+unilineal,O
+BPAD,B-Gene
+families,O
+.,O
+ , 
+These,O
+findings,O
+may,O
+implicate,O
+genes,O
+with,O
+expanding,O
+TNRs,O
+in,O
+the,O
+genetic,O
+etiology,O
+of,O
+BPAD,B-Gene
+.,I-Gene
+ , 
+#8755923
+The,O
+retrieval,O
+of,O
+ancient,O
+human,O
+DNA,O
+sequences,O
+.,O
+ , 
+DNA,O
+was,O
+extracted,O
+from,O
+approximately,O
+600,O
+-,O
+year,O
+-,O
+old,O
+human,O
+remains,O
+found,O
+at,O
+an,O
+archaeological,O
+site,O
+in,O
+the,O
+southwestern,O
+United,O
+States,O
+,,O
+and,O
+mtDNA,O
+fragments,O
+were,O
+amplified,O
+by,O
+PCR,O
+.,O
+ , 
+When,O
+these,O
+fragments,O
+were,O
+sequenced,O
+directly,O
+,,O
+multiple,O
+sequences,O
+seemed,O
+to,O
+be,O
+present,O
+.,O
+ , 
+From,O
+three,O
+representative,O
+individuals,O
+,,O
+DNA,O
+fragments,O
+of,O
+different,O
+lengths,O
+were,O
+quantified,O
+and,O
+short,O
+overlapping,O
+amplification,O
+products,O
+cloned,O
+.,O
+ , 
+When,O
+amplifications,O
+started,O
+from,O
+<,O
+40,O
+molecules,O
+,,O
+clones,O
+contained,O
+several,O
+different,O
+sequences,O
+.,O
+ , 
+In,O
+contrast,O
+,,O
+when,O
+they,O
+were,O
+initiated,O
+by,O
+a,O
+few,O
+thousand,O
+molecules,O
+,,O
+unambiguous,O
+and,O
+reproducible,O
+results,O
+were,O
+achieved,O
+.,O
+ , 
+These,O
+results,O
+show,O
+that,O
+more,O
+experimental,O
+work,O
+than,O
+is,O
+often,O
+applied,O
+is,O
+necessary,O
+to,O
+ensure,O
+that,O
+DNA,O
+sequences,O
+amplified,O
+from,O
+ancient,O
+human,O
+remains,O
+are,O
+authentic,O
+.,O
+ , 
+In,O
+particular,O
+,,O
+quantitation,O
+of,O
+the,O
+numbers,O
+of,O
+amplifiable,O
+molecules,O
+is,O
+a,O
+useful,O
+tool,O
+to,O
+determine,O
+the,O
+role,O
+of,O
+contaminating,O
+contemporary,O
+molecules,O
+and,O
+PCR,O
+errors,O
+in,O
+amplifications,O
+from,O
+ancient,O
+DNA,O
+.,O
+ , 
+#9838272
+The,O
+sib,O
+transmission,O
+/,O
+disequilibrium,O
+test,O
+is,O
+a,O
+Mantel,O
+-,O
+Haenszel,O
+test,O
+.,O
+ , 
+#21549343
+Whole,O
+-,O
+Exome,O
+sequencing,O
+identifies,O
+FAM20A,B-Gene
+mutations,O
+as,O
+a,O
+cause,O
+of,O
+amelogenesis,O
+imperfecta,O
+and,O
+gingival,O
+hyperplasia,O
+syndrome,O
+.,O
+ , 
+Amelogenesis,O
+imperfecta,O
+(,O
+AI,O
+),O
+describes,O
+a,O
+clinically,O
+and,O
+genetically,O
+heterogeneous,O
+group,O
+of,O
+disorders,O
+of,O
+biomineralization,O
+resulting,O
+from,O
+failure,O
+of,O
+normal,O
+enamel,O
+formation,O
+.,O
+ , 
+AI,O
+is,O
+found,O
+as,O
+an,O
+isolated,O
+entity,O
+or,O
+as,O
+part,O
+of,O
+a,O
+syndrome,O
+,,O
+and,O
+an,O
+autosomal,O
+-,O
+recessive,O
+syndrome,O
+associating,O
+AI,O
+and,O
+gingival,O
+hyperplasia,O
+was,O
+recently,O
+reported,O
+.,O
+ , 
+Using,O
+whole,O
+-,O
+exome,O
+sequencing,O
+,,O
+we,O
+identified,O
+a,O
+homozygous,O
+nonsense,O
+mutation,O
+in,O
+exon,O
+2,O
+of,O
+FAM20A,B-Gene
+that,O
+was,O
+not,O
+present,O
+in,O
+the,O
+Single,O
+Nucleotide,O
+Polymorphism,O
+database,O
+(,O
+dbSNP,O
+),O
+,,O
+the,O
+1000,O
+Genomes,O
+database,O
+,,O
+or,O
+the,O
+Centre,O
+d'Etude,O
+du,O
+Polymorphisme,O
+Humain,O
+(,O
+CEPH,O
+),O
+ , 
+Diversity,O
+Panel,O
+.,O
+ , 
+Expression,O
+analyses,O
+indicated,O
+that,O
+Fam20a,B-Gene
+is,O
+expressed,O
+in,O
+ameloblasts,O
+and,O
+gingivae,O
+,,O
+providing,O
+biological,O
+plausibility,O
+for,O
+mutations,O
+in,O
+FAM20A,B-Gene
+underlying,O
+the,O
+pathogenesis,O
+of,O
+this,O
+syndrome,O
+.,O
+ , 
+#1373934
+Identification,O
+of,O
+a,O
+nonframeshift,O
+84,O
+-,O
+bp,O
+deletion,O
+in,O
+exon,O
+13,O
+of,O
+the,O
+cystic,B-Gene
+fibrosis,I-Gene
+gene,O
+.,O
+ , 
+Cystic,O
+fibrosis,O
+(,O
+CF,O
+),O
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+the,O
+most,O
+frequent,O
+autosomal,O
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+inherited,O
+disorder,O
+in,O
+Caucasian,O
+populations,O
+.,O
+ , 
+The,O
+disease,O
+is,O
+caused,O
+by,O
+mutations,O
+in,O
+the,O
+CF,B-Gene
+transmembrane,I-Gene
+conductance,I-Gene
+regulator,I-Gene
+(,B-Gene
+CFTR,I-Gene
+),I-Gene
+gene,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+an,O
+84,O
+-,O
+bp,O
+deletion,O
+in,O
+exon,O
+13,O
+of,O
+the,O
+CFTR,B-Gene
+gene,O
+,,O
+detected,O
+by,O
+DNA,O
+amplification,O
+and,O
+direct,O
+sequencing,O
+of,O
+500,O
+bp,O
+of,O
+the,O
+5,O
+',O
+end,O
+of,O
+exon,O
+13,O
+.,O
+ , 
+The,O
+deletion,O
+was,O
+in,O
+the,O
+maternal,O
+allele,O
+of,O
+a,O
+CF,O
+patient,O
+bearing,O
+the,O
+delta,O
+F508,O
+deletion,O
+in,O
+the,O
+father,O
+'s,O
+allele,O
+.,O
+ , 
+The,O
+same,O
+84,O
+-,O
+bp,O
+deletion,O
+could,O
+also,O
+be,O
+detected,O
+in,O
+the,O
+patient,O
+'s,O
+mother,O
+.,O
+ , 
+The,O
+deletion,O
+spanned,O
+from,O
+a,O
+four,O
+-,O
+A,O
+cluster,O
+in,O
+positions,O
+1949,O
+-,O
+1952,O
+to,O
+another,O
+four,O
+-,O
+A,O
+cluster,O
+in,O
+positions,O
+2032,O
+-,O
+2035,O
+,,O
+including,O
+84,O
+bp,O
+which,O
+correspond,O
+to,O
+codons,O
+607,O
+-,O
+634,O
+(,B-SNP
+1949del84,I-SNP
+),I-SNP
+.,O
+ , 
+The,O
+reported,O
+mutation,O
+would,O
+result,O
+in,O
+the,O
+loss,O
+of,O
+28,O
+amino,O
+acid,O
+residues,O
+of,O
+the,O
+R,O
+domain,O
+of,O
+the,O
+CFTR,B-Gene
+protein,O
+.,O
+ , 
+#9143924
+Two,O
+mutations,O
+in,O
+the,O
+same,O
+low,O
+-,O
+density,O
+lipoprotein,O
+receptor,O
+allele,O
+act,O
+in,O
+synergy,O
+to,O
+reduce,O
+receptor,O
+function,O
+in,O
+heterozygous,O
+familial,O
+hypercholesterolemia,O
+.,O
+ , 
+Mutations,O
+in,O
+genes,O
+are,O
+not,O
+necessarily,O
+pathogenic,O
+.,O
+ , 
+Expression,O
+of,O
+mutant,O
+genes,O
+in,O
+cells,O
+can,O
+therefore,O
+be,O
+required,O
+to,O
+demonstrate,O
+that,O
+mutations,O
+in,O
+fact,O
+disturb,O
+protein,O
+function,O
+.,O
+ , 
+This,O
+applies,O
+especially,O
+to,O
+missense,O
+mutations,O
+,,O
+which,O
+cause,O
+an,O
+amino,O
+acid,O
+to,O
+be,O
+replaced,O
+by,O
+another,O
+amino,O
+acid,O
+.,O
+ , 
+In,O
+the,O
+present,O
+study,O
+of,O
+two,O
+families,O
+with,O
+familial,O
+hypercholesterolemia,O
+in,O
+the,O
+heterozygous,O
+form,O
+,,O
+we,O
+found,O
+two,O
+mutations,O
+in,O
+the,O
+same,O
+allele,O
+of,O
+the,O
+low,B-Gene
+-,I-Gene
+density,I-Gene
+lipoprotein,I-Gene
+(,B-Gene
+LDL,I-Gene
+),I-Gene
+receptor,O
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+:,O
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+missense,B-SNP
+Asn543,I-SNP
+.,I-SNP
+ , 
+His,O
+mutation,O
+(,B-SNP
+N543H,I-SNP
+),I-SNP
+in,O
+exon,O
+11,O
+,,O
+and,O
+an,O
+in,O
+-,O
+frame,O
+9,O
+-,O
+bp,O
+deletion,O
+(,B-SNP
+2393del9,I-SNP
+),I-SNP
+in,O
+exon,O
+17,O
+.,O
+ , 
+The,O
+two,O
+mutations,O
+were,O
+identified,O
+in,O
+heterozygous,O
+FH,O
+index,O
+patients,O
+in,O
+whom,O
+no,O
+other,O
+pathogenic,O
+mutations,O
+were,O
+detected,O
+by,O
+SSCP,O
+analysis,O
+of,O
+the,O
+remaining,O
+16,O
+exons,O
+and,O
+the,O
+promoter,O
+region,O
+.,O
+ , 
+Both,O
+mutations,O
+cosegregated,O
+with,O
+hypercholesterolemia,O
+within,O
+the,O
+families,O
+.,O
+ , 
+Each,O
+of,O
+these,O
+mutations,O
+had,O
+little,O
+or,O
+no,O
+effect,O
+on,O
+receptor,O
+function,O
+in,O
+transfected,O
+COS,O
+cells,O
+,,O
+but,O
+when,O
+both,O
+mutations,O
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+present,O
+simultaneously,O
+,,O
+receptor,O
+function,O
+,,O
+as,O
+assessed,O
+by,O
+flow,O
+cytometric,O
+measurement,O
+of,O
+fluorescent,O
+LDL,O
+uptake,O
+in,O
+cells,O
+,,O
+was,O
+reduced,O
+by,O
+75,O
+%,O
+.,O
+ , 
+Immunostainable,O
+receptors,O
+on,O
+the,O
+cell,O
+surface,O
+were,O
+decreased,O
+by,O
+80,O
+%,O
+as,O
+measured,O
+by,O
+flow,O
+cytometry,O
+.,O
+ , 
+The,O
+two,O
+mutations,O
+therefore,O
+acted,O
+in,O
+synergy,O
+to,O
+affect,O
+receptor,O
+function,O
+,,O
+possibly,O
+during,O
+intracellular,O
+receptor,O
+transport,O
+,,O
+since,O
+Northern,O
+blot,O
+analysis,O
+suggested,O
+that,O
+mRNA,O
+levels,O
+were,O
+unaffected,O
+.,O
+ , 
+Without,O
+screening,O
+of,O
+the,O
+entire,O
+coding,O
+regions,O
+of,O
+the,O
+gene,O
+,,O
+the,O
+synergistic,O
+action,O
+of,O
+these,O
+two,O
+LDL,B-Gene
+receptor,O
+mutations,O
+would,O
+not,O
+have,O
+been,O
+detected,O
+.,O
+ , 
+#15195659
+Modes,O
+of,O
+action,O
+of,O
+HLA,B-Gene
+-,I-Gene
+DR,I-Gene
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+in,O
+multiple,O
+sclerosis,O
+.,O
+ , 
+#11023809
+Major,O
+genes,O
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+total,O
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+E,O
+levels,O
+in,O
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+.,O
+ , 
+Immunoglobulin,B-Gene
+E,I-Gene
+(,B-Gene
+IgE,I-Gene
+),I-Gene
+has,O
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+major,O
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+of,O
+allergic,O
+disorders,O
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+asthma,O
+.,O
+ , 
+Previous,O
+data,O
+from,O
+92,O
+families,O
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+through,O
+a,O
+proband,O
+with,O
+asthma,O
+,,O
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+total,O
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+IgE,B-Gene
+levels,O
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+ , 
+One,O
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+genes,O
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+to,O
+5q31,O
+-,O
+33,O
+.,O
+ , 
+In,O
+the,O
+current,O
+study,O
+,,O
+the,O
+segregation,O
+analysis,O
+was,O
+extended,O
+by,O
+the,O
+addition,O
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+108,O
+probands,O
+and,O
+their,O
+families,O
+,,O
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+in,O
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+same,O
+manner,O
+.,O
+ , 
+A,O
+mixed,O
+recessive,O
+model,O
+(,O
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+,,O
+major,O
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+gene,O
+and,O
+residual,O
+genetic,O
+effect,O
+),O
+was,O
+the,O
+best,O
+-,O
+fitting,O
+and,O
+most,O
+-,O
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+one,O
+-,O
+locus,O
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+of,O
+the,O
+segregation,O
+analysis,O
+.,O
+ , 
+A,O
+mixed,O
+two,O
+-,O
+major,O
+-,O
+gene,O
+model,O
+(,O
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+,,O
+two,O
+major,O
+genes,O
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+genetic,O
+effect,O
+),O
+fit,O
+the,O
+data,O
+significantly,O
+better,O
+than,O
+did,O
+the,O
+mixed,O
+recessive,O
+one,O
+-,O
+major,O
+-,O
+gene,O
+model,O
+.,O
+ , 
+The,O
+second,O
+gene,O
+modified,O
+the,O
+effect,O
+of,O
+the,O
+first,O
+recessive,O
+gene,O
+.,O
+ , 
+Individuals,O
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+the,O
+genotype,O
+aaBB,O
+(,O
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+high,O
+-,O
+risk,O
+allele,O
+at,O
+the,O
+first,O
+gene,O
+and,O
+homozygous,O
+low,O
+-,O
+risk,O
+allele,O
+at,O
+the,O
+second,O
+locus,O
+),O
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+normal,O
+IgE,B-Gene
+levels,O
+(,O
+mean,O
+23,O
+IU,O
+/,O
+ml,O
+),O
+,,O
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+only,O
+individuals,O
+with,O
+genotypes,O
+aaBb,O
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+aabb,O
+had,O
+high,O
+IgE,B-Gene
+levels,O
+(,O
+mean,O
+282,O
+IU,O
+/,O
+ml,O
+),O
+.,O
+ , 
+A,O
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+variance,O
+-,O
+component,O
+analysis,O
+.,O
+ , 
+Significant,O
+evidence,O
+for,O
+linkage,O
+was,O
+found,O
+for,O
+a,O
+novel,O
+locus,O
+at,O
+7q,O
+,,O
+with,O
+a,O
+multipoint,O
+LOD,O
+score,O
+of,O
+3,O
+.,O
+ , 
+36,O
+(,O
+P=.00004,O
+),O
+.,O
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+A,O
+LOD,O
+score,O
+of,O
+3.65,O
+(,O
+P=.00002,O
+),O
+was,O
+obtained,O
+after,O
+genotyping,O
+additional,O
+markers,O
+in,O
+this,O
+region,O
+.,O
+ , 
+Evidence,O
+for,O
+linkage,O
+was,O
+also,O
+found,O
+for,O
+two,O
+previously,O
+reported,O
+regions,O
+,,O
+5q,O
+and,O
+12q,O
+,,O
+with,O
+LOD,O
+scores,O
+of,O
+2.73,O
+(,O
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+),O
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+(,O
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+),O
+,,O
+respectively,O
+.,O
+ , 
+These,O
+results,O
+suggest,O
+that,O
+several,O
+major,O
+genes,O
+,,O
+plus,O
+residual,O
+genetic,O
+effects,O
+,,O
+regulate,O
+total,O
+serum,O
+IgE,B-Gene
+levels,O
+.,O
+ , 
+#12424708
+Structural,O
+and,O
+functional,O
+characterization,O
+of,O
+factor,B-Gene
+H,I-Gene
+mutations,O
+associated,O
+with,O
+atypical,O
+hemolytic,O
+uremic,O
+syndrome,O
+.,O
+ , 
+Genetic,O
+studies,O
+have,O
+demonstrated,O
+the,O
+involvement,O
+of,O
+the,O
+complement,O
+regulator,O
+factor,B-Gene
+H,I-Gene
+in,O
+nondiarrheal,O
+,,O
+nonverocytotoxin,O
+(,O
+i.e.,O
+,,O
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+),O
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+of,O
+hemolytic,O
+uremic,O
+syndrome,O
+.,O
+ , 
+Different,O
+factor,B-Gene
+H,I-Gene
+mutations,O
+have,O
+been,O
+identified,O
+in,O
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+%,O
+of,O
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+atypical,O
+hemolytic,O
+uremic,O
+syndrome,O
+(,O
+aHUS,O
+),O
+,,O
+and,O
+most,O
+of,O
+these,O
+mutations,O
+alter,O
+single,O
+amino,O
+acids,O
+in,O
+the,O
+C,O
+-,O
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+region,O
+of,O
+factor,B-Gene
+H.,I-Gene
+ , 
+Although,O
+these,O
+mutations,O
+are,O
+considered,O
+to,O
+be,O
+responsible,O
+for,O
+the,O
+disease,O
+,,O
+the,O
+precise,O
+role,O
+that,O
+factor,B-Gene
+H,I-Gene
+plays,O
+in,O
+the,O
+pathogenesis,O
+of,O
+aHUS,O
+is,O
+unknown,O
+.,O
+ , 
+We,O
+report,O
+here,O
+the,O
+structural,O
+and,O
+functional,O
+characterization,O
+of,O
+three,O
+different,O
+factor,B-Gene
+H,I-Gene
+proteins,O
+purified,O
+from,O
+the,O
+plasma,O
+of,O
+patients,O
+with,O
+aHUS,O
+who,O
+carry,O
+the,O
+factor,B-Gene
+H,I-Gene
+mutations,O
+W1183L,B-SNP
+,,I-SNP
+V1197A,B-SNP
+,,I-SNP
+or,O
+R1210C.,B-SNP
+Structural,O
+anomalies,O
+in,O
+factor,B-Gene
+H,I-Gene
+were,O
+found,O
+only,O
+in,O
+R1210C,B-SNP
+carriers,O
+;,O
+these,O
+individuals,O
+show,O
+,,O
+in,O
+their,O
+plasma,O
+,,O
+a,O
+characteristic,O
+high,O
+-,O
+molecular,O
+-,O
+weight,O
+factor,B-Gene
+H,I-Gene
+protein,O
+that,O
+results,O
+from,O
+the,O
+covalent,O
+interaction,O
+between,O
+factor,B-Gene
+H,I-Gene
+and,O
+human,O
+serum,O
+albumin,O
+.,O
+ , 
+Most,O
+important,O
+,,O
+all,O
+three,O
+aHUS,O
+-,O
+associated,O
+factor,B-Gene
+H,I-Gene
+proteins,O
+have,O
+a,O
+normal,O
+cofactor,O
+activity,O
+in,O
+the,O
+proteolysis,O
+of,O
+fluid,O
+-,O
+phase,O
+C3b,O
+by,O
+factor,O
+I,O
+but,O
+show,O
+very,O
+low,O
+binding,O
+to,O
+surface,O
+-,O
+bound,O
+C3b,O
+.,O
+ , 
+This,O
+functional,O
+impairment,O
+was,O
+also,O
+demonstrated,O
+in,O
+recombinant,O
+mutant,O
+factor,B-Gene
+H,I-Gene
+proteins,O
+expressed,O
+in,O
+COS7,O
+cells,O
+.,O
+ , 
+These,O
+data,O
+support,O
+the,O
+hypothesis,O
+that,O
+patients,O
+with,O
+aHUS,O
+carry,O
+a,O
+specific,O
+dysfunction,O
+in,O
+the,O
+protection,O
+of,O
+cellular,O
+surfaces,O
+from,O
+complement,O
+activation,O
+,,O
+offering,O
+new,O
+possibilities,O
+to,O
+improve,O
+diagnosis,O
+and,O
+develop,O
+appropriate,O
+therapies,O
+.,O
+ , 
+#9973271
+Biological,O
+implications,O
+of,O
+the,O
+DNA,O
+structures,O
+associated,O
+with,O
+disease,O
+-,O
+causing,O
+triplet,O
+repeats,O
+.,O
+ , 
+#8023855
+Small,O
+marker,O
+X,O
+chromosomes,O
+lack,O
+the,O
+X,O
+inactivation,O
+center,O
+:,O
+implications,O
+for,O
+karyotype,O
+/,O
+phenotype,O
+correlations,O
+.,O
+ , 
+The,O
+abnormal,O
+phenotype,O
+and/or,O
+mental,O
+retardation,O
+seen,O
+in,O
+persons,O
+with,O
+small,O
+marker,O
+X,O
+(,O
+mar(X,O
+),O
+),O
+chromosomes,O
+has,O
+been,O
+hypothesized,O
+to,O
+be,O
+due,O
+to,O
+the,O
+loss,O
+of,O
+the,O
+X,O
+inactivation,O
+center,O
+(,O
+XIC,O
+),O
+at,O
+Xq13.2,O
+,,O
+resulting,O
+in,O
+two,O
+active,O
+copies,O
+of,O
+genes,O
+in,O
+the,O
+pericentromeric,O
+region,O
+.,O
+ , 
+In,O
+order,O
+to,O
+define,O
+precisely,O
+the,O
+DNA,O
+content,O
+of,O
+mar(X,O
+),O
+chromosomes,O
+and,O
+to,O
+correlate,O
+phenotype,O
+with,O
+karyotype,O
+,,O
+we,O
+studied,O
+small,O
+mar(X,O
+),O
+chromosomes,O
+,,O
+using,O
+FISH,O
+with,O
+probes,O
+in,O
+the,O
+juxtacentromeric,O
+region,O
+.,O
+ , 
+One,O
+of,O
+the,O
+probes,O
+was,O
+a,O
+40,O
+-,O
+kb,O
+genomic,O
+cosmid,O
+for,O
+the,O
+XIST,B-Gene
+gene,O
+,,O
+which,O
+maps,O
+to,O
+the,O
+smallest,O
+interval,O
+known,O
+to,O
+contain,O
+the,O
+XIC,O
+and,O
+is,O
+thought,O
+to,O
+be,O
+involved,O
+in,O
+X,O
+inactivation,O
+.,O
+ , 
+Our,O
+findings,O
+reveal,O
+that,O
+small,O
+mar(X,O
+),O
+chromosomes,O
+do,O
+not,O
+include,O
+the,O
+XIC,O
+and,O
+therefore,O
+can,O
+not,O
+be,O
+subject,O
+to,O
+X,O
+inactivation,O
+,,O
+supporting,O
+the,O
+premise,O
+that,O
+abnormal,O
+dosage,O
+of,O
+expressed,O
+genes,O
+in,O
+the,O
+pericentromeric,O
+region,O
+of,O
+the,O
+X,O
+generates,O
+the,O
+aberrant,O
+phenotype,O
+seen,O
+in,O
+patients,O
+with,O
+small,O
+mar(X,O
+),O
+chromosomes,O
+.,O
+ , 
+#8105686
+High,O
+prevalence,O
+of,O
+the,O
+point,O
+mutation,O
+in,O
+exon,O
+6,O
+of,O
+the,O
+xeroderma,B-Gene
+pigmentosum,I-Gene
+group,I-Gene
+A,I-Gene
+-,I-Gene
+complementing,I-Gene
+(,B-Gene
+XPAC,I-Gene
+),I-Gene
+gene,O
+in,O
+xeroderma,O
+pigmentosum,O
+group,O
+A,O
+patients,O
+in,O
+Tunisia,O
+.,O
+ , 
+Xeroderma,O
+pigmentosum,O
+(,O
+XP,O
+),O
+patients,O
+in,O
+Tunisia,O
+who,O
+belong,O
+to,O
+the,O
+genetic,O
+complementation,O
+group,O
+A,O
+(,O
+XPA,O
+),O
+have,O
+milder,O
+skin,O
+symptoms,O
+than,O
+do,O
+Japanese,O
+XPA,O
+patients,O
+.,O
+ , 
+Such,O
+difference,O
+in,O
+the,O
+clinical,O
+features,O
+might,O
+be,O
+caused,O
+by,O
+the,O
+difference,O
+in,O
+the,O
+site,O
+of,O
+mutation,O
+in,O
+the,O
+XP,B-Gene
+A,I-Gene
+-,I-Gene
+complementing,I-Gene
+(,B-Gene
+XPAC,I-Gene
+),I-Gene
+gene,O
+.,O
+ , 
+The,O
+purpose,O
+of,O
+this,O
+study,O
+is,O
+to,O
+identify,O
+the,O
+genetic,O
+alterations,O
+in,O
+the,O
+XPAC,B-Gene
+gene,O
+in,O
+the,O
+Tunisian,O
+XPA,O
+patients,O
+and,O
+to,O
+investigate,O
+the,O
+relationship,O
+between,O
+the,O
+clinical,O
+symptoms,O
+and,O
+the,O
+genetic,O
+alterations,O
+.,O
+ , 
+Three,O
+sites,O
+of,O
+mutation,O
+in,O
+the,O
+XPAC,B-Gene
+gene,O
+have,O
+been,O
+identified,O
+in,O
+the,O
+Japanese,O
+XPA,O
+patients,O
+,,O
+and,O
+about,O
+85,O
+%,O
+of,O
+them,O
+have,O
+a,O
+G-->C,O
+point,O
+mutation,O
+at,O
+the,O
+splicing,O
+acceptor,O
+site,O
+of,O
+intron,O
+3,O
+.,O
+ , 
+We,O
+found,O
+that,O
+six,O
+(,O
+86,O
+%,O
+),O
+of,O
+seven,O
+Tunisian,O
+XPA,O
+patients,O
+had,O
+a,O
+nonsense,O
+mutation,O
+in,O
+codon,B-SNP
+228,I-SNP
+in,I-SNP
+exon,I-SNP
+6,I-SNP
+,,I-SNP
+because,I-SNP
+of,I-SNP
+a,I-SNP
+CGA-->TGA,I-SNP
+point,O
+mutation,O
+,,O
+which,O
+can,O
+be,O
+detected,O
+by,O
+the,O
+HphI,O
+RFLP,O
+.,O
+ , 
+This,O
+type,O
+of,O
+mutation,O
+is,O
+the,O
+same,O
+as,O
+those,O
+found,O
+in,O
+two,O
+Japanese,O
+XPA,O
+patients,O
+with,O
+mild,O
+clinical,O
+symptoms,O
+.,O
+ , 
+Milder,O
+skin,O
+symptoms,O
+in,O
+the,O
+XPA,O
+patients,O
+in,O
+Tunisia,O
+than,O
+in,O
+those,O
+in,O
+Japan,O
+,,O
+despite,O
+mostly,O
+sunny,O
+weather,O
+and,O
+the,O
+unsatisfactory,O
+sun,O
+protection,O
+in,O
+Tunisia,O
+,,O
+should,O
+be,O
+due,O
+to,O
+the,O
+difference,O
+in,O
+the,O
+mutation,O
+site,O
+.,O
+ , 
+#10417286
+Linkage,O
+analysis,O
+in,O
+a,O
+large,O
+Brazilian,O
+family,O
+with,O
+van,O
+der,O
+Woude,O
+syndrome,O
+suggests,O
+the,O
+existence,O
+of,O
+a,O
+susceptibility,O
+locus,O
+for,O
+cleft,O
+palate,O
+at,O
+17p11.2,O
+-,O
+11.1,O
+.,O
+ , 
+van,O
+der,O
+Woude,O
+syndrome,O
+(,O
+VWS,O
+),O
+,,O
+which,O
+has,O
+been,O
+mapped,O
+to,O
+1q32,O
+-,O
+41,O
+,,O
+is,O
+characterized,O
+by,O
+pits,O
+and/or,O
+sinuses,O
+of,O
+the,O
+lower,O
+lip,O
+,,O
+cleft,O
+lip,O
+/,O
+palate,O
+(,O
+CL,O
+/,O
+P,O
+),O
+,,O
+cleft,O
+palate,O
+(,O
+CP,O
+),O
+,,O
+bifid,O
+uvula,O
+,,O
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+hypodontia,O
+(,O
+H,O
+),O
+.,O
+ , 
+The,O
+expression,O
+of,O
+VWS,B-Gene
+,,I-Gene
+which,O
+has,O
+incomplete,O
+penetrance,O
+,,O
+is,O
+highly,O
+variable,O
+.,O
+ , 
+Both,O
+the,O
+occurrence,O
+of,O
+CL,O
+/,O
+P,O
+and,O
+CP,O
+within,O
+the,O
+same,O
+genealogy,O
+and,O
+a,O
+recurrence,O
+risk,O
+<,O
+40,O
+%,O
+for,O
+CP,O
+among,O
+descendants,O
+with,O
+VWS,O
+have,O
+suggested,O
+that,O
+the,O
+development,O
+of,O
+clefts,O
+in,O
+this,O
+syndrome,O
+is,O
+influenced,O
+by,O
+modifying,O
+genes,O
+at,O
+other,O
+loci,O
+.,O
+ , 
+To,O
+test,O
+this,O
+hypothesis,O
+,,O
+we,O
+have,O
+conducted,O
+linkage,O
+analysis,O
+in,O
+a,O
+large,O
+Brazilian,O
+kindred,O
+with,O
+VWS,O
+,,O
+considering,O
+as,O
+affected,O
+the,O
+individuals,O
+with,O
+CP,O
+,,O
+regardless,O
+of,O
+whether,O
+it,O
+is,O
+associated,O
+with,O
+other,O
+clinical,O
+signs,O
+of,O
+VWS,O
+.,O
+ , 
+Our,O
+results,O
+suggest,O
+that,O
+a,O
+gene,O
+at,O
+17p11.2,O
+-,O
+11.1,O
+,,O
+together,O
+with,O
+the,O
+VWS,B-Gene
+gene,O
+at,O
+1p32,O
+-,O
+41,O
+,,O
+enhances,O
+the,O
+probability,O
+of,O
+CP,O
+in,O
+an,O
+individual,O
+carrying,O
+the,O
+two,O
+at,O
+-,O
+risk,O
+genes,O
+.,O
+ , 
+If,O
+this,O
+hypothesis,O
+is,O
+confirmed,O
+in,O
+other,O
+VWS,O
+pedigrees,O
+,,O
+it,O
+will,O
+represent,O
+one,O
+of,O
+the,O
+first,O
+examples,O
+of,O
+a,O
+gene,O
+,,O
+mapped,O
+through,O
+linkage,O
+analysis,O
+,,O
+which,O
+modifies,O
+the,O
+expression,O
+of,O
+a,O
+major,O
+gene,O
+.,O
+ , 
+It,O
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+also,O
+have,O
+important,O
+implications,O
+for,O
+genetic,O
+counseling,O
+,,O
+particularly,O
+for,O
+more,O
+accurately,O
+predicting,O
+recurrence,O
+risks,O
+of,O
+clefts,O
+among,O
+the,O
+offspring,O
+of,O
+patients,O
+with,O
+VWS,O
+.,O
+ , 
+#9973270
+Protein,O
+fate,O
+in,O
+neurodegenerative,O
+proteinopathies,O
+:,O
+polyglutamine,O
+diseases,O
+join,O
+the,O
+(,O
+mis)fold,O
+.,O
+ , 
+#7611293
+A,O
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+mutation,O
+(,B-SNP
+I278,I-SNP
+T,I-SNP
+),I-SNP
+in,O
+the,O
+cystathionine,B-Gene
+beta,I-Gene
+-,I-Gene
+synthase,I-Gene
+gene,O
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+in,O
+pyridoxine,O
+-,O
+responsive,O
+homocystinuria,O
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+associated,O
+with,O
+mild,O
+clinical,O
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+.,O
+ , 
+Cystathionine,B-Gene
+beta,I-Gene
+-,I-Gene
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+(,B-Gene
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+deficiency,O
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+recessive,O
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+by,O
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+and,O
+multisystem,O
+clinical,O
+disease,O
+.,O
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+Patients,O
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+to,O
+pyridoxine,O
+usually,O
+have,O
+a,O
+milder,O
+clinical,O
+phenotype,O
+than,O
+do,O
+nonresponsive,O
+patients,O
+,,O
+and,O
+we,O
+studied,O
+the,O
+molecular,O
+pathology,O
+of,O
+this,O
+disorder,O
+in,O
+an,O
+attempt,O
+to,O
+understand,O
+the,O
+molecular,O
+basis,O
+of,O
+the,O
+clinical,O
+variation,O
+.,O
+ , 
+We,O
+previously,O
+reported,O
+a,O
+T833C,B-SNP
+transition,O
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+8,O
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+a,O
+substitution,O
+of,O
+threonine,B-SNP
+for,I-SNP
+isoleucine,I-SNP
+at,I-SNP
+codon,I-SNP
+278,I-SNP
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+I278,I-SNP
+T,I-SNP
+),I-SNP
+.,O
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+By,O
+PCR,O
+amplification,O
+and,O
+sequencing,O
+of,O
+exon,O
+8,O
+from,O
+genomic,O
+DNA,O
+we,O
+have,O
+now,O
+detected,O
+the,O
+I278,B-SNP
+T,I-SNP
+mutation,O
+in,O
+7,O
+of,O
+11,O
+patients,O
+with,O
+in,O
+vivo,O
+pyridoxine,O
+responsiveness,O
+and,O
+in,O
+0,O
+of,O
+27,O
+pyridoxine,O
+-,O
+nonresponsive,O
+patients,O
+.,O
+ , 
+Two,O
+pyridoxine,O
+-,O
+responsive,O
+patients,O
+are,O
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+five,O
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+for,O
+I278T.,B-SNP
+ , 
+We,O
+have,O
+now,O
+observed,O
+the,O
+I278,B-SNP
+T,I-SNP
+mutation,O
+in,O
+41,O
+%,O
+(,O
+9,O
+of,O
+22,O
+),O
+of,O
+the,O
+independent,O
+alleles,O
+in,O
+pyridoxine,O
+-,O
+responsive,O
+patients,O
+of,O
+varied,O
+ethnic,O
+backgrounds,O
+.,O
+ , 
+In,O
+two,O
+of,O
+the,O
+compound,O
+heterozygotes,O
+we,O
+identified,O
+a,O
+novel,O
+mutation,O
+(,B-SNP
+G139R,I-SNP
+and,O
+E144,B-SNP
+K,I-SNP
+),I-SNP
+in,O
+the,O
+other,O
+allele,O
+.,O
+ , 
+The,O
+finding,O
+that,O
+the,O
+two,O
+patients,O
+who,O
+are,O
+homozygous,O
+for,O
+I278,B-SNP
+T,I-SNP
+have,O
+only,O
+ectopia,O
+lentis,O
+and,O
+mild,O
+bone,O
+demineralization,O
+suggests,O
+that,O
+this,O
+mutation,O
+is,O
+associated,O
+with,O
+both,O
+in,O
+vivo,O
+pyridoxine,O
+responsiveness,O
+and,O
+mild,O
+clinical,O
+disease,O
+.,O
+ , 
+Compound,O
+heterozygous,O
+patients,O
+who,O
+have,O
+one,O
+copy,O
+of,O
+this,O
+missense,O
+mutation,O
+are,O
+likely,O
+to,O
+retain,O
+some,O
+degree,O
+of,O
+pyridoxine,O
+responsiveness,O
+.,O
+ , 
+#16642441
+Association,O
+of,O
+polymorphisms,O
+in,O
+the,O
+Angiotensin,B-Gene
+-,I-Gene
+converting,I-Gene
+enzyme,I-Gene
+gene,O
+with,O
+Alzheimer,O
+disease,O
+in,O
+an,O
+Israeli,O
+Arab,O
+community,O
+.,O
+ , 
+Several,O
+lines,O
+of,O
+evidence,O
+support,O
+for,O
+a,O
+role,O
+of,O
+angiotensin,B-Gene
+converting,I-Gene
+enzyme,I-Gene
+(,B-Gene
+ACE,I-Gene
+),I-Gene
+in,O
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+disease,O
+(,O
+AD,O
+),O
+.,O
+ , 
+Most,O
+genetic,O
+studies,O
+have,O
+focused,O
+on,O
+an,O
+Alu,O
+insertion,O
+/,O
+deletion,O
+(,O
+I,O
+/,O
+D,O
+),O
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+in,O
+the,O
+ACE,B-Gene
+gene,O
+(,B-Gene
+DCP1,I-Gene
+),I-Gene
+and,O
+have,O
+yielded,O
+conflicting,O
+results,O
+.,O
+ , 
+We,O
+evaluated,O
+the,O
+association,O
+between,O
+15,O
+single,O
+-,O
+nucleotide,O
+polymorphisms,O
+(,O
+SNPs,O
+),O
+in,O
+DCP1,B-Gene
+,,I-Gene
+including,O
+the,O
+I,O
+/,O
+D,O
+variant,O
+,,O
+and,O
+AD,O
+in,O
+a,O
+sample,O
+of,O
+92,O
+patients,O
+with,O
+AD,O
+and,O
+166,O
+nondemented,O
+controls,O
+from,O
+an,O
+inbred,O
+Israeli,O
+Arab,O
+community,O
+.,O
+ , 
+Although,O
+there,O
+was,O
+no,O
+evidence,O
+for,O
+association,O
+between,O
+AD,O
+and,O
+I,O
+/,O
+D,O
+,,O
+we,O
+observed,O
+significant,O
+association,O
+with,O
+SNPs,O
+rs4343,O
+ , 
+(,O
+P,O
+=,O
+.00001,O
+),O
+and,O
+rs4351,O
+(,O
+P,O
+=,O
+.01,O
+),O
+.,O
+ , 
+Haplotype,O
+analysis,O
+revealed,O
+remarkably,O
+significant,O
+evidence,O
+of,O
+association,O
+with,O
+the,O
+SNP,O
+combination,O
+rs4343,O
+and,O
+rs4351,O
+(,O
+global,O
+P,O
+=,O
+7.5,O
+x,O
+10(-7,O
+),O
+),O
+.,O
+ , 
+Individuals,O
+possessing,O
+the,O
+haplotype,O
+",O
+GA,O
+",O
+(,O
+frequency,O
+0.21,O
+in,O
+cases,O
+and,O
+0.01,O
+in,O
+controls,O
+),O
+derived,O
+from,O
+these,O
+SNPs,O
+had,O
+a,O
+45,O
+-,O
+fold,O
+increased,O
+risk,O
+of,O
+developing,O
+AD,O
+(,O
+95,O
+%,O
+CI,O
+6.0,O
+-,O
+343.2,O
+),O
+compared,O
+with,O
+those,O
+possessing,O
+any,O
+of,O
+the,O
+other,O
+three,O
+haplotypes,O
+.,O
+ , 
+Longer,O
+range,O
+haplotypes,O
+including,O
+I,O
+/,O
+D,O
+were,O
+even,O
+more,O
+significant,O
+(,O
+lowest,O
+global,O
+P,O
+=,O
+1.1,O
+x,O
+10(-12,O
+),O
+),O
+,,O
+but,O
+the,O
+only,O
+consistently,O
+associated,O
+alleles,O
+were,O
+in,O
+rs4343,O
+and,O
+rs4351,O
+.,O
+ , 
+These,O
+results,O
+suggest,O
+that,O
+a,O
+variant,O
+in,O
+close,O
+proximity,O
+to,O
+rs4343,O
+and,O
+rs4351,O
+modulates,O
+susceptibility,O
+to,O
+AD,O
+in,O
+this,O
+community,O
+.,O
+ , 
+#8755927
+Allelic,O
+loss,O
+is,O
+frequent,O
+in,O
+tuberous,O
+sclerosis,O
+kidney,O
+lesions,O
+but,O
+rare,O
+in,O
+brain,O
+lesions,O
+.,O
+ , 
+Tuberous,O
+sclerosis,O
+(,O
+TSC,O
+),O
+is,O
+an,O
+autosomal,O
+dominant,O
+disorder,O
+characterized,O
+by,O
+seizures,O
+,,O
+mental,O
+retardation,O
+,,O
+and,O
+hamartomatous,O
+lesions,O
+.,O
+ , 
+Although,O
+hamartomas,O
+can,O
+occur,O
+in,O
+almost,O
+any,O
+organ,O
+,,O
+they,O
+are,O
+most,O
+common,O
+in,O
+the,O
+brain,O
+,,O
+kidney,O
+,,O
+heart,O
+,,O
+and,O
+skin,O
+.,O
+ , 
+Allelic,O
+loss,O
+or,O
+loss,O
+of,O
+heterozygosity,O
+(,O
+LOH,O
+),O
+in,O
+TSC,O
+lesions,O
+has,O
+previously,O
+been,O
+reported,O
+on,O
+chromosomes,O
+16p13,O
+and,O
+9q34,O
+,,O
+the,O
+locations,O
+of,O
+the,O
+TSC2,B-Gene
+and,O
+TSC1,B-Gene
+genes,O
+,,O
+respectively,O
+,,O
+suggesting,O
+that,O
+the,O
+TSC,O
+genes,O
+act,O
+as,O
+tumor,O
+-,O
+suppressor,O
+genes,O
+.,O
+ , 
+In,O
+our,O
+study,O
+,,O
+87,O
+lesions,O
+from,O
+47,O
+TSC,O
+patients,O
+were,O
+analyzed,O
+for,O
+LOH,O
+in,O
+the,O
+TSC1,B-Gene
+and,O
+TSC2,B-Gene
+chromosomal,O
+regions,O
+.,O
+ , 
+Three,O
+findings,O
+resulted,O
+from,O
+this,O
+analysis,O
+.,O
+ , 
+First,O
+,,O
+we,O
+confirmed,O
+that,O
+the,O
+TSC1,B-Gene
+critical,O
+region,O
+is,O
+distal,O
+to,O
+D9S149,O
+.,O
+ , 
+Second,O
+,,O
+we,O
+found,O
+LOH,O
+more,O
+frequently,O
+on,O
+chromosome,O
+16p13,O
+than,O
+on,O
+9q34,O
+.,O
+ , 
+Of,O
+the,O
+28,O
+patients,O
+with,O
+angiomyolipomas,O
+or,O
+rhabdomyomas,O
+,,O
+16p13,O
+LOH,O
+was,O
+detected,O
+in,O
+lesions,O
+from,O
+12,O
+(,O
+57,O
+%,O
+),O
+of,O
+21,O
+informative,O
+patients,O
+,,O
+while,O
+9q34,O
+LOH,O
+was,O
+detected,O
+in,O
+lesions,O
+from,O
+only,O
+1,O
+patient,O
+(,O
+4,O
+%,O
+),O
+.,O
+ , 
+This,O
+could,O
+indicate,O
+that,O
+TSC2,B-Gene
+tumors,O
+are,O
+more,O
+likely,O
+than,O
+TSC1,B-Gene
+tumors,O
+to,O
+require,O
+surgical,O
+resection,O
+or,O
+that,O
+TSC2,B-Gene
+is,O
+more,O
+common,O
+than,O
+TSC1,B-Gene
+in,O
+our,O
+patient,O
+population,O
+.,O
+ , 
+It,O
+is,O
+also,O
+possible,O
+that,O
+small,O
+regions,O
+of,O
+9q34,O
+LOH,O
+were,O
+missed,O
+.,O
+ , 
+Lastly,O
+,,O
+LOH,O
+was,O
+found,O
+in,O
+56,O
+%,O
+of,O
+renal,O
+angiomyolipomas,O
+and,O
+cardiac,O
+rhabdomyormas,O
+but,O
+in,O
+only,O
+4,O
+%,O
+of,O
+TSC,O
+brain,O
+lesions,O
+.,O
+ , 
+This,O
+suggests,O
+that,O
+brain,O
+lesions,O
+can,O
+result,O
+from,O
+different,O
+pathogenic,O
+mechanisms,O
+than,O
+kidney,O
+and,O
+heart,O
+lesions,O
+.,O
+ , 
+#10477438
+Racial,O
+differences,O
+in,O
+the,O
+frequencies,O
+of,O
+cardiac,O
+beta(1)-adrenergic,B-Gene
+receptor,I-Gene
+polymorphisms,O
+:,O
+analysis,O
+of,O
+c145A,B-SNP
+>,I-SNP
+G,I-SNP
+and,O
+c1165G,B-SNP
+>,I-SNP
+C.,I-SNP
+ , 
+#9497249
+Assignment,O
+of,O
+the,O
+tibial,O
+muscular,O
+dystrophy,O
+locus,O
+to,O
+chromosome,O
+2q31,O
+.,O
+ , 
+Tibial,O
+muscular,O
+dystrophy,O
+(,O
+TMD,O
+),O
+is,O
+a,O
+rare,O
+autosomal,O
+dominant,O
+distal,O
+myopathy,O
+with,O
+late,O
+adult,O
+onset,O
+.,O
+ , 
+The,O
+phenotype,O
+is,O
+relatively,O
+mild,O
+:,O
+muscle,O
+weakness,O
+manifests,O
+in,O
+the,O
+patient,O
+'s,O
+early,O
+40s,O
+and,O
+remains,O
+confined,O
+to,O
+the,O
+tibial,O
+anterior,O
+muscles,O
+.,O
+ , 
+Histopathological,O
+changes,O
+in,O
+muscle,O
+are,O
+compatible,O
+with,O
+muscular,O
+dystrophy,O
+,,O
+with,O
+the,O
+exception,O
+that,O
+rimmed,O
+vacuoles,O
+are,O
+a,O
+rather,O
+common,O
+finding,O
+.,O
+ , 
+We,O
+performed,O
+a,O
+genomewide,O
+scan,O
+,,O
+with,O
+279,O
+highly,O
+polymorphic,O
+Cooperative,O
+Human,O
+Linkage,O
+Center,O
+microsatellite,O
+markers,O
+,,O
+on,O
+11,O
+affected,O
+individuals,O
+of,O
+one,O
+Finnish,O
+TMD,O
+family,O
+.,O
+ , 
+The,O
+only,O
+evidence,O
+for,O
+linkage,O
+emerged,O
+from,O
+markers,O
+in,O
+a,O
+43,O
+-,O
+cM,O
+region,O
+on,O
+chromosome,O
+2q,O
+.,O
+ , 
+In,O
+further,O
+linkage,O
+analyses,O
+,,O
+which,O
+included,O
+three,O
+other,O
+Finnish,O
+TMD,O
+families,O
+and,O
+which,O
+used,O
+a,O
+denser,O
+set,O
+of,O
+markers,O
+,,O
+a,O
+maximum,O
+two,O
+-,O
+point,O
+LOD,O
+score,O
+of,O
+10.14,O
+(,O
+recombination,O
+fraction,O
+of,O
+.05,O
+),O
+was,O
+obtained,O
+with,O
+marker,O
+D2S364,O
+.,O
+ , 
+Multipoint,O
+likelihood,O
+calculations,O
+,,O
+combined,O
+with,O
+the,O
+haplotype,O
+and,O
+recombination,O
+analyses,O
+,,O
+restricted,O
+the,O
+TMD,O
+locus,O
+to,O
+an,O
+approximately,O
+1,O
+-,O
+cM,O
+critical,O
+chromosomal,O
+region,O
+without,O
+any,O
+evidence,O
+of,O
+heterogeneity,O
+.,O
+ , 
+Since,O
+all,O
+the,O
+affecteds,O
+share,O
+one,O
+core,O
+haplotype,O
+,,O
+the,O
+dominance,O
+of,O
+one,O
+ancestor,O
+mutation,O
+is,O
+obvious,O
+in,O
+the,O
+Finnish,O
+TMD,O
+families,O
+.,O
+ , 
+The,O
+disease,O
+locus,O
+that,O
+was,O
+found,O
+represents,O
+a,O
+novel,O
+muscular,O
+dystrophy,O
+locus,O
+,,O
+providing,O
+evidence,O
+for,O
+the,O
+involvement,O
+of,O
+one,O
+additional,O
+gene,O
+in,O
+the,O
+distal,O
+myopathy,O
+group,O
+of,O
+muscle,O
+disorders,O
+.,O
+ , 
+#8503442
+The,O
+haplotype,O
+-,O
+relative,O
+-,O
+risk,O
+(,O
+HRR,O
+),O
+method,O
+for,O
+analysis,O
+of,O
+association,O
+in,O
+nuclear,O
+families,O
+.,O
+ , 
+One,O
+major,O
+problem,O
+in,O
+studying,O
+an,O
+association,O
+between,O
+a,O
+marker,O
+locus,O
+and,O
+a,O
+disease,O
+is,O
+the,O
+selection,O
+of,O
+an,O
+appropriate,O
+group,O
+of,O
+controls,O
+.,O
+ , 
+However,O
+,,O
+this,O
+problem,O
+of,O
+population,O
+stratification,O
+can,O
+be,O
+circumvented,O
+in,O
+a,O
+quite,O
+elegant,O
+manner,O
+by,O
+family,O
+-,O
+based,O
+methods,O
+.,O
+ , 
+The,O
+haplotype,O
+-,O
+relative,O
+-,O
+risk,O
+(,O
+HRR,O
+),O
+method,O
+,,O
+which,O
+samples,O
+nuclear,O
+families,O
+with,O
+a,O
+single,O
+affected,O
+child,O
+and,O
+uses,O
+the,O
+parental,O
+haplotypes,O
+not,O
+transmitted,O
+to,O
+that,O
+child,O
+as,O
+a,O
+control,O
+individual,O
+,,O
+represents,O
+such,O
+a,O
+method,O
+for,O
+estimating,O
+the,O
+relative,O
+risk,O
+of,O
+a,O
+marker,O
+phenotype,O
+.,O
+ , 
+In,O
+the,O
+special,O
+case,O
+of,O
+a,O
+recessive,O
+disease,O
+,,O
+it,O
+was,O
+already,O
+known,O
+that,O
+the,O
+equivalence,O
+of,O
+the,O
+HRR,O
+method,O
+with,O
+the,O
+classical,O
+relative,O
+risk,O
+(,O
+RR,O
+),O
+obtained,O
+from,O
+independent,O
+samples,O
+holds,O
+only,O
+if,O
+the,O
+probability,O
+theta,O
+of,O
+a,O
+recombination,O
+between,O
+marker,O
+and,O
+disease,O
+locus,O
+is,O
+zero,O
+.,O
+ , 
+We,O
+extend,O
+this,O
+result,O
+to,O
+an,O
+arbitrary,O
+mode,O
+of,O
+inheritance,O
+.,O
+ , 
+Furthermore,O
+,,O
+we,O
+compare,O
+the,O
+distribution,O
+of,O
+the,O
+estimators,O
+for,O
+HRR,O
+and,O
+RR,O
+and,O
+show,O
+that,O
+,,O
+in,O
+the,O
+case,O
+of,O
+a,O
+positive,O
+linkage,O
+disequilibrium,O
+between,O
+a,O
+marker,O
+and,O
+disease,O
+allele,O
+,,O
+the,O
+distribution,O
+of,O
+the,O
+estimator,O
+for,O
+HRR,O
+is,O
+(,O
+stochastically,O
+),O
+smaller,O
+than,O
+that,O
+for,O
+RR,O
+,,O
+irrespective,O
+of,O
+the,O
+recombination,O
+fraction,O
+.,O
+ , 
+The,O
+practical,O
+implication,O
+of,O
+this,O
+result,O
+is,O
+that,O
+,,O
+for,O
+the,O
+HRR,O
+method,O
+,,O
+there,O
+is,O
+no,O
+tendency,O
+to,O
+give,O
+unduly,O
+high,O
+risk,O
+estimators,O
+,,O
+even,O
+for,O
+theta,O
+>,O
+0,O
+.,O
+ , 
+Finally,O
+,,O
+we,O
+give,O
+an,O
+expression,O
+for,O
+the,O
+standard,O
+error,O
+of,O
+the,O
+estimator,O
+for,O
+HRR,O
+by,O
+taking,O
+into,O
+account,O
+the,O
+nonindependence,O
+of,O
+transmitted,O
+and,O
+nontransmitted,O
+parental,O
+marker,O
+alleles,O
+in,O
+the,O
+case,O
+of,O
+theta,O
+>,O
+0,O
+.,O
+ , 
+#8829645
+A,O
+66,O
+-,O
+basepair,O
+insertion,O
+in,O
+exon,O
+6,O
+of,O
+the,O
+alpha,B-Gene
+-,I-Gene
+L,I-Gene
+-,I-Gene
+fucosidase,I-Gene
+gene,O
+of,O
+a,O
+fucosidosis,O
+patient,O
+.,O
+ , 
+#15988677
+A,O
+combined,O
+genomewide,O
+linkage,O
+scan,O
+of,O
+1,233,O
+families,O
+for,O
+prostate,O
+cancer,O
+-,O
+susceptibility,O
+genes,O
+conducted,O
+by,O
+the,O
+international,O
+consortium,O
+for,O
+prostate,O
+cancer,O
+genetics,O
+.,O
+ , 
+Evidence,O
+of,O
+the,O
+existence,O
+of,O
+major,O
+prostate,O
+cancer,O
+(,O
+PC)-susceptibility,O
+genes,O
+has,O
+been,O
+provided,O
+by,O
+multiple,O
+segregation,O
+analyses,O
+.,O
+ , 
+Although,O
+genomewide,O
+screens,O
+have,O
+been,O
+performed,O
+in,O
+over,O
+a,O
+dozen,O
+independent,O
+studies,O
+,,O
+few,O
+chromosomal,O
+regions,O
+have,O
+been,O
+consistently,O
+identified,O
+as,O
+regions,O
+of,O
+interest,O
+.,O
+ , 
+One,O
+of,O
+the,O
+major,O
+difficulties,O
+is,O
+genetic,O
+heterogeneity,O
+,,O
+possibly,O
+due,O
+to,O
+multiple,O
+,,O
+incompletely,O
+penetrant,O
+PC,O
+-,O
+susceptibility,O
+genes,O
+.,O
+ , 
+In,O
+this,O
+study,O
+,,O
+we,O
+explored,O
+two,O
+approaches,O
+to,O
+overcome,O
+this,O
+difficulty,O
+,,O
+in,O
+an,O
+analysis,O
+of,O
+a,O
+large,O
+number,O
+of,O
+families,O
+with,O
+PC,O
+in,O
+the,O
+International,O
+Consortium,O
+for,O
+Prostate,O
+Cancer,O
+Genetics,O
+(,O
+ICPCG,O
+),O
+.,O
+ , 
+One,O
+approach,O
+was,O
+to,O
+combine,O
+linkage,O
+data,O
+from,O
+a,O
+total,O
+of,O
+1,233,O
+families,O
+to,O
+increase,O
+the,O
+statistical,O
+power,O
+for,O
+detecting,O
+linkage,O
+.,O
+ , 
+Using,O
+parametric,O
+(,O
+dominant,O
+and,O
+recessive,O
+),O
+and,O
+nonparametric,O
+analyses,O
+,,O
+we,O
+identified,O
+five,O
+regions,O
+with,O
+",O
+suggestive,O
+",O
+linkage,O
+(,O
+LOD,O
+score,O
+>,O
+1.86,O
+):,O
+5q12,O
+,,O
+8p21,O
+,,O
+15q11,O
+,,O
+17q21,O
+,,O
+and,O
+22q12,O
+.,O
+ , 
+The,O
+second,O
+approach,O
+was,O
+to,O
+focus,O
+on,O
+subsets,O
+of,O
+families,O
+that,O
+are,O
+more,O
+likely,O
+to,O
+segregate,O
+highly,O
+penetrant,O
+mutations,O
+,,O
+including,O
+families,O
+with,O
+large,O
+numbers,O
+of,O
+affected,O
+individuals,O
+or,O
+early,O
+age,O
+at,O
+diagnosis,O
+.,O
+ , 
+Stronger,O
+evidence,O
+of,O
+linkage,O
+in,O
+several,O
+regions,O
+was,O
+identified,O
+,,O
+including,O
+a,O
+",O
+significant,O
+",O
+linkage,O
+at,O
+22q12,O
+,,O
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+a,O
+LOD,O
+score,O
+of,O
+3.57,O
+,,O
+and,O
+five,O
+suggestive,O
+linkages,O
+(,O
+1q25,O
+,,O
+8q13,O
+,,O
+13q14,O
+,,O
+16p13,O
+,,O
+and,O
+17q21,O
+),O
+in,O
+269,O
+families,O
+with,O
+at,O
+least,O
+five,O
+affected,O
+members,O
+.,O
+ , 
+In,O
+addition,O
+,,O
+four,O
+additional,O
+suggestive,O
+linkages,O
+(,O
+3p24,O
+,,O
+5q35,O
+,,O
+11q22,O
+,,O
+and,O
+Xq12,O
+),O
+were,O
+found,O
+in,O
+606,O
+families,O
+with,O
+mean,O
+age,O
+at,O
+diagnosis,O
+of,O
+<,O
+or,O
+=,O
+65,O
+years,O
+.,O
+ , 
+Although,O
+it,O
+is,O
+difficult,O
+to,O
+determine,O
+the,O
+true,O
+statistical,O
+significance,O
+of,O
+these,O
+findings,O
+,,O
+a,O
+conservative,O
+interpretation,O
+of,O
+these,O
+results,O
+would,O
+be,O
+that,O
+if,O
+major,O
+PC,O
+-,O
+susceptibility,O
+genes,O
+do,O
+exist,O
+,,O
+they,O
+are,O
+most,O
+likely,O
+located,O
+in,O
+the,O
+regions,O
+generating,O
+suggestive,O
+or,O
+significant,O
+linkage,O
+signals,O
+in,O
+this,O
+large,O
+study,O
+.,O
+ , 
+#20817137
+Exome,O
+sequencing,O
+identifies,O
+WDR35,B-Gene
+variants,O
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+in,O
+Sensenbrenner,O
+syndrome,O
+.,O
+ , 
+Sensenbrenner,O
+syndrome,O
+/,O
+cranioectodermal,O
+dysplasia,O
+(,O
+CED,O
+),O
+is,O
+an,O
+autosomal,O
+-,O
+recessive,O
+disease,O
+that,O
+is,O
+characterized,O
+by,O
+craniosynostosis,O
+and,O
+ectodermal,O
+and,O
+skeletal,O
+abnormalities,O
+.,O
+ , 
+We,O
+sequenced,O
+the,O
+exomes,O
+of,O
+two,O
+unrelated,O
+CED,O
+patients,O
+and,O
+identified,O
+compound,O
+heterozygous,O
+mutations,O
+in,O
+WDR35,B-Gene
+as,O
+the,O
+cause,O
+of,O
+the,O
+disease,O
+in,O
+each,O
+of,O
+the,O
+two,O
+patients,O
+independently,O
+,,O
+showing,O
+that,O
+it,O
+is,O
+possible,O
+to,O
+find,O
+the,O
+causative,O
+gene,O
+by,O
+sequencing,O
+the,O
+exome,O
+of,O
+a,O
+single,O
+sporadic,O
+patient,O
+.,O
+ , 
+With,O
+RT,O
+-,O
+PCR,O
+,,O
+we,O
+demonstrate,O
+that,O
+a,O
+splice,O
+-,O
+site,O
+mutation,O
+in,O
+exon,O
+2,O
+of,O
+WDR35,B-Gene
+alters,O
+splicing,O
+of,O
+RNA,O
+on,O
+the,O
+affected,O
+allele,O
+,,O
+introducing,O
+a,O
+premature,O
+stop,O
+codon,O
+.,O
+ , 
+WDR35,B-Gene
+is,O
+homologous,O
+to,O
+TULP4,B-Gene
+(,O
+from,O
+the,O
+Tubby,O
+superfamily,O
+),O
+and,O
+has,O
+previously,O
+been,O
+characterized,O
+as,O
+an,O
+intraflagellar,O
+transport,O
+component,O
+,,O
+confirming,O
+that,O
+Sensenbrenner,O
+syndrome,O
+is,O
+a,O
+ciliary,O
+disorder,O
+.,O
+ , 
+#20598277
+Terminal,O
+osseous,O
+dysplasia,O
+is,O
+caused,O
+by,O
+a,O
+single,O
+recurrent,O
+mutation,O
+in,O
+the,O
+FLNA,B-Gene
+gene,O
+.,O
+ , 
+Terminal,O
+osseous,O
+dysplasia,O
+(,O
+TOD,O
+),O
+is,O
+an,O
+X,O
+-,O
+linked,O
+dominant,O
+male,O
+-,O
+lethal,O
+disease,O
+characterized,O
+by,O
+skeletal,O
+dysplasia,O
+of,O
+the,O
+limbs,O
+,,O
+pigmentary,O
+defects,O
+of,O
+the,O
+skin,O
+,,O
+and,O
+recurrent,O
+digital,O
+fibroma,O
+with,O
+onset,O
+in,O
+female,O
+infancy,O
+.,O
+ , 
+After,O
+performing,O
+X,O
+-,O
+exome,O
+capture,O
+and,O
+sequencing,O
+,,O
+we,O
+identified,O
+a,O
+mutation,O
+at,O
+the,O
+last,O
+nucleotide,O
+of,O
+exon,O
+31,O
+of,O
+the,O
+FLNA,B-Gene
+gene,O
+as,O
+the,O
+most,O
+likely,O
+cause,O
+of,O
+the,O
+disease,O
+.,O
+ , 
+The,O
+variant,O
+c.5217G,B-SNP
+>,I-SNP
+A,I-SNP
+was,O
+found,O
+in,O
+six,O
+unrelated,O
+cases,O
+(,O
+three,O
+families,O
+and,O
+three,O
+sporadic,O
+cases,O
+),O
+and,O
+was,O
+not,O
+found,O
+in,O
+400,O
+control,O
+X,O
+chromosomes,O
+,,O
+pilot,O
+data,O
+from,O
+the,O
+1000,O
+Genomes,O
+Project,O
+,,O
+or,O
+the,O
+FLNA,B-Gene
+gene,O
+variant,O
+database,O
+.,O
+ , 
+In,O
+the,O
+families,O
+,,O
+the,O
+variant,O
+segregated,O
+with,O
+the,O
+disease,O
+,,O
+and,O
+it,O
+was,O
+transmitted,O
+four,O
+times,O
+from,O
+a,O
+mildly,O
+affected,O
+mother,O
+to,O
+a,O
+more,O
+seriously,O
+affected,O
+daughter,O
+.,O
+ , 
+We,O
+show,O
+that,O
+,,O
+because,O
+of,O
+nonrandom,O
+X,O
+chromosome,O
+inactivation,O
+,,O
+the,O
+mutant,O
+allele,O
+was,O
+not,O
+expressed,O
+in,O
+patient,O
+fibroblasts,O
+.,O
+ , 
+RNA,O
+expression,O
+of,O
+the,O
+mutant,O
+allele,O
+was,O
+detected,O
+only,O
+in,O
+cultured,O
+fibroma,O
+cells,O
+obtained,O
+from,O
+15,O
+-,O
+year,O
+-,O
+old,O
+surgically,O
+removed,O
+material,O
+.,O
+ , 
+The,O
+variant,O
+activates,O
+a,O
+cryptic,O
+splice,O
+site,O
+,,O
+removing,O
+the,O
+last,O
+48,O
+nucleotides,O
+from,O
+exon,O
+31,O
+.,O
+ , 
+At,O
+the,O
+protein,O
+level,O
+,,O
+this,O
+results,O
+in,O
+a,O
+loss,O
+of,O
+16,O
+amino,O
+acids,O
+(,B-SNP
+p.,I-SNP
+Val1724_Thr1739del,I-SNP
+),I-SNP
+,,O
+predicted,O
+to,O
+remove,O
+a,O
+sequence,O
+at,O
+the,O
+surface,O
+of,O
+filamin,O
+repeat,O
+15,O
+.,O
+ , 
+Our,O
+data,O
+show,O
+that,O
+TOD,O
+is,O
+caused,O
+by,O
+this,O
+single,O
+recurrent,O
+mutation,O
+in,O
+the,O
+FLNA,B-Gene
+gene,O
+.,O
+ , 
+#19847796
+Evaluation,O
+of,O
+SNPs,O
+in,O
+miR-146a,O
+,,O
+miR196a2,O
+and,O
+miR-499,O
+as,O
+low,O
+-,O
+penetrance,O
+alleles,O
+in,O
+German,O
+and,O
+Italian,O
+familial,O
+breast,O
+cancer,O
+cases,O
+.,O
+ , 
+Recently,O
+,,O
+the,O
+SNPs,O
+rs11614913,B-RS
+in,O
+hsa,B-Gene
+-,I-Gene
+mir-196a2,I-Gene
+and,O
+rs3746444,B-RS
+in,O
+hsa,B-Gene
+-,I-Gene
+mir-499,I-Gene
+were,O
+reported,O
+to,O
+be,O
+associated,O
+with,O
+increased,O
+breast,O
+cancer,O
+risk,O
+,,O
+and,O
+the,O
+SNP,O
+rs2910164,B-RS
+in,O
+hsa,B-Gene
+-,I-Gene
+mir-146a,I-Gene
+was,O
+shown,O
+to,O
+have,O
+an,O
+effect,O
+on,O
+age,O
+of,O
+breast,O
+cancer,O
+diagnosis,O
+.,O
+ , 
+In,O
+order,O
+to,O
+further,O
+investigate,O
+the,O
+effect,O
+of,O
+these,O
+SNPs,O
+,,O
+we,O
+genotyped,O
+a,O
+total,O
+of,O
+1894,O
+breast,O
+cancer,O
+cases,O
+negative,O
+for,O
+disease,O
+-,O
+causing,O
+mutations,O
+or,O
+unclassified,O
+variants,O
+in,O
+BRCA1,B-Gene
+and,O
+BRCA2,B-Gene
+,,I-Gene
+and,O
+2760,O
+controls,O
+from,O
+Germany,O
+and,O
+Italy,O
+.,O
+ , 
+We,O
+compared,O
+the,O
+genotype,O
+and,O
+allele,O
+frequencies,O
+of,O
+rs2910164,B-RS
+,,I-RS
+rs11614913,B-RS
+and,O
+rs3746444,B-RS
+in,O
+cases,O
+versus,O
+controls,O
+of,O
+the,O
+German,O
+and,O
+Italian,O
+series,O
+,,O
+and,O
+of,O
+the,O
+two,O
+series,O
+combined,O
+;,O
+we,O
+also,O
+investigated,O
+the,O
+effect,O
+of,O
+the,O
+three,O
+SNPs,O
+on,O
+age,O
+at,O
+breast,O
+cancer,O
+diagnosis,O
+.,O
+ , 
+None,O
+of,O
+the,O
+performed,O
+analyses,O
+showed,O
+statistically,O
+significant,O
+results,O
+.,O
+ , 
+In,O
+conclusion,O
+,,O
+our,O
+data,O
+suggested,O
+lack,O
+of,O
+association,O
+between,O
+SNPs,O
+rs2910164,B-RS
+,,I-RS
+rs11614913,B-RS
+and,O
+rs3746444,B-RS
+and,O
+breast,O
+cancer,O
+risk,O
+,,O
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+age,O
+at,O
+breast,O
+cancer,O
+onset,O
+.,O
+ , 
+#8460646
+BRCA1,B-Gene
+maps,O
+proximal,O
+to,O
+D17S579,O
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+chromosome,O
+17q21,O
+by,O
+genetic,O
+analysis,O
+.,O
+ , 
+Previous,O
+studies,O
+have,O
+demonstrated,O
+linkage,O
+between,O
+early,O
+-,O
+onset,O
+breast,O
+cancer,O
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+ovarian,O
+cancer,O
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+genetic,O
+markers,O
+on,O
+chromosome,O
+17q21,O
+.,O
+ , 
+These,O
+markers,O
+define,O
+the,O
+location,O
+of,O
+a,O
+gene,O
+(,B-Gene
+BRCA1,I-Gene
+),I-Gene
+which,O
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+to,O
+be,O
+inherited,O
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+an,O
+autosomal,O
+dominant,O
+susceptibility,O
+allele,O
+.,O
+ , 
+We,O
+analyzed,O
+five,O
+families,O
+with,O
+multiple,O
+affected,O
+individuals,O
+for,O
+evidence,O
+of,O
+linkage,O
+to,O
+the,O
+BRCA1,B-Gene
+region,O
+.,O
+ , 
+Two,O
+of,O
+the,O
+five,O
+families,O
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+to,O
+be,O
+linked,O
+to,O
+BRCA1,B-Gene
+.,I-Gene
+ , 
+One,O
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+linked,O
+family,O
+contains,O
+critical,O
+recombinants,O
+,,O
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+that,O
+the,O
+gene,O
+is,O
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+to,O
+the,O
+marker,O
+D17S579,O
+(,O
+Mfd188,O
+),O
+.,O
+ , 
+These,O
+findings,O
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+consistent,O
+with,O
+the,O
+maximum,O
+-,O
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+position,O
+estimated,O
+by,O
+the,O
+Breast,O
+Cancer,O
+Linkage,O
+Consortium,O
+and,O
+with,O
+recombination,O
+events,O
+detected,O
+in,O
+other,O
+linked,O
+families,O
+.,O
+ , 
+Linkage,O
+analysis,O
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+greatly,O
+aided,O
+by,O
+PCR,O
+-,O
+based,O
+analysis,O
+of,O
+paraffin,O
+-,O
+embedded,O
+normal,O
+breast,O
+tissue,O
+from,O
+deceased,O
+family,O
+members,O
+,,O
+demonstrating,O
+the,O
+feasibility,O
+and,O
+importance,O
+of,O
+this,O
+approach,O
+.,O
+ , 
+One,O
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+the,O
+two,O
+families,O
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+evidence,O
+of,O
+linkage,O
+between,O
+breast,O
+cancer,O
+and,O
+genetic,O
+markers,O
+flanking,O
+BRCA1,B-Gene
+represents,O
+the,O
+first,O
+such,O
+family,O
+of,O
+African,O
+-,O
+American,O
+descent,O
+to,O
+be,O
+reported,O
+in,O
+detail,O
+.,O
+ , 
+#12145742
+Neuregulin,O
+1,O
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+schizophrenia,O
+.,O
+ , 
+The,O
+cause,O
+of,O
+schizophrenia,O
+is,O
+unknown,O
+,,O
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+it,O
+has,O
+a,O
+significant,O
+genetic,O
+component,O
+.,O
+ , 
+Pharmacologic,O
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+gene,O
+expression,O
+in,O
+man,O
+,,O
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+studies,O
+of,O
+mouse,O
+mutants,O
+suggest,O
+involvement,O
+of,O
+glutamate,O
+and,O
+dopamine,O
+neurotransmitter,O
+systems,O
+.,O
+ , 
+However,O
+,,O
+so,O
+far,O
+,,O
+strong,O
+association,O
+has,O
+not,O
+been,O
+found,O
+between,O
+schizophrenia,O
+and,O
+variants,O
+of,O
+the,O
+genes,O
+encoding,O
+components,O
+of,O
+these,O
+systems,O
+.,O
+ , 
+Here,O
+,,O
+we,O
+report,O
+the,O
+results,O
+of,O
+a,O
+genomewide,O
+scan,O
+of,O
+schizophrenia,O
+families,O
+in,O
+Iceland,O
+;,O
+these,O
+results,O
+support,O
+previous,O
+work,O
+,,O
+done,O
+in,O
+five,O
+populations,O
+,,O
+showing,O
+that,O
+schizophrenia,O
+maps,O
+to,O
+chromosome,O
+8p,O
+.,O
+ , 
+Extensive,O
+fine,O
+-,O
+mapping,O
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+8p,O
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+haplotype,O
+-,O
+association,O
+analysis,O
+,,O
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+by,O
+a,O
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+neuregulin,B-Gene
+1,I-Gene
+(,B-Gene
+NRG1,I-Gene
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+.,O
+ , 
+NRG1,B-Gene
+is,O
+expressed,O
+at,O
+central,O
+nervous,O
+system,O
+synapses,O
+and,O
+has,O
+a,O
+clear,O
+role,O
+in,O
+the,O
+expression,O
+and,O
+activation,O
+of,O
+neurotransmitter,O
+receptors,O
+,,O
+including,O
+glutamate,O
+receptors,O
+.,O
+ , 
+Mutant,O
+mice,O
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+either,O
+NRG1,B-Gene
+or,O
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+receptor,O
+,,O
+ErbB4,O
+,,O
+show,O
+a,O
+behavioral,O
+phenotype,O
+that,O
+overlaps,O
+with,O
+mouse,O
+models,O
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+schizophrenia,O
+.,O
+ , 
+Furthermore,O
+,,O
+NRG1,B-Gene
+hypomorphs,O
+have,O
+fewer,O
+functional,O
+NMDA,O
+receptors,O
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+wild,O
+-,O
+type,O
+mice,O
+.,O
+ , 
+We,O
+also,O
+demonstrate,O
+that,O
+the,O
+behavioral,O
+phenotypes,O
+of,O
+the,O
+NRG1,B-Gene
+hypomorphs,O
+are,O
+partially,O
+reversible,O
+with,O
+clozapine,O
+,,O
+an,O
+atypical,O
+antipsychotic,O
+drug,O
+used,O
+to,O
+treat,O
+schizophrenia,O
+.,O
+ , 
+#1570829
+Familial,O
+case,O
+with,O
+sequence,O
+variant,O
+in,O
+the,O
+testis,O
+-,O
+determining,O
+region,O
+associated,O
+with,O
+two,O
+sex,O
+phenotypes,O
+.,O
+ , 
+The,O
+human,O
+Y,O
+chromosome,O
+encodes,O
+a,O
+testis,B-Gene
+-,I-Gene
+determining,I-Gene
+factor,I-Gene
+(,B-Gene
+TDF,I-Gene
+),I-Gene
+which,O
+is,O
+responsible,O
+for,O
+initiating,O
+male,O
+sex,O
+determination,O
+.,O
+ , 
+Recently,O
+a,O
+region,O
+of,O
+the,O
+Y,O
+chromosome,O
+(,B-Gene
+SRY,I-Gene
+),I-Gene
+was,O
+identified,O
+as,O
+part,O
+of,O
+the,O
+TDF,B-Gene
+gene,O
+.,O
+ , 
+We,O
+have,O
+identified,O
+a,O
+three,O
+-,O
+generation,O
+family,O
+(,O
+N,O
+),O
+in,O
+which,O
+all,O
+XY,O
+individuals,O
+have,O
+a,O
+single,O
+base,O
+-,O
+pair,O
+substitution,O
+resulting,O
+in,O
+a,O
+conservative,O
+amino,O
+acid,O
+change,O
+in,O
+the,O
+conserved,O
+domain,O
+of,O
+the,O
+SRY,B-Gene
+open,O
+reading,O
+frame,O
+.,O
+ , 
+Three,O
+individuals,O
+are,O
+XY,O
+sex,O
+-,O
+reversed,O
+females,O
+,,O
+and,O
+two,O
+are,O
+XY,O
+males,O
+.,O
+ , 
+Several,O
+models,O
+are,O
+proposed,O
+to,O
+explain,O
+association,O
+between,O
+a,O
+sequence,O
+variant,O
+in,O
+SRY,B-Gene
+and,O
+two,O
+sex,O
+phenotypes,O
+.,O
+ , 
+#19268277
+Mutations,O
+in,O
+SPATA7,B-Gene
+cause,O
+Leber,O
+congenital,O
+amaurosis,O
+and,O
+juvenile,O
+retinitis,O
+pigmentosa,O
+.,O
+ , 
+Leber,O
+congenital,O
+amaurosis,O
+(,O
+LCA,O
+),O
+and,O
+juvenile,O
+retinitis,O
+pigmentosa,O
+(,O
+RP,O
+),O
+are,O
+the,O
+most,O
+common,O
+hereditary,O
+causes,O
+of,O
+visual,O
+impairment,O
+in,O
+infants,O
+and,O
+children,O
+.,O
+ , 
+Using,O
+homozygosity,O
+mapping,O
+,,O
+we,O
+narrowed,O
+down,O
+the,O
+critical,O
+region,O
+of,O
+the,O
+LCA3,B-Gene
+locus,O
+to,O
+3.8,O
+Mb,O
+between,O
+markers,O
+D14S1022,O
+and,O
+D14S1005,O
+.,O
+ , 
+By,O
+direct,O
+Sanger,O
+sequencing,O
+of,O
+all,O
+genes,O
+within,O
+this,O
+region,O
+,,O
+we,O
+found,O
+a,O
+homozygous,O
+nonsense,O
+mutation,O
+in,O
+the,O
+SPATA7,B-Gene
+gene,O
+in,O
+Saudi,O
+Arabian,O
+family,O
+KKESH-060,O
+.,O
+ , 
+Three,O
+other,O
+loss,O
+-,O
+of,O
+-,O
+function,O
+mutations,O
+were,O
+subsequently,O
+discovered,O
+in,O
+patients,O
+with,O
+LCA,O
+or,O
+juvenile,O
+RP,O
+from,O
+distinct,O
+populations,O
+.,O
+ , 
+Furthermore,O
+,,O
+we,O
+determined,O
+that,O
+Spata7,B-Gene
+is,O
+expressed,O
+in,O
+the,O
+mature,O
+mouse,O
+retina,O
+.,O
+ , 
+Our,O
+findings,O
+reveal,O
+another,O
+human,O
+visual,O
+-,O
+disease,O
+gene,O
+that,O
+causes,O
+LCA,O
+and,O
+juvenile,O
+RP,O
+.,O
+ ,