Word,Tag
#10790217
Detection,O
of,O
point,O
mutations,O
of,O
BCL10,B-Gene
gene,O
in,O
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
the,O
first,O
exon,O
of,O
BCL10,B-Gene
gene,O
;,O
54.3,O
%,O
samples,O
were,O
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
inherited,O
mitochondrial,O
genetic,O
variation,O
can,O
cause,O
human,O
disease,O
,,O
no,O
validated,O
methods,O
exist,O
for,O
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
another,O
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
aimed,O
at,O
discovering,O
associations,O
in,O
meta,O
-,O
analysis,O
of,O
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
multiple,O
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
in,O
order,O
to,O
identify,O
associations,O
with,O
very,O
small,O
effect,O
sizes,O
.,O
 , 
Because,O
the,O
data,O
of,O
a,O
meta,O
-,O
analysis,O
can,O
be,O
heterogeneous,O
,,O
referring,O
to,O
the,O
differences,O
in,O
effect,O
sizes,O
between,O
the,O
collected,O
studies,O
,,O
what,O
is,O
often,O
done,O
in,O
the,O
literature,O
is,O
to,O
apply,O
both,O
the,O
fixed,O
-,O
effects,O
model,O
(,O
FE,O
),O
under,O
an,O
assumption,O
of,O
the,O
same,O
effect,O
size,O
between,O
studies,O
and,O
the,O
random,O
-,O
effects,O
model,O
(,O
RE,O
),O
under,O
an,O
assumption,O
of,O
varying,O
effect,O
size,O
between,O
studies,O
.,O
 , 
However,O
,,O
surprisingly,O
,,O
RE,O
gives,O
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
for,O
the,O
case,O
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
selected,O
sequence,O
variation,O
by,O
incorporating,O
mismatches,O
into,O
melting,O
analysis,O
probes,O
.,O
 , 
Hybridization,O
probe,O
melting,O
analysis,O
can,O
be,O
complicated,O
by,O
the,O
presence,O
of,O
sequence,O
variation,O
(,O
benign,O
polymorphisms,O
or,O
other,O
mutations,O
),O
near,O
the,O
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
or,O
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
/,O
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
 , 
This,O
",O
masking,O
technique,O
",O
was,O
applied,O
to,O
RET,B-Gene
protooncogene,O
and,O
HPA6,B-Gene
mutation,O
detection,O
using,O
unlabeled,O
hybridization,O
probes,O
,,O
a,O
saturating,O
dsDNA,O
dye,O
,,O
and,O
high,O
-,O
resolution,O
melting,O
analysis,O
.,O
 , 
Masking,O
probes,O
clearly,O
distinguished,O
all,O
targeted,O
mutations,O
from,O
polymorphisms,O
when,O
at,O
least,O
1,O
base,O
pair,O
(,O
bp,O
),O
separated,O
the,O
mutation,O
from,O
the,O
masked,O
variation,O
.,O
 , 
We,O
were,O
able,O
to,O
mask,O
polymorphisms,O
immediately,O
adjacent,O
to,O
mutations,O
,,O
except,O
in,O
certain,O
cases,O
,,O
such,O
as,O
those,O
involving,O
single,O
-,O
base,O
deletion,O
probes,O
when,O
both,O
adjacent,O
positions,O
had,O
the,O
same,O
polymorphic,O
nucleotides,O
.,O
 , 
The,O
masking,O
probes,O
can,O
also,O
localize,O
mutations,O
to,O
specific,O
codons,O
or,O
nucleotide,O
positions,O
.,O
 , 
Masking,O
probes,O
can,O
simplify,O
melting,O
analysis,O
of,O
complex,O
regions,O
and,O
eliminate,O
the,O
need,O
for,O
sequencing,O
.,O
 , 
#16252233
High,O
-,O
resolution,O
identification,O
of,O
chromosomal,O
abnormalities,O
using,O
oligonucleotide,O
arrays,O
containing,O
116,204,O
SNPs,O
.,O
 , 
Mutation,O
of,O
the,O
human,O
genome,O
ranges,O
from,O
single,O
base,O
-,O
pair,O
changes,O
to,O
whole,O
-,O
chromosome,O
aneuploidy,O
.,O
 , 
Karyotyping,O
,,O
fluorescence,O
in,O
situ,O
hybridization,O
,,O
and,O
comparative,O
genome,O
hybridization,O
are,O
currently,O
used,O
to,O
detect,O
chromosome,O
abnormalities,O
of,O
clinical,O
significance,O
.,O
 , 
These,O
methods,O
,,O
although,O
powerful,O
,,O
suffer,O
from,O
limitations,O
in,O
speed,O
,,O
ease,O
of,O
use,O
,,O
and,O
resolution,O
,,O
and,O
they,O
do,O
not,O
detect,O
copy,O
-,O
neutral,O
chromosomal,O
aberrations,O
--,O
for,O
example,O
,,O
uniparental,O
disomy,O
(,O
UPD,O
),O
.,O
 , 
We,O
have,O
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
through,O
use,O
of,O
high,O
-,O
density,O
synthetic,O
oligonucleotide,O
arrays,O
containing,O
116,204,O
single,O
-,O
nucleotide,O
polymorphisms,O
,,O
spaced,O
at,O
an,O
average,O
distance,O
of,O
23.6,O
kb,O
across,O
the,O
genome,O
.,O
 , 
Using,O
this,O
approach,O
,,O
we,O
analyzed,O
samples,O
that,O
failed,O
conventional,O
karyotypic,O
analysis,O
,,O
and,O
we,O
detected,O
amplifications,O
and,O
deletions,O
across,O
a,O
wide,O
range,O
of,O
sizes,O
(,O
1.3,O
-,O
145.9,O
Mb,O
),O
,,O
identified,O
chromosomes,O
containing,O
anonymous,O
chromatin,O
,,O
and,O
used,O
genotype,O
data,O
to,O
determine,O
the,O
molecular,O
origin,O
of,O
two,O
cases,O
of,O
UPD,O
.,O
 , 
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
analysis,O
.,O
 , 
The,O
high,O
resolution,O
of,O
our,O
approach,O
provides,O
more,O
-,O
precise,O
breakpoint,O
mapping,O
,,O
which,O
allows,O
subtle,O
phenotypic,O
heterogeneity,O
to,O
be,O
distinguished,O
at,O
a,O
molecular,O
level,O
.,O
 , 
The,O
accurate,O
genotype,O
information,O
provided,O
on,O
these,O
arrays,O
enables,O
the,O
identification,O
of,O
copy,O
-,O
neutral,O
loss,O
-,O
of,O
-,O
heterozygosity,O
events,O
,,O
and,O
the,O
minimal,O
requirement,O
of,O
DNA,O
(,O
250,O
ng,O
per,O
array,O
),O
allows,O
rapid,O
analysis,O
of,O
samples,O
without,O
the,O
need,O
for,O
cell,O
culture,O
.,O
 , 
This,O
technology,O
overcomes,O
many,O
limitations,O
currently,O
encountered,O
in,O
routine,O
clinical,O
diagnostic,O
laboratories,O
tasked,O
with,O
accurate,O
and,O
rapid,O
diagnosis,O
of,O
chromosomal,O
abnormalities,O
.,O
 , 
#18179886
Oncostatin,B-Gene
M,I-Gene
receptor,I-Gene
-,I-Gene
beta,I-Gene
mutations,O
underlie,O
familial,O
primary,O
localized,O
cutaneous,O
amyloidosis,O
.,O
 , 
Familial,O
primary,O
localized,O
cutaneous,O
amyloidosis,O
(,O
FPLCA,O
),O
is,O
an,O
autosomal,O
-,O
dominant,O
disorder,O
associated,O
with,O
chronic,O
skin,O
itching,O
and,O
deposition,O
of,O
epidermal,O
keratin,O
filament,O
-,O
associated,O
amyloid,O
material,O
in,O
the,O
dermis,O
.,O
 , 
FPLCA,O
has,O
been,O
mapped,O
to,O
5p13.1,O
-,O
q11.2,O
,,O
and,O
by,O
candidate,O
gene,O
analysis,O
,,O
we,O
identified,O
missense,O
mutations,O
in,O
the,O
OSMR,B-Gene
gene,O
,,O
encoding,O
oncostatin,B-Gene
M,I-Gene
-,I-Gene
specific,I-Gene
receptor,I-Gene
beta,I-Gene
(,B-Gene
OSMRbeta,I-Gene
),I-Gene
,,O
in,O
three,O
families,O
.,O
 , 
OSMRbeta,B-Gene
is,O
a,O
component,O
of,O
the,O
oncostatin,B-Gene
M,I-Gene
(,I-Gene
OSM,I-Gene
),I-Gene
type,I-Gene
II,I-Gene
receptor,I-Gene
and,O
the,O
interleukin,B-Gene
(,I-Gene
IL)-31,I-Gene
receptor,I-Gene
,,I-Gene
and,O
cultured,O
FPLCA,O
keratinocytes,O
showed,O
reduced,O
activation,O
of,O
Jak,O
/,O
STAT,O
,,O
MAPK,O
,,O
and,O
PI3K,O
/,O
Akt,O
pathways,O
after,O
OSM,B-Gene
or,O
IL-31,B-Gene
cytokine,O
stimulation,O
.,O
 , 
The,O
pathogenic,O
amino,O
acid,O
substitutions,O
are,O
located,O
within,O
the,O
extracellular,O
fibronectin,O
type,O
III,O
-,O
like,O
(,O
FNIII,O
),O
domains,O
,,O
regions,O
critical,O
for,O
receptor,O
dimerization,O
and,O
function,O
.,O
 , 
OSM,B-Gene
and,O
IL-31,B-Gene
signaling,O
have,O
been,O
implicated,O
in,O
keratinocyte,O
cell,O
proliferation,O
,,O
differentiation,O
,,O
apoptosis,O
,,O
and,O
inflammation,O
,,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
mechanisms,O
of,O
skin,O
itching,O
.,O
 , 
#22521416
A,O
truncating,O
mutation,O
of,O
CEP135,B-Gene
causes,O
primary,O
microcephaly,O
and,O
disturbed,O
centrosomal,O
function,O
.,O
 , 
Autosomal,O
-,O
recessive,O
primary,O
microcephaly,O
(,O
MCPH,O
),O
is,O
a,O
rare,O
congenital,O
disorder,O
characterized,O
by,O
intellectual,O
disability,O
,,O
reduced,O
brain,O
and,O
head,O
size,O
,,O
but,O
usually,O
without,O
defects,O
in,O
cerebral,O
cortical,O
architecture,O
,,O
and,O
other,O
syndromic,O
abnormalities,O
.,O
 , 
MCPH,O
is,O
heterogeneous,O
.,O
 , 
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
studied,O
a,O
family,O
from,O
northern,O
Pakistan,O
with,O
two,O
microcephalic,O
children,O
using,O
homozygosity,O
mapping,O
and,O
found,O
suggestive,O
linkage,O
for,O
regions,O
on,O
chromosomes,O
2,O
,,O
4,O
,,O
and,O
9,O
.,O
 , 
We,O
sequenced,O
two,O
positional,O
candidate,O
genes,O
and,O
identified,O
a,O
homozygous,O
frameshift,O
mutation,O
in,O
the,O
gene,O
encoding,O
the,O
135,O
 ,O
kDa,O
centrosomal,O
protein,O
(,B-Gene
CEP135,I-Gene
),I-Gene
,,O
located,O
in,O
the,O
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
corroborated,O
this,O
mutation,O
's,O
identification,O
as,O
the,O
causal,O
variant,O
.,O
 , 
Fibroblasts,O
obtained,O
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
as,O
a,O
cause,O
of,O
heterozygous,O
familial,O
hypercholesterolemia,O
.,O
 , 
A,O
combined,O
deletion,O
/,O
inversion,O
rearrangement,O
of,O
the,O
LDL,B-Gene
receptor,O
gene,O
was,O
discovered,O
in,O
a,O
Finnish,O
patient,O
with,O
heterozygous,O
familial,O
hypercholesterolemia,O
(,O
FH,O
),O
.,O
 , 
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
at,I-SNP
amino,I-SNP
acid,I-SNP
position,I-SNP
538,I-SNP
.,I-SNP
 , 
Analysis,O
of,O
reverse,O
transcriptase,O
-,O
PCR,O
products,O
from,O
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
 , 
#11359216
Mitochondria,O
and,O
the,O
quality,O
of,O
human,O
gametes,O
.,O
 , 
#20052763
Ex,O
vivo,O
splicing,O
assays,O
of,O
mutations,O
at,O
noncanonical,O
positions,O
of,O
splice,O
sites,O
in,O
USHER,B-Gene
genes,O
.,O
 , 
Molecular,O
diagnosis,O
in,O
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
 , 
Aberrant,O
splicing,O
was,O
demonstrated,O
for,O
16,O
of,O
the,O
21,O
(,O
76.2,O
%,O
),O
tested,O
sequence,O
variations,O
.,O
 , 
The,O
mutations,O
resulted,O
more,O
frequently,O
in,O
activation,O
of,O
a,O
nearby,O
cryptic,O
splice,O
site,O
or,O
use,O
of,O
a,O
de,O
novo,O
splice,O
site,O
than,O
exon,O
skipping,O
(,O
37.5,O
%,O
),O
.,O
 , 
This,O
study,O
allowed,O
the,O
reclassification,O
as,O
splicing,O
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
),I-Gene
and,O
four,O
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
),I-SNP
,,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
MYO7A,B-Gene
),I-Gene
,,O
whereas,O
it,O
provided,O
clues,O
about,O
a,O
role,O
in,O
structure,O
/,O
function,O
in,O
four,O
other,O
cases,O
:,O
c.802G,B-SNP
>,I-SNP
 , 
A,B-SNP
(,B-SNP
p.,I-SNP
Gly268Arg,I-SNP
),I-SNP
,,O
c.653T,B-SNP
>,I-SNP
A,I-SNP
(,B-SNP
p.,I-SNP
Val218Glu,I-SNP
),I-SNP
(,B-Gene
USH2A,I-Gene
),I-Gene
,,O
and,O
c.397C,B-SNP
>,I-SNP
T,I-SNP
(,B-SNP
p.,I-SNP
His133Tyr,I-SNP
),I-SNP
,,O
c.3502C,B-SNP
>,I-SNP
T,I-SNP
(,B-SNP
p.,I-SNP
Arg1168Trp,I-SNP
),I-SNP
 , 
(,B-Gene
MYO7A,I-Gene
),I-Gene
.,O
 , 
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
globin,I-Gene
gene,O
mutations,O
and,O
polymorphisms,O
.,O
 , 
We,O
describe,O
a,O
scanning,O
procedure,O
for,O
the,O
detection,O
of,O
beta,O
-,O
globin,O
gene,O
mutations,O
and,O
the,O
prenatal,O
diagnosis,O
of,O
beta,O
-,O
thalassemias,O
.,O
 , 
The,O
method,O
is,O
based,O
on,O
the,O
combined,O
use,O
of,O
PCR,O
and,O
denaturing,O
gradient,O
gel,O
electrophoresis,O
(,O
DGGE,O
),O
of,O
six,O
amplified,O
fragments,O
encompassing,O
the,O
whole,O
beta,O
-,O
globin,O
coding,O
region,O
and,O
splice,O
junctions,O
,,O
as,O
well,O
as,O
the,O
promoter,O
and,O
3,O
',O
untranslated,O
regions,O
.,O
 , 
The,O
whole,O
beta,B-Gene
-,I-Gene
globin,I-Gene
gene,O
can,O
be,O
rapidly,O
scanned,O
for,O
the,O
presence,O
of,O
deleterious,O
mutations,O
.,O
 , 
The,O
proposed,O
diagnostic,O
strategy,O
provides,O
a,O
major,O
improvement,O
over,O
current,O
approaches,O
to,O
beta,B-Gene
-,I-Gene
globin,I-Gene
gene,O
analysis,O
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
individuals,O
belonging,O
to,O
various,O
ethnic,O
or,O
population,O
groups,O
.,O
 , 
The,O
use,O
of,O
this,O
procedure,O
has,O
enabled,O
us,O
to,O
detect,O
six,O
novel,O
sequence,O
changes,O
in,O
the,O
beta,O
-,O
globin,O
gene,O
,,O
including,O
two,O
deleterious,O
mutations,O
and,O
four,O
polymorphisms,O
.,O
 , 
#21565291
Gain,O
-,O
of,O
-,O
function,O
mutations,O
of,O
ARHGAP31,B-Gene
,,I-Gene
a,O
Cdc42,B-Gene
/,B-Gene
Rac1,I-Gene
GTPase,O
regulator,O
,,O
cause,O
syndromic,O
cutis,O
aplasia,O
and,O
limb,O
anomalies,O
.,O
 , 
Regulation,O
of,O
cell,O
proliferation,O
and,O
motility,O
is,O
essential,O
for,O
normal,O
development,O
.,O
 , 
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
membrane,O
trafficking,O
,,O
and,O
cell,O
adhesion,O
.,O
 , 
We,O
investigated,O
a,O
recognized,O
developmental,O
disorder,O
,,O
Adams,O
-,O
Oliver,O
syndrome,O
(,O
AOS,O
),O
,,O
characterized,O
by,O
the,O
combination,O
of,O
aplasia,O
cutis,O
congenita,O
(,O
ACC,O
),O
and,O
 ,O
terminal,O
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
maximum,O
LOD,O
score,O
of,O
4.93,O
at,O
marker,O
rs1464311,O
.,O
 , 
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
,,O
ARHGAP31,B-Gene
,,I-Gene
which,O
encodes,O
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
 , 
These,O
data,O
identify,O
the,O
requirement,O
for,O
regulated,O
Cdc42,B-Gene
and/or,O
Rac1,B-Gene
signaling,O
processes,O
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
of,O
hypertrophic,O
chondrocyte,O
-,O
specific,O
genes,O
during,O
chondrocyte,O
maturation,O
.,O
 , 
#10915611
Rare,O
etiology,O
of,O
autosomal,O
recessive,O
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
be,O
homozygous,O
for,O
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
purported,O
parents,O
were,O
tested,O
,,O
and,O
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
and,O
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
microdeletion,O
.,O
 , 
Sotos,O
syndrome,O
(,O
SoS,O
),O
is,O
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
was,O
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
and,O
DLCR-2B,O
are,O
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
and,O
the,O
DLCR,O
,,O
with,O
a,O
size,O
of,O
of,O
429.8,O
kb,O
,,O
showed,O
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
recombination,O
-,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
average,O
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
was,O
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
the,O
loci,O
,,O
on,O
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
deletion,O
spanning,O
the,O
D15S63,O
locus,O
was,O
identified,O
in,O
five,O
unrelated,O
patients,O
;,O
in,O
each,O
of,O
them,O
the,O
deletion,O
was,O
inherited,O
from,O
a,O
normal,O
parent,O
.,O
 , 
Three,O
of,O
the,O
five,O
families,O
segregating,O
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
who,O
were,O
referred,O
for,O
molecular,O
diagnosis,O
of,O
PWS,O
/,O
AS,O
,,O
of,O
whom,O
89,O
were,O
Ashkenazi,O
and,O
47,O
were,O
of,O
mixed,O
origin,O
(,O
Ashkenazi,O
and,O
non,O
-,O
Ashkenazi,O
Jews,O
),O
.,O
 , 
In,O
the,O
control,O
group,O
,,O
three,O
individuals,O
were,O
carriers,O
of,O
the,O
deletion,O
;,O
among,O
the,O
patients,O
,,O
three,O
were,O
carriers,O
,,O
all,O
of,O
whom,O
were,O
Ashkenazi,O
Jews,O
.,O
 , 
There,O
was,O
no,O
significant,O
difference,O
between,O
the,O
control,O
group,O
and,O
the,O
Ashkenazi,O
patients,O
,,O
indicating,O
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
frequency,O
of,O
the,O
28,O
-,O
kb,O
deletion,O
in,O
the,O
Ashkenazi,O
population,O
was,O
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
the,O
diagnosis,O
of,O
PWS,O
/,O
AS,O
.,O
 , 
#12428213
myotilin,B-Gene
Mutation,O
found,O
in,O
second,O
pedigree,O
with,O
LGMD1A.,B-Gene
Limb,B-Gene
-,I-Gene
girdle,I-Gene
muscular,I-Gene
dystrophy,I-Gene
1A,I-Gene
(,B-Gene
LGMD1A,I-Gene
[,O
MIM,O
159000,O
],O
),O
is,O
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
between,O
D5S519,O
(,O
proximal,O
),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
is,O
associated,O
with,O
fetal,O
growth,O
.,O
 , 
Fetal,O
growth,O
restriction,O
(,O
FGR,O
),O
affects,O
>,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
 , 
Subsequently,O
,,O
we,O
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
FGR,O
was,O
observed,O
in,O
this,O
sample,O
.,O
 , 
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
underlying,O
Hurler,O
syndrome,O
(,O
mucopolysaccharidosis,O
IH,O
),O
in,O
Druze,O
and,O
Muslim,O
Israeli,O
Arab,O
patients,O
have,O
been,O
characterized,O
.,O
 , 
Four,O
alleles,O
were,O
identified,O
,,O
using,O
a,O
combination,O
of,O
(,O
a,O
),O
PCR,O
amplification,O
of,O
reverse,O
-,O
transcribed,O
RNA,O
or,O
genomic,O
DNA,O
segments,O
,,O
(,O
b,O
),O
cycle,O
sequencing,O
of,O
PCR,O
products,O
,,O
and,O
(,O
c,O
),O
restriction,O
-,O
enzyme,O
analysis,O
.,O
 , 
One,O
allele,O
has,O
two,O
amino,O
acid,O
substitutions,O
,,O
Gly409,B-SNP
-,I-SNP
->Arg,I-SNP
in,O
exon,O
9,O
and,O
Ter-->Cys,O
in,O
exon,O
14,O
.,O
 , 
The,O
other,O
three,O
alleles,O
have,O
mutations,O
in,O
exon,O
2,O
(,B-SNP
Tyr64,I-SNP
-,I-SNP
->Ter,I-SNP
),I-SNP
,,O
exon,O
7,O
(,B-SNP
Gln310,I-SNP
-,I-SNP
->Ter,I-SNP
),I-SNP
,,O
or,O
exon,O
8,O
(,B-SNP
Thr366,I-SNP
-,I-SNP
->Pro,I-SNP
),I-SNP
.,O
 , 
Transfection,O
of,O
mutagenized,O
cDNAs,O
into,O
Cos-1,O
cells,O
showed,O
that,O
two,O
missense,O
mutations,O
,,O
Thr366,B-SNP
-,I-SNP
->Pro,I-SNP
and,O
Ter-->Cys,O
,,O
permitted,O
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
anticipated,O
from,O
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
 , 
Since,O
such,O
clustering,O
suggests,O
a,O
classic,O
founder,O
effect,O
,,O
the,O
presence,O
of,O
three,O
mutant,O
alleles,O
of,O
the,O
IDUA,B-Gene
gene,O
was,O
unexpected,O
.,O
 , 
#10762557
Complement,B-Gene
factor,I-Gene
H,I-Gene
gene,O
mutation,O
associated,O
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
methylmalonic,O
aciduria,O
:,O
identification,O
of,O
five,O
novel,O
mutations,O
.,O
 , 
Mutase,O
-,O
deficient,O
(,O
MUT,O
),O
methylmalonic,O
aciduria,O
(,O
MMA,O
),O
is,O
an,O
autosomal,O
recessive,O
inborn,O
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
mutase,O
(,O
MCM,O
),O
(,O
EC.5.4.99.2,O
),O
.,O
 , 
The,O
enzyme,O
requires,O
5'-deoxyadenosylcobalamin,O
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
thiolase,I-Gene
gene,O
:,O
a,O
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
 , 
The,O
report,O
of,O
the,O
2006,O
Human,O
Variome,O
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
 , 
Based,O
on,O
statistical,O
parameters,O
280,O
of,O
these,O
have,O
been,O
denominated,O
candidate,O
cancer,O
(,O
CAN,O
),O
genes,O
.,O
 , 
This,O
analysis,O
has,O
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
,,I-Gene
MYO18B,B-Gene
,,I-Gene
NAV3,B-Gene
and,O
MMP2,B-Gene
),I-Gene
were,O
also,O
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
wide,O
mutational,O
profiling,O
will,O
be,O
required,O
to,O
identify,O
',O
hill,O
',O
type,O
CAN,B-Gene
genes,O
that,O
characterize,O
the,O
genomic,O
landscapes,O
of,O
each,O
cancer,O
lineage,O
.,O
 , 
#19559399
Loss,O
-,O
of,O
-,O
function,O
mutation,O
in,O
the,O
dioxygenase,O
-,O
encoding,O
FTO,B-Gene
gene,O
causes,O
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
 , 
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
polymalformation,O
syndrome,O
.,O
 , 
#8079996
Design,O
and,O
sample,O
-,O
size,O
considerations,O
in,O
the,O
detection,O
of,O
linkage,O
disequilibrium,O
with,O
a,O
disease,O
locus,O
.,O
 , 
The,O
presence,O
of,O
linkage,O
disequilibrium,O
between,O
closely,O
linked,O
loci,O
can,O
aid,O
in,O
the,O
fine,O
mapping,O
of,O
disease,O
loci,O
.,O
 , 
We,O
investigate,O
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
heritable,O
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
were,O
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
chondrodysplasia,O
but,O
were,O
polymorphic,O
in,O
nature,O
.,O
 , 
The,O
sequence,O
changes,O
were,O
used,O
to,O
demonstrate,O
discordant,O
segregation,O
between,O
the,O
COL10A1,B-Gene
locus,O
and,O
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
with,O
intermediate,O
motor,O
nerve,O
conduction,O
velocities,O
:,O
characterization,O
of,O
14,O
Cx32,B-Gene
mutations,O
in,O
35,O
families,O
.,O
 , 
Charcot,O
-,O
Marie,O
-,O
Tooth,O
disease,O
can,O
be,O
inherited,O
either,O
autosomal,O
dominantly,O
or,O
recessively,O
or,O
linked,O
to,O
the,O
X,O
chromosome,O
.,O
 , 
X,O
-,O
linked,O
dominant,O
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
and,O
decreased,O
nerve,O
conduction,O
velocities,O
than,O
do,O
females,O
.,O
 , 
CMTX,O
is,O
usually,O
associated,O
with,O
mutations,O
in,O
exon,O
2,O
of,O
the,O
connexin,B-Gene
32,I-Gene
(,B-Gene
Cx32,I-Gene
),I-Gene
gene,O
.,O
 , 
DNA,O
from,O
35,O
unrelated,O
CMT,O
patients,O
,,O
without,O
the,O
17p11.2,O
duplication,O
,,O
but,O
with,O
median,O
nerve,O
conduction,O
between,O
30,O
and,O
40,O
m,O
/,O
s,O
,,O
were,O
tested,O
for,O
the,O
presence,O
of,O
Cx32,B-Gene
mutations,O
.,O
 , 
The,O
entire,O
coding,O
sequence,O
of,O
the,O
Cx32,B-Gene
gene,O
was,O
explored,O
using,O
a,O
rapid,O
nonradioactive,O
technique,O
to,O
detect,O
single,O
-,O
strand,O
conformation,O
polymorphisms,O
(,O
SSCP,O
),O
on,O
large,O
PCR,O
fragments,O
.,O
 , 
Thirteen,O
abnormal,O
SSCP,O
profiles,O
were,O
detected,O
and,O
characterized,O
by,O
sequencing,O
.,O
 , 
In,O
addition,O
,,O
systematic,O
sequencing,O
of,O
the,O
entire,O
Cx32,B-Gene
coding,O
region,O
in,O
the,O
remaining,O
index,O
cases,O
revealed,O
another,O
mutation,O
that,O
was,O
not,O
detected,O
by,O
SSCP,O
.,O
 , 
A,O
total,O
of,O
14,O
mutations,O
were,O
found,O
,,O
five,O
of,O
which,O
were,O
not,O
previously,O
reported,O
.,O
 , 
These,O
results,O
demonstrate,O
the,O
high,O
frequency,O
(,O
40,O
%,O
),O
of,O
mutations,O
in,O
the,O
coding,O
region,O
of,O
the,O
Cx32,B-Gene
gene,O
in,O
CMT,O
patients,O
with,O
intermediate,O
MNCV,O
,,O
without,O
17p11.2,O
duplications,O
.,O
 , 
Most,O
of,O
these,O
mutations,O
(,O
93,O
%,O
),O
can,O
be,O
detected,O
by,O
SSCP,O
.,O
 , 
#12687502
Preferential,O
paternal,O
origin,O
of,O
microdeletions,O
caused,O
by,O
prezygotic,O
chromosome,O
or,O
chromatid,O
rearrangements,O
in,O
Sotos,O
syndrome,O
.,O
 , 
Sotos,O
syndrome,O
(,O
SoS,O
),O
is,O
characterized,O
by,O
pre-,O
and,O
postnatal,O
overgrowth,O
with,O
advanced,O
bone,O
age,O
;,O
a,O
dysmorphic,O
face,O
with,O
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
had,O
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
of,O
16,O
microsatellite,O
markers,O
at,O
or,O
flanking,O
the,O
commonly,O
deleted,O
region,O
.,O
 , 
Deletions,O
in,O
18,O
of,O
the,O
20,O
informative,O
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
and,O
two,O
unaffected,O
parents,O
who,O
are,O
distant,O
relatives,O
(,O
fifth,O
degree,O
),O
.,O
 , 
All,O
family,O
members,O
were,O
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
of,O
the,O
coding,O
region,O
of,O
the,O
COL9A1,B-Gene
gene,O
showed,O
a,O
homozygous,O
R295X,B-SNP
mutation,O
in,O
the,O
four,O
affected,O
children,O
.,O
 , 
The,O
parents,O
and,O
four,O
unaffected,O
children,O
were,O
heterozygous,O
carriers,O
of,O
the,O
R295X,B-SNP
mutation,O
.,O
 , 
Two,O
unaffected,O
children,O
were,O
homozygous,O
for,O
the,O
wild,O
-,O
type,O
allele,O
.,O
 , 
None,O
of,O
the,O
family,O
members,O
except,O
the,O
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
the,O
fourth,O
identified,O
gene,O
that,O
can,O
cause,O
Stickler,O
syndrome,O
.,O
 , 
In,O
contrast,O
to,O
the,O
three,O
previously,O
reported,O
Stickler,O
syndrome,O
-,O
causing,O
genes,O
,,O
this,O
gene,O
causes,O
a,O
form,O
of,O
Stickler,O
syndrome,O
with,O
an,O
autosomal,O
recessive,O
inheritance,O
pattern,O
.,O
 , 
This,O
finding,O
will,O
have,O
a,O
major,O
impact,O
on,O
the,O
genetic,O
counseling,O
of,O
patients,O
with,O
Stickler,O
syndrome,O
and,O
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
],O
),O
are,O
associated,O
with,O
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
have,O
been,O
observed,O
in,O
patients,O
with,O
CS,O
and,O
BRRS,O
,,O
as,O
well,O
as,O
in,O
patients,O
with,O
incomplete,O
features,O
of,O
CS,O
,,O
referred,O
to,O
as,O
CS,O
-,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
or,O
BRRS,O
.,O
 , 
Interestingly,O
,,O
we,O
observed,O
differential,O
expression,O
of,O
miR-19a,O
and,O
miR-21,O
in,O
our,O
PTEN,O
-,O
mutation,O
-,O
positive,O
patients,O
.,O
 , 
Both,O
were,O
found,O
to,O
be,O
significantly,O
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
and,O
decreased,O
full,O
-,O
length,O
PTEN,B-Gene
protein,O
expression,O
.,O
 , 
Among,O
PTEN,O
-,O
mutation,O
-,O
positive,O
patients,O
with,O
CS,O
,,O
both,O
miRNAs,O
were,O
significantly,O
overexpressed,O
(,O
p,O
=,O
0.006,O
-,O
0.013,O
),O
.,O
 , 
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
and,O
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
.,O
 , 
Complete,O
laminin,B-Gene
alpha2,I-Gene
(,B-Gene
LAMA2,I-Gene
),I-Gene
deficiency,O
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
and,O
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
alpha2,O
mRNA,O
from,O
patient,O
muscle,O
biopsy,O
by,O
direct,O
capillary,O
automated,O
sequencing,O
,,O
single,O
strand,O
conformational,O
polymorphism,O
(,O
SSCP,O
),O
,,O
or,O
denaturing,O
high,O
performance,O
liquid,O
chromatography,O
(,O
DHPLC,O
),O
of,O
overlapping,O
RT,O
-,O
PCR,O
products,O
followed,O
by,O
direct,O
sequencing,O
of,O
heteroduplexes,O
.,O
 , 
We,O
identified,O
laminin,O
alpha2,B-Gene
sequence,O
changes,O
in,O
six,O
of,O
nine,O
CMD,O
patients,O
.,O
 , 
Each,O
of,O
the,O
gene,O
changes,O
identified,O
,,O
except,O
one,O
,,O
was,O
novel,O
,,O
including,O
three,O
missense,O
changes,O
and,O
two,O
splice,O
-,O
site,O
mutations,O
.,O
 , 
The,O
finding,O
of,O
partial,O
laminin,O
alpha2,B-Gene
deficiency,O
by,O
immunostaining,O
is,O
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
showing,O
clear,O
causative,O
mutations,O
,,O
and,O
an,O
additional,O
three,O
patients,O
(,O
33,O
%,O
),O
showing,O
possible,O
mutations,O
.,O
 , 
The,O
clinical,O
presentation,O
and,O
disease,O
progression,O
was,O
homogeneous,O
in,O
the,O
laminin,O
alpha2,B-Gene
-,I-Gene
mutation,O
positive,O
and,O
negative,O
CMD,O
patients,O
.,O
 , 
#7550232
Four,O
novel,O
mutations,O
underlying,O
mild,O
or,O
intermediate,O
forms,O
of,O
alpha,O
-,O
L,O
-,O
iduronidase,O
deficiency,O
(,O
MPS,O
IS,O
and,O
MPS,O
IH,O
/,O
S,O
),O
.,O
 , 
The,O
alpha,O
-,O
L,O
-,O
iduronidase,O
deficiency,O
diseases,O
(,O
Mucopolysaccharidosis,O
I,O
),O
cover,O
a,O
spectrum,O
of,O
clinical,O
severity,O
ranging,O
from,O
the,O
very,O
severe,O
(,O
Hurler,O
syndrome,O
,,O
MPS,O
IH,O
),O
through,O
an,O
intermediate,O
(,O
Hurler,O
/,O
Scheie,O
syndrome,O
,,O
MPS,O
IH,O
/,O
S,O
),O
to,O
a,O
relatively,O
mild,O
form,O
(,O
Scheie,O
syndrome,O
,,O
MPS,O
IS,O
),O
.,O
 , 
Numerous,O
mutations,O
of,O
the,O
gene,O
encoding,O
alpha,O
-,O
L,O
-,O
iduronidase,O
(,O
IDUA,O
),O
are,O
known,O
in,O
Hurler,O
syndrome,O
,,O
but,O
only,O
three,O
in,O
the,O
other,O
disorders,O
.,O
 , 
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
syndrome,O
and,O
in,O
three,O
patients,O
with,O
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
TNFRSF13B,B-Gene
,,I-Gene
IKBKG,B-Gene
,,I-Gene
AICDA,B-Gene
,,I-Gene
as,O
well,O
as,O
rare,O
nucleotide,O
changes,O
in,O
other,O
genes,O
such,O
as,O
TRAF3IP2,B-Gene
,,I-Gene
were,O
identified,O
in,O
patient,O
DNA,O
samples,O
and,O
validated,O
by,O
direct,O
sequencing,O
.,O
 , 
We,O
conclude,O
that,O
the,O
Hyper,O
-,O
IgM,O
/,O
CVID,O
chip,O
combined,O
with,O
SNP,O
Explorer,O
may,O
provide,O
a,O
cost,O
-,O
effective,O
tool,O
for,O
high,O
-,O
throughput,O
discovery,O
of,O
novel,O
mutations,O
among,O
hundreds,O
of,O
disease,O
-,O
relevant,O
genes,O
in,O
patients,O
with,O
inherited,O
antibody,O
deficiency,O
.,O
 , 
#11295840
Identification,O
of,O
a,O
novel,O
de,O
novo,O
mutation,O
(,B-SNP
G373D,I-SNP
),I-SNP
in,O
the,O
alpha,B-Gene
-,I-Gene
galactosidase,I-Gene
A,I-Gene
gene,O
(,B-Gene
GLA,I-Gene
),I-Gene
in,O
a,O
patient,O
affected,O
with,O
Fabry,O
disease,O
.,O
 , 
#11156534
A,O
novel,O
syndrome,O
affecting,O
multiple,O
mitochondrial,O
functions,O
,,O
located,O
by,O
microcell,O
-,O
mediated,O
transfer,O
to,O
chromosome,O
2p14,O
-,O
2p13,O
.,O
 , 
We,O
have,O
studied,O
cultured,O
skin,O
fibroblasts,O
from,O
three,O
siblings,O
and,O
one,O
unrelated,O
individual,O
,,O
all,O
of,O
whom,O
had,O
fatal,O
mitochondrial,O
disease,O
manifesting,O
soon,O
after,O
birth,O
.,O
 , 
After,O
incubation,O
with,O
1,O
mM,O
glucose,O
,,O
these,O
four,O
cell,O
strains,O
exhibited,O
lactate,O
/,O
pyruvate,O
ratios,O
that,O
were,O
six,O
times,O
greater,O
than,O
those,O
of,O
controls,O
.,O
 , 
On,O
further,O
analysis,O
,,O
enzymatic,O
activities,O
of,O
the,O
pyruvate,O
dehydrogenase,O
complex,O
,,O
the,O
2,O
-,O
oxoglutarate,O
dehydrogenase,O
complex,O
,,O
NADH,O
cytochrome,O
c,O
reductase,O
,,O
succinate,O
dehydrogenase,O
,,O
and,O
succinate,O
cytochrome,O
c,O
reductase,O
were,O
severely,O
deficient,O
.,O
 , 
In,O
two,O
of,O
the,O
siblings,O
the,O
enzymatic,O
activity,O
of,O
cytochrome,O
oxidase,O
was,O
mildly,O
decreased,O
(,O
by,O
approximately,O
50,O
%,O
),O
.,O
 , 
Metabolite,O
analysis,O
performed,O
on,O
urine,O
samples,O
taken,O
from,O
these,O
patients,O
revealed,O
high,O
levels,O
of,O
glycine,O
,,O
leucine,O
,,O
valine,O
,,O
and,O
isoleucine,O
,,O
indicating,O
abnormalities,O
of,O
both,O
the,O
glycine,O
-,O
cleavage,O
system,O
and,O
branched,O
-,O
chain,O
alpha,O
-,O
ketoacid,O
dehydrogenase,O
.,O
 , 
In,O
contrast,O
,,O
the,O
activities,O
of,O
fibroblast,O
pyruvate,O
carboxylase,O
,,O
mitochondrial,O
aconitase,O
,,O
and,O
citrate,O
synthase,O
were,O
normal,O
.,O
 , 
Immunoblot,O
analysis,O
of,O
selected,O
complex,O
III,O
subunits,O
(,O
core,O
1,O
,,O
cyt,O
c(1,O
),O
,,O
and,O
iron,O
-,O
sulfur,O
protein,O
),O
and,O
of,O
the,O
pyruvate,O
dehydrogenase,O
complex,O
subunits,O
revealed,O
no,O
visible,O
changes,O
in,O
the,O
levels,O
of,O
all,O
examined,O
proteins,O
,,O
decreasing,O
the,O
possibility,O
that,O
an,O
import,O
and/or,O
assembly,O
factor,O
is,O
involved,O
.,O
 , 
To,O
elucidate,O
the,O
underlying,O
molecular,O
defect,O
,,O
analysis,O
of,O
microcell,O
-,O
mediated,O
chromosome,O
-,O
fusion,O
was,O
performed,O
between,O
the,O
present,O
study,O
's,O
fibroblasts,O
(,O
recipients,O
),O
and,O
a,O
panel,O
of,O
A9,O
mouse,O
:,O
human,O
hybrids,O
(,O
donors,O
),O
developed,O
by,O
Cuthbert,O
et,O
al,O
.,O
(,O
1995,O
),O
.,O
 , 
Complementation,O
was,O
observed,O
between,O
the,O
recipient,O
cells,O
from,O
both,O
families,O
and,O
the,O
mouse,O
:,O
human,O
hybrid,O
clone,O
carrying,O
human,O
chromosome,O
2,O
.,O
 , 
These,O
results,O
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
the,O
locus,O
of,O
which,O
is,O
on,O
chromosome,O
2,O
.,O
 , 
A,O
5,O
-,O
cM,O
interval,O
has,O
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
to,O
region,O
2p14,O
-,O
2p13,O
.,O
 , 
#8956047
A,O
new,O
mutation,O
(,B-Gene
LIPA,I-Gene
Tyr22X,B-SNP
),I-SNP
of,O
lysosomal,B-Gene
acid,I-Gene
lipase,I-Gene
gene,O
in,O
a,O
Japanese,O
patient,O
with,O
Wolman,O
disease,O
.,O
 , 
#17594715
Spectrum,O
of,O
ALMS1,B-Gene
variants,O
and,O
evaluation,O
of,O
genotype,O
-,O
phenotype,O
correlations,O
in,O
Alström,O
syndrome,O
.,O
 , 
Alström,O
syndrome,O
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
childhood,O
obesity,O
,,O
diabetes,O
mellitus,O
,,O
dilated,O
cardiomyopathy,O
(,O
DCM,O
),O
,,O
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
of,O
which,O
55,O
are,O
novel,O
mutations,O
.,O
 , 
The,O
variants,O
are,O
primarily,O
clustered,O
in,O
exons,O
8,O
,,O
10,O
,,O
and,O
16,O
,,O
although,O
we,O
also,O
identified,O
novel,O
mutations,O
in,O
exons,O
12,O
and,O
18,O
.,O
 , 
Most,O
alleles,O
were,O
identified,O
only,O
once,O
(,O
45/79,O
),O
,,O
but,O
several,O
were,O
found,O
recurrently,O
.,O
 , 
Founder,O
effects,O
are,O
likely,O
in,O
families,O
of,O
English,O
and,O
Turkish,O
descent,O
.,O
 , 
We,O
also,O
identified,O
66,O
SNPs,O
and,O
assessed,O
the,O
functional,O
significance,O
of,O
these,O
variants,O
based,O
on,O
the,O
conserved,O
identity,O
of,O
the,O
protein,O
and,O
the,O
severity,O
of,O
the,O
resulting,O
amino,O
acid,O
substitution,O
.,O
 , 
A,O
genotype,O
-,O
phenotype,O
association,O
study,O
examining,O
18,O
phenotypic,O
parameters,O
in,O
a,O
subset,O
of,O
58,O
patients,O
found,O
suggestive,O
associations,O
between,O
disease,O
-,O
causing,O
variants,O
in,O
exon,O
16,O
and,O
the,O
onset,O
of,O
retinal,O
degeneration,O
before,O
the,O
age,O
of,O
1,O
year,O
(,O
P,O
=,O
0.02,O
),O
,,O
the,O
occurrence,O
of,O
urological,O
dysfunction,O
(,O
P,O
=,O
0.02,O
),O
,,O
of,O
DCM,O
(,O
P,O
=,O
0.03,O
),O
,,O
and,O
of,O
diabetes,O
(,O
P,O
=,O
0.03,O
),O
.,O
 , 
A,O
significant,O
association,O
was,O
found,O
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
.,O
 , 
This,O
data,O
may,O
have,O
implications,O
for,O
the,O
understanding,O
of,O
the,O
molecular,O
mechanisms,O
of,O
ALMS1,O
and,O
provides,O
the,O
basis,O
for,O
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
mild,O
neurofibromatosis,O
type,O
1,O
phenotype,O
produced,O
by,O
the,O
combination,O
of,O
the,O
benign,O
nature,O
of,O
a,O
leaky,O
NF1,B-Gene
-,I-Gene
splice,O
mutation,O
and,O
the,O
presence,O
of,O
a,O
complex,O
mosaicism,O
.,O
 , 
Here,O
we,O
analyze,O
the,O
genetic,O
and,O
molecular,O
basis,O
responsible,O
for,O
a,O
very,O
benign,O
phenotype,O
observed,O
in,O
an,O
NF1,O
patient,O
.,O
 , 
Quantification,O
of,O
cells,O
carrying,O
the,O
NF1,B-Gene
mutation,O
in,O
different,O
samples,O
derived,O
from,O
the,O
three,O
embryonic,O
layers,O
revealed,O
mosaicism,O
.,O
 , 
Furthermore,O
,,O
the,O
construction,O
of,O
a,O
minigene,O
with,O
patient,O
's,O
mutation,O
(,B-SNP
c.3198,I-SNP
-,I-SNP
314G,I-SNP
>,I-SNP
A,I-SNP
),I-SNP
confirmed,O
its,O
benign,O
nature,O
due,O
to,O
the,O
leakiness,O
of,O
the,O
splicing,O
mechanism,O
that,O
generated,O
a,O
proportion,O
of,O
correctly,O
spliced,O
transcripts,O
.,O
 , 
Hence,O
,,O
we,O
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
nature,O
of,O
a,O
leaky,O
NF1,B-Gene
-,I-Gene
splice,O
mutation,O
.,O
 , 
Finally,O
,,O
with,O
the,O
aim,O
of,O
developing,O
a,O
personalized,O
therapeutic,O
approach,O
for,O
this,O
patient,O
,,O
we,O
demonstrated,O
correction,O
of,O
the,O
splicing,O
defect,O
by,O
using,O
specific,O
antisense,O
morpholino,O
oligomers,O
.,O
 , 
Our,O
results,O
provide,O
an,O
example,O
of,O
the,O
molecular,O
complexity,O
behind,O
disease,O
phenotypes,O
and,O
highlight,O
the,O
importance,O
of,O
using,O
comprehensive,O
genetic,O
approaches,O
to,O
better,O
assess,O
phenotype,O
-,O
genotype,O
correlations,O
.,O
 , 
#15386213
Statistical,O
tests,O
for,O
admixture,O
mapping,O
with,O
case,O
-,O
control,O
and,O
cases,O
-,O
only,O
data,O
.,O
 , 
Admixture,O
mapping,O
is,O
a,O
promising,O
new,O
tool,O
for,O
discovering,O
genes,O
that,O
contribute,O
to,O
complex,O
traits,O
.,O
 , 
This,O
mapping,O
approach,O
uses,O
samples,O
from,O
recently,O
admixed,O
populations,O
to,O
detect,O
susceptibility,O
loci,O
at,O
which,O
the,O
risk,O
alleles,O
have,O
different,O
frequencies,O
in,O
the,O
original,O
contributing,O
populations,O
.,O
 , 
Although,O
the,O
idea,O
for,O
admixture,O
mapping,O
has,O
been,O
around,O
for,O
more,O
than,O
a,O
decade,O
,,O
the,O
genomic,O
tools,O
are,O
only,O
now,O
becoming,O
available,O
to,O
make,O
this,O
a,O
feasible,O
and,O
attractive,O
option,O
for,O
complex,O
-,O
trait,O
mapping,O
.,O
 , 
In,O
this,O
article,O
,,O
we,O
describe,O
new,O
statistical,O
methods,O
for,O
analyzing,O
multipoint,O
data,O
from,O
admixture,O
-,O
mapping,O
studies,O
to,O
detect,O
",O
ancestry,O
association,O
.,O
",O
 , 
The,O
new,O
test,O
statistics,O
do,O
not,O
assume,O
a,O
particular,O
disease,O
model,O
;,O
instead,O
,,O
they,O
are,O
based,O
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
the,O
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
informative,O
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
,,O
random,O
SNPs,O
can,O
perform,O
quite,O
well,O
when,O
AIMs,O
are,O
not,O
available,O
.,O
 , 
Hence,O
,,O
researchers,O
who,O
study,O
admixed,O
populations,O
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
either,O
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
frequent,O
causes,O
of,O
LCA,O
identified,O
so,O
far,O
.,O
 , 
#15154117
A,O
common,O
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
is,O
associated,O
with,O
vulnerability,O
to,O
nicotine,O
addiction,O
in,O
men,O
.,O
 , 
Nicotine,O
is,O
the,O
major,O
addictive,O
substance,O
in,O
cigarettes,O
,,O
and,O
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
the,O
CHRNA4,B-Gene
gene,O
and,O
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
with,O
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
and,O
the,O
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
men,O
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
were,O
significantly,O
associated,O
with,O
a,O
protective,O
effect,O
against,O
nicotine,O
addiction,O
as,O
either,O
a,O
dichotomized,O
trait,O
or,O
a,O
quantitative,O
phenotype,O
(,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
specific,O
FBAT,O
showed,O
a,O
common,O
(,O
22.5,O
%,O
),O
CHRNA4,B-Gene
haplotype,O
,,O
GCTATA,O
,,O
which,O
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
homozygosity,O
mapping,O
.,O
 , 
Familial,O
hemophagocytic,O
lymphohistiocytosis,O
(,O
FHL,O
),O
,,O
also,O
known,O
as,O
familial,O
erythrophagocytic,O
lymphohistiocytosis,O
and,O
familial,O
histiocytic,O
reticulosis,O
,,O
is,O
a,O
rare,O
autosomal,O
recessive,O
disorder,O
of,O
early,O
childhood,O
characterized,O
by,O
excessive,O
immune,O
activation,O
.,O
 , 
Linkage,O
of,O
the,O
disease,O
gene,O
to,O
an,O
approximately,O
7.8,O
-,O
cM,O
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
described,O
in,O
FHL,O
.,O
 , 
However,O
,,O
homozygosity,O
by,O
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
whose,O
maximum,O
multipoint,O
LOD,O
score,O
was,O
-0.12,O
.,O
 , 
The,O
combined,O
sample,O
revealed,O
significant,O
evidence,O
for,O
linkage,O
to,O
9q,O
markers,O
(,O
LOD,O
score,O
with,O
heterogeneity,O
,,O
5.00,O
),O
.,O
 , 
Identification,O
of,O
the,O
gene(s,O
),O
involved,O
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
and,O
macrophage,O
activation,O
,,O
which,O
is,O
central,O
to,O
homeostasis,O
in,O
the,O
immune,O
system,O
.,O
 , 
#8430703
The,O
postulated,O
X,O
-,O
inactivation,O
center,O
at,O
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
powerful,O
means,O
of,O
detecting,O
unbalanced,O
X,O
inactivation,O
.,O
 , 
#8723680
Characterization,O
of,O
two,O
arylsulfatase,B-Gene
A,I-Gene
missense,O
mutations,O
D335V,B-SNP
and,O
T274,B-SNP
M,I-SNP
causing,O
late,O
infantile,O
metachromatic,O
leukodystrophy,O
.,O
 , 
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,B-Gene
A.,I-Gene
We,O
describe,O
a,O
novel,O
missense,O
mutation,O
in,O
exon,O
6,O
causing,O
the,O
substitution,O
of,O
Asp335,B-SNP
by,I-SNP
Val,I-SNP
.,I-SNP
 , 
In,O
transient,O
transfections,O
no,O
enzyme,O
activity,O
could,O
be,O
expressed,O
from,O
the,O
arylsulfatase,O
A,O
cDNA,O
carrying,O
this,O
mutation,O
.,O
 , 
Examination,O
of,O
the,O
effects,O
of,O
the,O
mutation,O
in,O
cells,O
stably,O
overexpressing,O
the,O
mutant,O
enzyme,O
revealed,O
,,O
that,O
the,O
mutant,O
enzyme,O
is,O
catalytically,O
inactive,O
and,O
degraded,O
in,O
an,O
early,O
biosynthetic,O
compartment,O
.,O
 , 
We,O
have,O
also,O
investigated,O
the,O
effects,O
of,O
a,O
previously,O
identified,O
mutation,O
(,B-SNP
T274,I-SNP
M,I-SNP
),I-SNP
.,O
 , 
The,O
specific,O
catalytic,O
activity,O
of,O
the,O
Met274,B-SNP
substituted,I-SNP
arylsulfatase,I-SNP
is,O
reduced,O
to,O
about,O
35,O
%,O
of,O
the,O
normal,O
enzyme,O
when,O
measured,O
with,O
an,O
artificial,O
substrate,O
.,O
 , 
Most,O
of,O
this,O
enzyme,O
is,O
also,O
degraded,O
in,O
an,O
early,O
biosynthetic,O
compartment,O
.,O
 , 
#12474144
Support,O
for,O
association,O
of,O
schizophrenia,O
with,O
genetic,O
variation,O
in,O
the,O
6p22.3,O
gene,O
,,O
dysbindin,B-Gene
,,I-Gene
in,O
sib,O
-,O
pair,O
families,O
with,O
linkage,O
and,O
in,O
an,O
additional,O
sample,O
of,O
triad,O
families,O
.,O
 , 
Genetic,O
variants,O
in,O
a,O
gene,O
on,O
6p22.3,O
,,O
dysbindin,B-Gene
,,I-Gene
have,O
been,O
shown,O
recently,O
to,O
be,O
associated,O
with,O
schizophrenia,O
(,O
Straub,O
et,O
al,O
.,O
2002a,O
),O
.,O
 , 
There,O
is,O
no,O
doubt,O
that,O
replication,O
in,O
other,O
independent,O
samples,O
would,O
enhance,O
the,O
significance,O
of,O
this,O
finding,O
considerably,O
.,O
 , 
Since,O
the,O
gene,O
is,O
located,O
in,O
the,O
center,O
of,O
the,O
linkage,O
peak,O
on,O
chromosome,O
6p,O
that,O
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
polymorphisms,O
in,O
a,O
sib,O
-,O
pair,O
sample,O
and,O
in,O
an,O
independently,O
ascertained,O
sample,O
of,O
triads,O
comprising,O
203,O
families,O
,,O
including,O
the,O
families,O
for,O
which,O
we,O
detected,O
linkage,O
on,O
chromosome,O
6p,O
.,O
 , 
Evidence,O
for,O
association,O
was,O
observed,O
in,O
the,O
two,O
samples,O
separately,O
as,O
well,O
as,O
in,O
the,O
combined,O
sample,O
(,O
P=.00068,O
for,O
SNP,O
rs760761,O
),O
.,O
 , 
Multilocus,O
haplotype,O
analysis,O
increased,O
the,O
significance,O
further,O
to,O
.00002,O
for,O
a,O
two,O
-,O
locus,O
haplotype,O
and,O
to,O
.00001,O
for,O
a,O
three,O
-,O
locus,O
haplotype,O
.,O
 , 
Estimation,O
of,O
frequencies,O
for,O
six,O
-,O
locus,O
haplotypes,O
revealed,O
one,O
common,O
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
other,O
six,O
-,O
locus,O
haplotypes,O
occurring,O
at,O
a,O
frequency,O
of,O
>,O
1,O
%,O
were,O
less,O
often,O
transmitted,O
than,O
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
was,O
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
protein,O
(,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
dystrophy,O
caused,O
by,O
mutation,O
of,O
the,O
red,O
and,O
green,O
cone,O
opsins,O
.,O
 , 
X,O
-,O
linked,O
cone,O
and,O
cone,O
-,O
rod,O
dystrophies,O
(,O
XLCOD,O
and,O
XLCORD,O
),O
are,O
a,O
heterogeneous,O
group,O
of,O
progressive,O
disorders,O
that,O
solely,O
or,O
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
 , 
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
was,O
detected,O
with,O
marker,O
DXS8045,O
(,O
Z(max,O
),O
 , 
=,O
2.41,O
 , 
[,O
theta,O
=,O
0.0,O
],O
),O
.,O
 , 
The,O
disease,O
locus,O
encompasses,O
the,O
cone,O
opsin,O
gene,O
array,O
on,O
Xq28,O
.,O
 , 
Analysis,O
of,O
the,O
array,O
revealed,O
a,O
missense,O
mutation,O
(,B-SNP
c.,I-SNP
529T,I-SNP
>,I-SNP
C,I-SNP
 , 
[,B-SNP
p.,I-SNP
W177R,I-SNP
],I-SNP
),O
in,O
exon,O
3,O
of,O
both,O
the,O
long,O
-,O
wavelength,O
-,O
sensitive,O
(,B-SNP
LW,I-SNP
,,I-SNP
red,O
),O
and,O
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
cardiovascular,O
and,O
metabolic,O
conditions,O
.,O
 , 
Variance,O
-,O
components,O
linkage,O
analysis,O
revealed,O
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
 , 
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
syndrome,O
):,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
20q13,O
,,O
near,O
marker,O
D20S173,O
(,O
empirical,O
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
by,O
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
is,O
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
established,O
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
various,O
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
a,O
missense,O
mutation,O
,,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
van,I-Gene
Buchem,I-Gene
disease,I-Gene
gene,O
(,B-Gene
SOST,I-Gene
),I-Gene
region,O
are,O
associated,O
with,O
bone,O
-,O
mineral,O
density,O
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
is,O
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
result,O
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
bp,O
insertion,O
(,O
f=0.38,O
),O
in,O
the,O
presumed,O
SOST,B-Gene
promoter,O
region,O
(,B-Gene
SRP3,I-Gene
),I-Gene
was,O
associated,O
with,O
decreased,O
BMD,O
in,O
women,O
at,O
the,O
femoral,O
neck,O
(,O
FN,O
),O
(,O
P=.05,O
),O
and,O
lumbar,O
spine,O
(,O
LS,O
),O
(,O
P=.01,O
),O
,,O
with,O
evidence,O
of,O
an,O
allele,O
-,O
dose,O
effect,O
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
in,O
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
 , 
In,O
both,O
cases,O
,,O
differences,O
between,O
extreme,O
genotypes,O
reached,O
0.2,O
SD,O
.,O
 , 
We,O
observed,O
no,O
genotype,O
effects,O
on,O
fracture,O
risk,O
,,O
for,O
the,O
234,O
osteoporotic,O
fractures,O
validated,O
during,O
8.2,O
years,O
of,O
follow,O
-,O
up,O
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
polymorphism,O
but,O
not,O
with,O
haplotypes,O
of,O
3,O
',O
polymorphisms,O
in,O
the,O
vitamin,O
-,O
D,O
receptor,O
gene,O
.,O
 , 
The,O
SOST,B-Gene
-,I-Gene
COLIA1,I-Gene
additive,O
effect,O
increased,O
with,O
age,O
and,O
reached,O
0.5,O
SD,O
difference,O
in,O
BMD,O
at,O
LS,O
in,O
the,O
oldest,O
age,O
group,O
(,O
P=.02,O
),O
.,O
 , 
The,O
molecular,O
mechanism,O
whereby,O
these,O
moderate,O
SOST,B-Gene
genotype,O
effects,O
are,O
mediated,O
remains,O
to,O
be,O
elucidated,O
,,O
but,O
it,O
is,O
likely,O
to,O
involve,O
differences,O
in,O
regulation,O
of,O
SOST,B-Gene
gene,O
expression,O
.,O
 , 
#7977360
Molecular,O
characterization,O
of,O
de,O
novo,O
secondary,O
trisomy,O
13,O
.,O
 , 
Unbalanced,O
Robertsonian,O
translocations,O
are,O
a,O
significant,O
cause,O
of,O
mental,O
retardation,O
and,O
fetal,O
wastage,O
.,O
 , 
The,O
majority,O
of,O
homologous,O
rearrangements,O
of,O
chromosome,O
21,O
in,O
Down,O
syndrome,O
have,O
been,O
shown,O
to,O
be,O
isochromosomes,O
.,O
 , 
Aside,O
from,O
chromosome,O
21,O
,,O
very,O
little,O
is,O
known,O
about,O
other,O
acrocentric,O
homologous,O
rearrangements,O
.,O
 , 
In,O
this,O
study,O
,,O
four,O
cases,O
of,O
de,O
novo,O
secondary,O
trisomy,O
13,O
are,O
presented,O
.,O
 , 
FISH,O
using,O
alpha,O
-,O
satellite,O
sequences,O
,,O
rDNA,O
,,O
and,O
a,O
pTRI-6,O
satellite,O
I,O
sequence,O
specific,O
to,O
the,O
short,O
arm,O
of,O
chromosome,O
13,O
showed,O
all,O
four,O
rearrangements,O
to,O
be,O
dicentric,O
and,O
apparently,O
devoid,O
of,O
ribosomal,O
genes,O
.,O
 , 
Three,O
of,O
four,O
rearrangements,O
retained,O
the,O
pTRI-6,O
satellite,O
I,O
sequence,O
.,O
 , 
Case,O
1,O
was,O
the,O
exception,O
,,O
showing,O
a,O
deletion,O
of,O
this,O
sequence,O
in,O
the,O
rearrangement,O
,,O
although,O
both,O
parental,O
chromosomes,O
13,O
had,O
strong,O
positive,O
hybridization,O
signals,O
.,O
 , 
Eleven,O
microsatellite,O
markers,O
from,O
chromosome,O
13,O
were,O
also,O
used,O
to,O
characterize,O
the,O
rearrangements,O
.,O
 , 
Of,O
the,O
four,O
possible,O
outcomes,O
,,O
one,O
maternal,O
Robertsonian,O
translocation,O
,,O
two,O
paternal,O
isochromosomes,O
,,O
and,O
one,O
maternal,O
isochromosome,O
were,O
observed,O
.,O
 , 
A,O
double,O
recombination,O
was,O
observed,O
in,O
the,O
maternally,O
derived,O
rob(13q13q,O
),O
.,O
 , 
No,O
recombination,O
events,O
were,O
detected,O
in,O
any,O
isochromosome,O
.,O
 , 
The,O
parental,O
origins,O
and,O
molecular,O
chromosomal,O
structure,O
of,O
these,O
cases,O
are,O
compared,O
with,O
previous,O
studies,O
of,O
de,O
novo,O
acrocentric,O
rearrangements,O
.,O
 , 
#10712212
The,O
distribution,O
of,O
human,O
genetic,O
diversity,O
:,O
a,O
comparison,O
of,O
mitochondrial,O
,,O
autosomal,O
,,O
and,O
Y,O
-,O
chromosome,O
data,O
.,O
 , 
We,O
report,O
a,O
comparison,O
of,O
worldwide,O
genetic,O
variation,O
among,O
255,O
individuals,O
by,O
using,O
autosomal,O
,,O
mitochondrial,O
,,O
and,O
Y,O
-,O
chromosome,O
polymorphisms,O
.,O
 , 
Variation,O
is,O
assessed,O
by,O
use,O
of,O
30,O
autosomal,O
restriction,O
-,O
site,O
polymorphisms,O
(,O
RSPs,O
),O
,,O
60,O
autosomal,O
short,O
-,O
tandem,O
-,O
repeat,O
polymorphisms,O
(,O
STRPs,O
),O
,,O
13,O
Alu,O
-,O
insertion,O
polymorphisms,O
and,O
one,O
LINE-1,O
element,O
,,O
611,O
bp,O
of,O
mitochondrial,O
control,O
-,O
region,O
sequence,O
,,O
and,O
10,O
Y,O
-,O
chromosome,O
polymorphisms,O
.,O
 , 
Analysis,O
of,O
these,O
data,O
reveals,O
substantial,O
congruity,O
among,O
this,O
diverse,O
array,O
of,O
genetic,O
systems,O
.,O
 , 
With,O
the,O
exception,O
of,O
the,O
autosomal,O
RSPs,O
,,O
in,O
which,O
an,O
ascertainment,O
bias,O
exists,O
,,O
all,O
systems,O
show,O
greater,O
gene,O
diversity,O
in,O
Africans,O
than,O
in,O
either,O
Europeans,O
or,O
Asians,O
.,O
 , 
Africans,O
also,O
have,O
the,O
largest,O
total,O
number,O
of,O
alleles,O
,,O
as,O
well,O
as,O
the,O
largest,O
number,O
of,O
unique,O
alleles,O
,,O
for,O
most,O
systems,O
.,O
 , 
GST,O
values,O
are,O
11%-18,O
%,O
for,O
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
and,O
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
synthase,O
(,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
for,O
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
in,O
retinoblastoma,O
patients,O
by,O
using,O
exon,O
-,O
by,O
-,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
and,O
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
identified,O
a,O
homozygous,O
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
all,O
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
,,I-SNP
G992R,B-SNP
,,I-SNP
and,O
the,O
recurrent,O
P1007A,B-SNP
),I-SNP
definitively,O
correlated,O
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
complexity,O
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
genetic,O
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
however,O
,,O
has,O
often,O
been,O
very,O
small,O
.,O
 , 
Much,O
of,O
the,O
",O
missing,O
heritability,O
",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
and,O
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
known,O
to,O
be,O
associated,O
with,O
rheumatoid,O
arthritis,O
(,O
RA,O
),O
,,O
Crohn,O
disease,O
(,O
CD,O
),O
,,O
type,O
1,O
diabetes,O
(,O
T1D,O
),O
,,O
or,O
type,O
2,O
diabetes,O
(,O
T2D,O
),O
were,O
selected,O
.,O
 , 
The,O
presence,O
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
and,O
imputed,O
with,O
SNP,O
genotype,O
information,O
from,O
the,O
HapMap,O
Project,O
and,O
the,O
1000,O
Genomes,O
Project,O
.,O
 , 
Eleven,O
loci,O
with,O
evidence,O
of,O
multiple,O
independent,O
effects,O
were,O
identified,O
in,O
the,O
study,O
,,O
and,O
the,O
number,O
was,O
expected,O
to,O
increase,O
at,O
larger,O
sample,O
sizes,O
and,O
improved,O
statistical,O
power,O
.,O
 , 
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
Association,O
Resource,O
(,O
KARE,O
),O
study,O
.,O
 , 
Genome,O
-,O
wide,O
associations,O
with,O
glycosylated,O
hemoglobin,O
,,O
which,O
reflects,O
the,O
long,O
-,O
term,O
glycemia,O
,,O
were,O
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
disequilibrium,O
block,O
(,O
r(2,O
),O
>,O
0.98,O
),O
in,O
the,O
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
associated,I-Gene
protein,I-Gene
1,I-Gene
-,I-Gene
like,I-Gene
1,I-Gene
(,B-Gene
CDKAL1,I-Gene
),I-Gene
gene,O
using,O
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
and,O
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
),I-Gene
and,O
lysosomal,B-Gene
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
are,O
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
is,O
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
 , 
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
aneuploidies,O
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
and,O
Y,O
were,O
used,O
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
aneuploid,O
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
rate,O
for,O
aneuploidies,O
was,O
73.3,O
%,O
(,O
107/146,O
),O
,,O
with,O
an,O
accuracy,O
of,O
informative,O
results,O
for,O
aneuploidies,O
of,O
93.9,O
%,O
(,O
107/114,O
),O
.,O
 , 
Compared,O
to,O
cytogenetics,O
,,O
the,O
accuracy,O
of,O
all,O
informative,O
FISH,O
results,O
,,O
euploid,O
and,O
aneuploid,O
,,O
was,O
99.8,O
%,O
,,O
and,O
the,O
specificity,O
was,O
99.9,O
%,O
.,O
 , 
In,O
those,O
pregnancies,O
where,O
fetal,O
abnormalities,O
had,O
been,O
observed,O
by,O
ultrasound,O
,,O
referring,O
physicians,O
requested,O
FISH,O
plus,O
cytogenetics,O
at,O
a,O
significantly,O
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
abnormalities,O
and,O
should,O
only,O
be,O
utilized,O
as,O
an,O
adjunctive,O
test,O
to,O
cytogenetics,O
.,O
 , 
This,O
experience,O
demonstrates,O
that,O
FISH,O
can,O
provide,O
a,O
rapid,O
and,O
accurate,O
clinical,O
method,O
for,O
prenatal,O
identification,O
of,O
chromosome,O
aneuploidies,O
.,O
 , 
#10521296
The,O
origins,O
of,O
hypertrophic,O
cardiomyopathy,O
-,O
causing,O
mutations,O
in,O
two,O
South,O
African,O
subpopulations,O
:,O
a,O
unique,O
profile,O
of,O
both,O
independent,O
and,O
founder,O
events,O
.,O
 , 
Hypertrophic,O
cardiomyopathy,O
(,O
HCM,O
),O
is,O
an,O
autosomal,O
dominantly,O
inherited,O
disease,O
of,O
the,O
cardiac,O
sarcomere,O
,,O
caused,O
by,O
numerous,O
mutations,O
in,O
genes,O
encoding,O
protein,O
components,O
of,O
this,O
structure,O
.,O
 , 
Mutation,O
carriers,O
are,O
at,O
risk,O
of,O
sudden,O
cardiac,O
death,O
,,O
mostly,O
as,O
adolescents,O
or,O
young,O
adults,O
.,O
 , 
The,O
reproductive,O
disadvantage,O
incurred,O
may,O
explain,O
both,O
the,O
global,O
occurrence,O
of,O
diverse,O
independent,O
HCM,O
-,O
associated,O
mutations,O
and,O
the,O
rare,O
reports,O
of,O
founder,O
effects,O
within,O
populations,O
.,O
 , 
We,O
have,O
investigated,O
whether,O
this,O
holds,O
true,O
for,O
two,O
South,O
African,O
subpopulations,O
,,O
one,O
of,O
mixed,O
ancestry,O
and,O
one,O
of,O
northern,O
-,O
European,O
descent,O
.,O
 , 
Previously,O
,,O
we,O
had,O
detected,O
three,O
novel,O
mutations,O
-,B-SNP
Ala797Thr,I-SNP
in,O
the,O
beta,B-Gene
-,I-Gene
myosin,I-Gene
heavy,I-Gene
-,I-Gene
chain,I-Gene
gene,I-Gene
(,B-Gene
betaMHC,I-Gene
),I-Gene
,,O
Arg92Trp,B-SNP
in,O
the,O
cardiac,B-Gene
troponin,I-Gene
T,I-Gene
gene,I-Gene
(,B-Gene
cTnT,I-Gene
),I-Gene
,,O
and,O
Arg645His,B-SNP
in,O
the,O
myosin,B-Gene
-,I-Gene
binding,I-Gene
protein,I-Gene
C,I-Gene
gene,I-Gene
(,B-Gene
MyBPC)-and,I-Gene
two,O
documented,O
betaMHC,B-Gene
mutations,O
(,B-SNP
Arg403Trp,I-SNP
and,O
Arg249Gln,B-SNP
),I-SNP
.,O
 , 
Here,O
we,O
report,O
three,O
additional,O
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
and,I-Gene
the,O
documented,O
betaMHC,B-Gene
Arg719Gln,B-SNP
mutation,O
.,O
 , 
Seven,O
of,O
the,O
nine,O
HCM,O
-,O
causing,O
mutations,O
arose,O
independently,O
;,O
no,O
conclusions,O
can,O
be,O
drawn,O
for,O
the,O
remaining,O
two,O
.,O
 , 
However,O
,,O
the,O
betaMHC,B-Gene
Arg403Trp,B-SNP
and,O
Ala797Thr,B-SNP
and,O
cTnT,O
Arg92Trp,B-SNP
mutations,O
were,O
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
disadvantage,O
incurred,O
by,O
the,O
more,O
lethal,O
,,O
cTnT,O
Arg92Trp,B-SNP
mutation,O
.,O
 , 
#18179885
Independent,O
introduction,O
of,O
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
correlates,O
perfectly,O
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
of,O
two,O
new,O
mutations,O
among,O
Saudis,O
,,O
also,O
known,O
for,O
the,O
high,O
prevalence,O
of,O
LP,O
.,O
 , 
We,O
confirmed,O
the,O
absence,O
of,O
the,O
European,O
T(-13910,O
),O
and,O
established,O
two,O
new,O
mutations,O
found,O
as,O
a,O
compound,O
allele,O
:,O
T,B-SNP
/,I-SNP
G(-13915,I-SNP
),I-SNP
within,O
the,O
-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
bp,O
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
of,O
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
 , 
High,O
selection,O
coefficient,O
(,O
s,O
),O
approximately,O
0.04,O
for,O
LP,O
phenotype,O
was,O
found,O
for,O
both,O
T(-13910,O
),O
and,O
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
shows,O
a,O
different,O
,,O
highly,O
divergent,O
ancestral,O
haplotype,O
,,O
suggesting,O
that,O
these,O
two,O
major,O
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
.,O
 , 
#15365989
Novel,O
homozygous,O
p.,B-SNP
E64D,I-SNP
mutation,O
in,O
DJ1,B-Gene
in,O
early,O
onset,O
Parkinson,O
disease,O
(,O
PARK7,O
),O
.,O
 , 
Mutations,O
in,O
the,O
parkin,O
gene,O
have,O
been,O
identified,O
as,O
a,O
common,O
cause,O
of,O
autosomal,O
recessive,O
inherited,O
Parkinson,O
disease,O
(,O
PD,O
),O
associated,O
with,O
early,O
disease,O
manifestation,O
.,O
 , 
However,O
,,O
based,O
on,O
linkage,O
data,O
,,O
mutations,O
in,O
other,O
genes,O
contribute,O
to,O
the,O
genetic,O
heterogeneity,O
of,O
early,O
-,O
onset,O
PD,O
(,O
EOPD,O
),O
.,O
 , 
Recently,O
,,O
two,O
mutations,O
in,O
the,O
DJ1,B-Gene
gene,O
were,O
described,O
as,O
a,O
second,O
cause,O
of,O
autosomal,O
recessive,O
EOPD,O
(,B-Gene
PARK7,I-Gene
),I-Gene
.,O
 , 
Analyzing,O
the,O
PARK7,B-Gene
/,B-Gene
DJ1,I-Gene
gene,O
in,O
104,O
EOPD,O
patients,O
,,O
we,O
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
associated,O
with,O
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
was,O
found,O
in,O
the,O
striatum,O
using,O
[,O
(,O
18)F]FP,O
-,O
CIT,O
and,O
PET,O
,,O
indicating,O
a,O
serious,O
loss,O
of,O
presynaptic,O
dopaminergic,O
afferents,O
.,O
 , 
His,O
sister,O
,,O
homozygous,O
for,O
E64D,B-SNP
,,I-SNP
was,O
clinically,O
unaffected,O
but,O
showed,O
reduced,O
dopamine,O
uptake,O
when,O
compared,O
with,O
a,O
clinically,O
unaffected,O
brother,O
,,O
who,O
is,O
heterozygous,O
for,O
E64D.,B-SNP
We,O
demonstrate,O
by,O
crystallography,O
that,O
the,O
E64D,B-SNP
mutation,O
does,O
not,O
alter,O
the,O
structure,O
of,O
the,O
DJ1,B-Gene
protein,O
,,O
however,O
we,O
observe,O
a,O
tendency,O
towards,O
decreased,O
levels,O
of,O
the,O
mutant,O
protein,O
when,O
overexpressed,O
in,O
HEK293,O
or,O
COS7,O
cells,O
.,O
 , 
Using,O
immunocytochemistry,O
in,O
contrast,O
to,O
the,O
homogenous,O
nuclear,O
and,O
cytoplasmic,O
staining,O
in,O
HEK293,O
cells,O
overexpressing,O
wild,O
-,O
type,O
DJ1,B-Gene
,,I-Gene
about,O
5,O
%,O
of,O
the,O
cells,O
expressing,O
E64D,B-SNP
and,O
up,O
to,O
80,O
%,O
of,O
the,O
cells,O
expressing,O
the,O
recently,O
described,O
L166P,B-SNP
mutation,O
displayed,O
a,O
predominant,O
nuclear,O
localization,O
of,O
the,O
mutant,O
DJ1,B-Gene
protein,O
.,O
 , 
#15776395
Localization,O
of,O
a,O
type,O
1,O
diabetes,O
locus,O
in,O
the,O
IL2RA,B-Gene
/,I-Gene
CD25,I-Gene
region,O
by,O
use,O
of,O
tag,O
single,O
-,O
nucleotide,O
polymorphisms,O
.,O
 , 
As,O
part,O
of,O
an,O
ongoing,O
search,O
for,O
genes,O
associated,O
with,O
type,O
1,O
diabetes,O
(,O
T1D,O
),O
,,O
a,O
common,O
autoimmune,O
disease,O
,,O
we,O
tested,O
the,O
biological,O
candidate,O
gene,O
IL2RA,B-Gene
(,B-Gene
CD25,I-Gene
),I-Gene
,,O
which,O
encodes,O
a,O
subunit,O
(,B-Gene
IL-2R,I-Gene
alpha,I-Gene
),I-Gene
of,O
the,O
high,O
-,O
affinity,O
interleukin-2,B-Gene
(,B-Gene
IL-2,I-Gene
),I-Gene
receptor,O
complex,O
.,O
 , 
We,O
employed,O
a,O
tag,O
single,O
-,O
nucleotide,O
polymorphism,O
(,O
tag,O
SNP,O
),O
approach,O
in,O
large,O
T1D,O
sample,O
collections,O
consisting,O
of,O
7,457,O
cases,O
and,O
controls,O
and,O
725,O
multiplex,O
families,O
.,O
 , 
Tag,O
SNPs,O
were,O
analyzed,O
using,O
a,O
multilocus,O
test,O
to,O
provide,O
a,O
regional,O
test,O
for,O
association,O
.,O
 , 
We,O
found,O
strong,O
statistical,O
evidence,O
in,O
the,O
case,O
-,O
control,O
collection,O
(,O
P=6.5x10(-8,O
),O
),O
for,O
a,O
T1D,O
locus,O
in,O
the,O
CD25,O
region,O
of,O
chromosome,O
10p15,O
and,O
replicated,O
the,O
association,O
in,O
the,O
family,O
collection,O
(,O
P=7.3x10(-3,O
),O
;,O
combined,O
P=1.3x10(-10,O
),O
),O
.,O
 , 
These,O
results,O
illustrate,O
the,O
utility,O
of,O
tag,O
SNPs,O
in,O
a,O
chromosome,O
-,O
regional,O
test,O
of,O
disease,O
association,O
and,O
justify,O
future,O
fine,O
mapping,O
of,O
the,O
causal,O
variant,O
in,O
the,O
region,O
.,O
 , 
#8477263
Molecular,O
characterization,O
of,O
beta,O
-,O
thalassemia,O
in,O
Egyptians,O
.,O
 , 
We,O
sought,O
to,O
determine,O
the,O
spectrum,O
of,O
mutations,O
producing,O
beta,O
-,O
thalassemia,O
in,O
Egypt,O
using,O
genomic,O
PCR,O
and,O
a,O
variety,O
of,O
mutation,O
-,O
screening,O
procedures,O
.,O
 , 
Thirty,O
-,O
four,O
beta,O
-,O
thalassemia,O
and,O
three,O
Hb,O
S,O
/,O
beta,O
-,O
thalassemia,O
patients,O
originating,O
from,O
different,O
regions,O
of,O
Egypt,O
were,O
studied,O
,,O
and,O
the,O
causative,O
mutation,O
was,O
found,O
in,O
69,O
of,O
71,O
(,O
97,O
%,O
),O
beta,O
-,O
thalassemia,O
genes,O
.,O
 , 
Four,O
mutations,O
accounted,O
for,O
78,O
%,O
of,O
beta,B-Gene
-,I-Gene
thalassemia,I-Gene
genes,O
in,O
this,O
population,O
;,O
IVS-1,O
,,O
nt,O
110,O
(,O
41,O
%,O
),O
,,O
IVS-1,O
nt,O
6,O
(,O
13,O
%,O
),O
,,O
IVS-1,O
,,O
nt,O
1,O
(,O
13,O
%,O
),O
,,O
and,O
IVS-2,O
,,O
nt,O
848,O
(,O
11,O
%,O
),O
.,O
 , 
The,O
latter,O
allele,O
,,O
a,O
C,O
-,O
A,O
mutation,O
at,O
the,O
third,O
nucleotide,O
of,O
an,O
acceptor,O
site,O
consensus,O
sequence,O
,,O
has,O
been,O
described,O
previously,O
only,O
in,O
one,O
Egyptian,O
,,O
one,O
Iranian,O
,,O
one,O
Tunisian,O
,,O
and,O
one,O
Black,O
American,O
patient,O
.,O
 , 
Nine,O
other,O
alleles,O
each,O
accounted,O
for,O
1,O
-,O
3,O
%,O
of,O
beta,O
-,O
thalassemia,O
genes,O
.,O
 , 
Among,O
these,O
was,O
one,O
codon,O
27,O
allele,O
(,O
Hb,O
Knossos,O
),O
,,O
two,O
frameshift,O
106/107,O
alleles,O
previously,O
seen,O
only,O
in,O
a,O
Black,O
American,O
,,O
and,O
a,O
rarely,O
observed,O
mutation,O
in,O
the,O
distal,O
promoter,O
region,O
of,O
the,O
beta,B-Gene
-,I-Gene
globin,I-Gene
gene,O
,,O
-87,B-SNP
(,I-SNP
C,I-SNP
-,I-SNP
A,I-SNP
),I-SNP
.,I-SNP
 , 
Our,O
results,O
suggest,O
that,O
from,O
a,O
molecular,O
genetic,O
standpoint,O
a,O
beta,O
-,O
thalassemia,O
prevention,O
program,O
based,O
on,O
carrier,O
screening,O
and,O
prenatal,O
diagnosis,O
can,O
be,O
implemented,O
in,O
Egypt,O
.,O
 , 
In,O
couples,O
at,O
risk,O
for,O
beta,O
-,O
thalassemia,O
,,O
the,O
causative,O
mutation,O
should,O
be,O
identifiable,O
in,O
both,O
members,O
in,O
92,O
%,O
and,O
in,O
one,O
member,O
in,O
the,O
remaining,O
8,O
%,O
.,O
 , 
#8554049
Molecular,O
definition,O
of,O
red,O
cell,O
Rh,O
haplotypes,O
by,O
tightly,O
linked,O
SphI,O
RFLPs,O
.,O
 , 
The,O
Rh,O
blood,O
group,O
system,O
of,O
human,O
red,O
cells,O
contains,O
five,O
major,O
antigens,O
D,O
,,O
C,O
/,O
c,O
,,O
and,O
E,O
/,O
e,O
(,O
the,O
latter,O
four,O
designated,O
",O
non,O
-,O
D,O
",O
),O
that,O
are,O
specified,O
by,O
eight,O
gene,O
complexes,O
known,O
as,O
Rh,O
haplotypes,O
.,O
 , 
In,O
this,O
paper,O
,,O
we,O
report,O
on,O
the,O
mapping,O
of,O
RH,O
locus,O
and,O
identification,O
of,O
a,O
set,O
of,O
SphI,O
RFLPs,O
that,O
are,O
tightly,O
linked,O
with,O
the,O
Rh,O
structural,O
genes,O
.,O
 , 
Using,O
exon,O
-,O
specific,O
probes,O
,,O
we,O
have,O
localized,O
the,O
SphI,O
cleavage,O
sites,O
resulting,O
in,O
these,O
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
with,O
autosomal,O
recessive,O
retinitis,O
pigmentosa,O
.,O
 , 
#17847001
Copy,O
-,O
number,O
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
and,O
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
in,O
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
-,O
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
mechanism,O
might,O
therefore,O
exist,O
between,O
NF1,O
microdeletion,O
patients,O
and,O
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
was,O
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
>,I-SNP
C,I-SNP
(,B-SNP
p.,I-SNP
Asp98Ala,I-SNP
),I-SNP
,,O
and,O
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
and,O
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
differs,O
significantly,O
(,O
chi,O
2,O
=,O
4.88,O
),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
of,O
-,O
principle,O
in,O
HapMap,O
SNPs,O
.,O
 , 
SNP,O
-,O
based,O
research,O
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
nonuniquely,O
(,O
long,O
and,O
short,O
,,O
respectively,O
),O
.,O
 , 
Furthermore,O
,,O
an,O
average,O
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
in,O
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
and,O
apolipoprotein,O
B,O
in,O
individuals,O
with,O
inherited,O
hypercholesterolemia,O
.,O
 , 
Patients,O
with,O
familial,O
hypercholesterolemia,O
(,O
FH,O
),O
have,O
elevated,O
LDL,O
-,O
C,O
levels,O
,,O
usually,O
above,O
the,O
90th,O
percentile,O
(,O
P90,O
),O
for,O
age,O
and,O
gender,O
.,O
 , 
However,O
,,O
large,O
-,O
scale,O
genetic,O
cascade,O
screening,O
for,O
FH,O
showed,O
that,O
15,O
%,O
of,O
the,O
LDL,B-Gene
-,I-Gene
receptor,I-Gene
(,B-Gene
LDLR,I-Gene
),I-Gene
or,O
Apolipoprotein,B-Gene
B,I-Gene
(,B-Gene
APOB,I-Gene
),I-Gene
mutation,O
carriers,O
have,O
LDL,O
-,O
C,O
levels,O
below,O
P75,O
.,O
 , 
Nonpathogenicity,O
of,O
sequence,O
changes,O
may,O
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
4P75,O
in,O
untreated,O
mutation,O
carriers,O
;,O
(,O
2,O
),O
higher,O
mean,O
LDL,O
-,O
C,O
level,O
in,O
untreated,O
carriers,O
than,O
in,O
untreated,O
noncarriers,O
;,O
and,O
(,O
3,O
),O
higher,O
percentage,O
of,O
medication,O
users,O
in,O
carriers,O
than,O
in,O
noncarriers,O
at,O
screening,O
.,O
 , 
We,O
considered,O
a,O
mutation,O
nonpathogenic,O
when,O
none,O
of,O
the,O
three,O
criteria,O
were,O
met,O
.,O
 , 
We,O
applied,O
these,O
criteria,O
to,O
mutations,O
that,O
had,O
been,O
determined,O
in,O
more,O
than,O
50,O
untreated,O
adults,O
.,O
 , 
Segregation,O
analysis,O
was,O
performed,O
to,O
confirm,O
nonpathogenicity,O
.,O
 , 
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
and,O
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
,,I-SNP
exon,O
2,O
),O
and,O
two,O
in,O
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
also,O
indicated,O
nonpathogenicity,O
.,O
 , 
According,O
to,O
our,O
criteria,O
,,O
three,O
sequence,O
variants,O
were,O
nonpathogenic,O
.,O
 , 
The,O
criteria,O
may,O
help,O
to,O
identify,O
nonpathogenic,O
sequence,O
changes,O
in,O
genetic,O
cascade,O
screening,O
programs,O
.,O
 , 
#16252239
Severely,O
incapacitating,O
mutations,O
in,O
patients,O
with,O
extreme,O
short,O
stature,O
identify,O
RNA,B-Gene
-,I-Gene
processing,I-Gene
endoribonuclease,I-Gene
RMRP,B-Gene
as,O
an,O
essential,O
cell,O
growth,O
regulator,O
.,O
 , 
The,O
growth,O
of,O
an,O
individual,O
is,O
deeply,O
influenced,O
by,O
the,O
regulation,O
of,O
cell,O
growth,O
and,O
division,O
,,O
both,O
of,O
which,O
also,O
contribute,O
to,O
a,O
wide,O
variety,O
of,O
pathological,O
conditions,O
,,O
including,O
cancer,O
,,O
diabetes,O
,,O
and,O
inflammation,O
.,O
 , 
To,O
identify,O
a,O
major,O
regulator,O
of,O
human,O
growth,O
,,O
we,O
performed,O
positional,O
cloning,O
in,O
an,O
autosomal,O
recessive,O
type,O
of,O
profound,O
short,O
stature,O
,,O
anauxetic,O
dysplasia,O
.,O
 , 
Homozygosity,O
mapping,O
led,O
to,O
the,O
identification,O
of,O
novel,O
mutations,O
in,O
the,O
RMRP,B-Gene
gene,O
,,O
which,O
was,O
previously,O
known,O
to,O
cause,O
two,O
milder,O
types,O
of,O
short,O
stature,O
with,O
susceptibility,O
to,O
cancer,O
,,O
cartilage,O
hair,O
hypoplasia,O
,,O
and,O
metaphyseal,O
dysplasia,O
without,O
hypotrichosis,O
.,O
 , 
We,O
show,O
that,O
different,O
RMRP,B-Gene
gene,O
mutations,O
lead,O
to,O
decreased,O
cell,O
growth,O
by,O
impairing,O
ribosomal,O
assembly,O
and,O
by,O
altering,O
cyclin,O
-,O
dependent,O
cell,O
cycle,O
regulation,O
.,O
 , 
Clinical,O
heterogeneity,O
is,O
explained,O
by,O
a,O
correlation,O
between,O
the,O
level,O
and,O
type,O
of,O
functional,O
impairment,O
in,O
vitro,O
and,O
the,O
severity,O
of,O
short,O
stature,O
or,O
predisposition,O
to,O
cancer,O
.,O
 , 
Whereas,O
the,O
cartilage,O
hair,O
hypoplasia,O
founder,O
mutation,O
affects,O
both,O
pathways,O
intermediately,O
,,O
anauxetic,O
dysplasia,O
mutations,O
do,O
not,O
affect,O
B,O
-,O
cyclin,O
messenger,O
RNA,O
(,O
mRNA,O
),O
levels,O
but,O
do,O
severely,O
incapacitate,O
ribosomal,O
assembly,O
via,O
defective,O
endonucleolytic,O
cleavage,O
.,O
 , 
Anauxetic,O
dysplasia,O
mutations,O
thus,O
lead,O
to,O
poor,O
processing,O
of,O
ribosomal,O
RNA,O
while,O
allowing,O
normal,O
mRNA,O
processing,O
and,O
,,O
therefore,O
,,O
genetically,O
separate,O
the,O
different,O
functions,O
of,O
RNase,B-Gene
MRP,I-Gene
.,I-Gene
 , 
#1357966
Linkage,O
disequilibrium,O
among,O
RFLPs,O
at,O
the,O
insulin,O
-,O
receptor,O
locus,O
despite,O
intervening,O
Alu,O
repeat,O
sequences,O
.,O
 , 
Multiple,O
mutations,O
of,O
the,O
insulin,B-Gene
receptor,I-Gene
(,B-Gene
INSR,I-Gene
),I-Gene
gene,O
have,O
been,O
identified,O
in,O
individuals,O
with,O
extreme,O
insulin,O
resistance,O
.,O
 , 
These,O
mutations,O
have,O
included,O
recombination,O
events,O
between,O
Alu,O
repeat,O
units,O
in,O
the,O
tyrosine,O
kinase,O
-,O
encoding,O
beta,O
-,O
chain,O
region,O
of,O
the,O
gene,O
.,O
 , 
To,O
evaluate,O
the,O
influence,O
of,O
Alu,O
and,O
dinucleotide,O
repetitive,O
sequences,O
on,O
recombination,O
events,O
within,O
the,O
insulin,O
receptor,O
gene,O
,,O
I,O
examined,O
the,O
degree,O
of,O
linkage,O
disequilibrium,O
between,O
RFLP,O
pairs,O
spanning,O
the,O
gene,O
.,O
 , 
I,O
established,O
228,O
independent,O
haplotypes,O
for,O
seven,O
RFLPs,O
(,O
two,O
each,O
for,O
PstI,B-Gene
,,I-Gene
RsaI,B-Gene
,,I-Gene
and,O
SstI,B-Gene
and,O
one,O
for,O
MspI,B-Gene
and,O
172,O
independent,O
haplotypes,O
which,O
included,O
an,O
additional,O
RFLP,O
with,O
BglII,B-Gene
),I-Gene
from,O
19,O
pedigrees,O
.,O
 , 
These,O
RFLPs,O
span,O
>,O
130,O
kb,O
of,O
this,O
gene,O
,,O
and,O
my,O
colleagues,O
and,O
I,O
previously,O
demonstrated,O
that,O
multiple,O
Alu,O
sequences,O
separate,O
RFLP,O
pairs,O
.,O
 , 
Observed,O
haplotype,O
frequencies,O
deviated,O
significantly,O
from,O
those,O
predicted,O
.,O
 , 
Pairwise,O
analysis,O
of,O
RFLP,O
showed,O
high,O
levels,O
of,O
linkage,O
disequilibrium,O
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
not,O
between,O
alpha,O
-,O
chain,O
RFLPs,O
and,O
those,O
of,O
the,O
beta,O
-,O
chain,O
.,O
 , 
Disequilibrium,O
was,O
present,O
among,O
beta,O
-,O
chain,O
RFLPs,O
,,O
despite,O
separation,O
by,O
one,O
or,O
more,O
Alu,O
repeat,O
sequences,O
.,O
 , 
The,O
very,O
strong,O
linkage,O
disequilibrium,O
which,O
was,O
present,O
in,O
sizable,O
regions,O
of,O
the,O
INSR,B-Gene
gene,O
despite,O
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
.,O
 , 
We,O
have,O
found,O
an,O
allelic,O
deletion,O
of,O
the,O
haptoglobin,B-Gene
(,B-Gene
Hp,I-Gene
),I-Gene
gene,O
from,O
an,O
individual,O
with,O
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
and,O
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
 , 
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
compound,O
heterozygous,O
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
also,O
known,O
as,O
papillorenal,O
syndrome,O
is,O
an,O
autosomal,O
-,O
dominant,O
disorder,O
characterized,O
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
been,O
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
CLTD,B-Gene
,,I-Gene
HIRA,B-Gene
,,I-Gene
and,O
TMVCF,B-Gene
,,I-Gene
as,O
well,O
as,O
a,O
number,O
of,O
novel,O
ordered,O
ESTs,O
.,O
 , 
#20529654
ASHG,O
Awards,O
and,O
Addresses,O
.,O
 , 
2009,O
William,O
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
gene,O
encoding,O
the,O
Ca2,B-Gene
+,I-Gene
-binding,I-Gene
protein,I-Gene
4,I-Gene
,,I-Gene
cause,O
autosomal,O
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
of,O
CSNB,O
(,O
CSNB2,O
),O
,,O
which,O
can,O
be,O
distinguished,O
by,O
standard,O
electroretinography,O
(,O
ERG,O
),O
.,O
 , 
CSNB2,O
is,O
associated,O
with,O
a,O
reduced,O
rod,O
b,O
-,O
wave,O
,,O
a,O
substantially,O
reduced,O
cone,O
a,O
-,O
wave,O
,,O
and,O
a,O
reduced,O
30,O
-,O
Hz,O
flicker,O
ERG,O
response,O
.,O
 , 
CACNA1F,B-Gene
 , 
encodes,O
the,O
alpha,O
1,O
-,O
subunit,O
of,O
an,O
L,O
-,O
type,O
Ca2,O
+,O
channel,O
(,B-Gene
Cav1.4,I-Gene
alpha,I-Gene
),O
,,O
which,O
is,O
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
we,O
used,O
a,O
candidate,O
-,O
gene,O
approach,O
.,O
 , 
CABP4,B-Gene
,,I-Gene
a,O
member,O
of,O
the,O
calcium,O
-,O
binding,O
protein,O
(,O
CABP,O
),O
family,O
,,O
is,O
located,O
in,O
photoreceptor,O
synaptic,O
terminals,O
and,O
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
 , 
Mice,O
lacking,O
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
 , 
Our,O
studies,O
revealed,O
homozygous,O
and,O
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
to,O
30%-40,O
%,O
of,O
those,O
in,O
controls,O
.,O
 , 
This,O
suggests,O
that,O
the,O
reduced,O
amount,O
of,O
CABP4,B-Gene
is,O
the,O
reason,O
for,O
the,O
signaling,O
defect,O
in,O
these,O
patients,O
.,O
 , 
#10862097
Identification,O
of,O
3,O
novel,O
mutations,O
(,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
autosomal,O
dominant,O
polycystic,B-Gene
kidney,I-Gene
disease,I-Gene
1,I-Gene
gene,O
(,B-Gene
PKD1,I-Gene
),I-Gene
.,O
 , 
#20607857
UMD,O
-,O
CFTR,O
:,O
a,O
database,O
dedicated,O
to,O
CF,O
and,O
CFTR,O
-,O
related,O
disorders,O
.,O
 , 
With,O
the,O
increasing,O
knowledge,O
of,O
cystic,O
fibrosis,O
(,O
CF,O
),O
and,O
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
had,O
demonstrable,O
hemizygosity,O
for,O
22q11,O
.,O
 , 
Cytogenetic,O
analysis,O
had,O
identified,O
interstitial,O
deletion,O
in,O
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
and,O
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
and,O
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
 , 
#20537301
A,O
definitive,O
haplotype,O
map,O
as,O
determined,O
by,O
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
are,O
homozygous,O
.,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
of,O
Asian,O
populations,O
.,O
 , 
We,O
resolved,O
common,O
CNV,O
regions,O
(,O
merged,O
CNV,O
segments,O
across,O
the,O
examined,O
samples,O
),O
into,O
CNV,O
events,O
(,O
clusters,O
of,O
CNV,O
segments,O
),O
on,O
the,O
basis,O
of,O
mutual,O
overlap,O
and,O
found,O
that,O
the,O
haplotype,O
backgrounds,O
of,O
different,O
CNV,O
events,O
within,O
the,O
same,O
CNV,O
region,O
were,O
predominantly,O
similar,O
,,O
perhaps,O
because,O
of,O
inherent,O
structural,O
instability,O
.,O
 , 
#8328463
American,O
College,O
of,O
Medical,O
Genetics,O
.,O
 , 
Prenatal,O
interphase,O
fluorescence,O
in,O
situ,O
hybridization,O
(,O
FISH,O
),O
policy,O
statement,O
.,O
 , 
#9497253
Splice,O
-,O
site,O
mutations,O
:,O
a,O
novel,O
genetic,O
mechanism,O
of,O
Crigler,O
-,O
Najjar,O
syndrome,O
type,O
1,O
.,O
 , 
Crigler,O
-,O
Najjar,O
syndrome,O
type,O
1,O
(,O
CN-1,O
),O
is,O
a,O
recessively,O
inherited,O
,,O
potentially,O
lethal,O
disorder,O
characterized,O
by,O
severe,O
unconjugated,O
hyperbilirubinemia,O
resulting,O
from,O
deficiency,O
of,O
the,O
hepatic,O
enzyme,O
bilirubin,O
-,O
UDP,O
-,O
glucuronosyltransferase,O
.,O
 , 
In,O
all,O
CN-1,O
patients,O
studied,O
,,O
structural,O
mutations,O
in,O
one,O
of,O
the,O
five,O
exons,O
of,O
the,O
gene,O
(,B-Gene
UGT1A1,I-Gene
),I-Gene
encoding,O
the,O
uridinediphosphoglucuronate,B-Gene
glucuronosyltransferase,I-Gene
(,B-Gene
UGT,I-Gene
),I-Gene
isoform,O
bilirubin,B-Gene
-,I-Gene
UGT1,I-Gene
were,O
implicated,O
in,O
the,O
absence,O
or,O
inactivation,O
of,O
the,O
enzyme,O
.,O
 , 
We,O
report,O
two,O
patients,O
in,O
whom,O
CN-1,O
is,O
caused,O
,,O
instead,O
,,O
by,O
mutations,O
in,O
the,O
noncoding,O
intronic,O
region,O
of,O
the,O
UGT1A1,B-Gene
gene,O
.,O
 , 
One,O
patient,O
(,O
A,O
),O
was,O
homozygous,O
for,O
a,O
G-->C,O
mutation,O
at,O
the,O
splice,O
-,O
donor,O
site,O
in,O
the,O
intron,O
,,O
between,O
exon,O
1,O
and,O
exon,O
2,O
.,O
 , 
The,O
other,O
patient,O
(,O
B,O
),O
was,O
heterozygous,O
for,O
an,O
A-->G,O
shift,O
at,O
the,O
splice,O
-,O
acceptor,O
site,O
in,O
intron,O
3,O
,,O
and,O
in,O
the,O
second,O
allele,O
a,O
premature,O
translation,O
-,O
termination,O
codon,O
in,O
exon,O
1,O
was,O
identified,O
.,O
 , 
Bilirubin,B-Gene
-,I-Gene
UGT1,I-Gene
mRNA,O
is,O
difficult,O
to,O
obtain,O
,,O
since,O
it,O
is,O
expressed,O
in,O
the,O
liver,O
only,O
.,O
 , 
To,O
determine,O
the,O
effects,O
of,O
these,O
splice,O
-,O
junction,O
mutations,O
,,O
we,O
amplified,O
genomic,O
DNA,O
of,O
the,O
relevant,O
splice,O
junctions,O
.,O
 , 
The,O
amplicons,O
were,O
expressed,O
in,O
COS-7,O
cells,O
,,O
and,O
the,O
expressed,O
mRNAs,O
were,O
analyzed,O
.,O
 , 
In,O
both,O
cases,O
,,O
splice,O
-,O
site,O
mutations,O
led,O
to,O
the,O
use,O
of,O
cryptic,O
splice,O
sites,O
,,O
with,O
consequent,O
deletions,O
in,O
the,O
processed,O
mRNA,O
.,O
 , 
This,O
is,O
the,O
first,O
report,O
of,O
intronic,O
mutations,O
causing,O
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
structure,O
,,O
by,O
ex,O
vivo,O
expression,O
.,O
 , 
#11112662
A,O
narrow,O
segment,O
of,O
maternal,O
uniparental,O
disomy,O
of,O
chromosome,O
7q31,O
-,O
qter,O
in,O
Silver,O
-,O
Russell,O
syndrome,O
delimits,O
a,O
candidate,O
gene,O
region,O
.,O
 , 
Maternal,O
uniparental,O
disomy,O
of,O
chromosome,O
7,O
(,O
matUPD7,O
),O
,,O
the,O
inheritance,O
of,O
both,O
chromosomes,O
from,O
only,O
the,O
mother,O
,,O
is,O
observed,O
in,O
approximately,O
10,O
%,O
of,O
patients,O
with,O
Silver,O
-,O
Russell,O
syndrome,O
(,O
SRS,O
),O
.,O
 , 
It,O
has,O
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
gamma2,B-Gene
-,I-Gene
COP,I-Gene
,,I-Gene
and,O
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
gamma2,B-Gene
-,I-Gene
COP,I-Gene
at,O
7q32,O
.,O
 , 
GRB10,B-Gene
at,O
7p11.2,O
-,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
increase,O
in,O
males,O
.,O
 , 
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
syndrome,O
.,O
 , 
Mowat,O
-,O
Wilson,O
syndrome,O
(,O
MWS,O
),O
is,O
a,O
recently,O
delineated,O
mental,O
retardation,O
(,O
MR)-multiple,O
congenital,O
anomaly,O
syndrome,O
,,O
characterized,O
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
,,O
genital,O
anomalies,O
,,O
congenital,O
heart,O
disease,O
(,O
CHD,O
),O
,,O
and,O
agenesis,O
of,O
the,O
corpus,O
callosum,O
(,O
ACC,O
),O
.,O
 , 
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
interacting,I-Gene
protein-1,I-Gene
(,B-Gene
SMADIP1,I-Gene
or,O
SIP1,B-Gene
),I-Gene
,,O
a,O
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
suggesting,O
that,O
haploinsufficiency,O
is,O
the,O
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
splice,O
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
have,O
been,O
identified,O
,,O
and,O
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
and,O
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
difference,O
in,O
the,O
frequencies,O
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
partial,O
duplication,O
in,O
the,O
infertile,O
group,O
(,O
7.0,O
%,O
),O
was,O
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
partial,O
deletion,O
and,O
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
but,O
not,O
the,O
AZFc,O
partial,O
deletion,O
,,O
is,O
a,O
risk,O
factor,O
for,O
male,O
infertility,O
in,O
the,O
Taiwanese,O
population,O
.,O
 , 
#15776426
Mutational,O
analysis,O
of,O
the,O
NPHP4,B-Gene
gene,O
in,O
250,O
patients,O
with,O
nephronophthisis,O
.,O
 , 
Nephronophthisis,O
(,O
NPH,O
),O
,,O
a,O
recessive,O
cystic,O
kidney,O
disease,O
,,O
is,O
the,O
most,O
frequent,O
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
 , 
Mutations,O
in,O
three,O
genes,O
(,O
NPHP1,O
,,O
2,O
,,O
and,O
3,O
),O
were,O
identified,O
as,O
causative,O
.,O
 , 
Extrarenal,O
manifestations,O
are,O
known,O
,,O
such,O
as,O
retinitis,O
pigmentosa,O
(,O
Senior,O
-,O
Loken,O
syndrome,O
,,O
SLS,O
),O
and,O
ocular,O
motor,O
apraxia,O
type,O
Cogan,O
.,O
 , 
Recently,O
,,O
we,O
identified,O
a,O
novel,O
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
variants,O
in,O
26/250,O
different,O
patients,O
(,O
10,O
%,O
),O
.,O
 , 
Interestingly,O
,,O
we,O
detected,O
homozygous,O
or,O
compound,O
heterozygous,O
mutations,O
of,O
NPHP4,B-Gene
in,O
only,O
6/250,O
different,O
patients,O
(,O
2.4,O
%,O
),O
,,O
but,O
only,O
one,O
heterozygous,O
NPHP4,B-Gene
sequence,O
variant,O
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
was,O
a,O
likely,O
loss,O
-,O
of,O
-,O
function,O
(,O
i.e.,O
,,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
 , 
Implementation,O
of,O
multiplex,O
ligation,O
-,O
dependent,O
probe,O
amplification,O
(,O
MLPA,O
),O
for,O
thalassemia,O
causing,O
deletions,O
has,O
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
the,O
design,O
of,O
gap,O
-,O
PCRs,O
.,O
 , 
We,O
have,O
designed,O
a,O
custom,O
fine,O
-,O
tiling,O
array,O
with,O
oligonucleotides,O
covering,O
the,O
complete,O
globin,O
gene,O
clusters,O
.,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
and,O
analyzed,O
these,O
by,O
direct,O
sequencing,O
.,O
 , 
Results,O
from,O
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
amplification,O
was,O
successful,O
in,O
19,O
cases,O
.,O
 , 
For,O
12,O
of,O
these,O
,,O
the,O
exact,O
locations,O
of,O
the,O
breakpoints,O
were,O
determined,O
.,O
 , 
Seven,O
of,O
these,O
deletions,O
have,O
not,O
been,O
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
of,O
specific,O
deletions,O
occur,O
with,O
high,O
frequency,O
.,O
 , 
#10712225
A,O
recurrent,O
expansion,O
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
and,O
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
gonadal,O
mosaicism,O
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
with,O
long,O
repeats,O
might,O
explain,O
the,O
different,O
instability,O
behavior,O
of,O
the,O
male,O
and,O
the,O
female,O
germlines,O
.,O
 , 
#9718357
NTBC,B-Gene
and,O
alkaptonuria,O
.,O
 , 
#9633815
Spectrum,O
of,O
mutations,O
in,O
the,O
fumarylacetoacetate,B-Gene
hydrolase,I-Gene
gene,O
of,O
tyrosinemia,O
type,O
1,O
patients,O
in,O
northwestern,O
Europe,O
and,O
Mediterranean,O
countries,O
.,O
 , 
Hereditary,O
tyrosinemia,O
type,O
1,O
(,O
HT1,O
),O
is,O
a,O
rare,O
metabolic,O
disease,O
caused,O
by,O
a,O
deficient,O
activity,O
of,O
the,O
enzyme,O
fumarylacetoacetase,O
(,O
FAH,O
),O
.,O
 , 
To,O
investigate,O
the,O
molecular,O
heterogeneity,O
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
1,O
-,O
14,O
of,O
the,O
FAH,B-Gene
gene,O
,,O
followed,O
by,O
SSCP,O
analysis,O
and,O
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
a,O
deletion,O
of,O
three,O
nucleotides,O
causing,O
a,O
deletion,O
of,O
serine,O
(,B-SNP
DEL366S,I-SNP
),I-SNP
and,O
three,O
splice,O
site,O
mutations,O
:,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
-,I-SNP
c,I-SNP
),I-SNP
,,I-SNP
IVS8,B-SNP
-,I-SNP
1(g,I-SNP
-,I-SNP
c,I-SNP
),I-SNP
.,I-SNP
 , 
The,O
splice,O
site,O
mutations,O
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
the,O
unconventional,O
type,O
Vb,O
myosin,O
motor,O
protein,O
,,O
in,O
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
novel,O
nonsense,O
and,O
missense,O
mutations,O
in,O
MYO5B,B-Gene
in,O
11,O
unrelated,O
MVID,O
patients,O
.,O
 , 
Fluorescence,O
microscopy,O
,,O
Western,O
blotting,O
,,O
and,O
electron,O
microscopy,O
were,O
applied,O
to,O
analyze,O
the,O
effects,O
of,O
MYO5B,B-Gene
siRNA,O
knock,O
-,O
down,O
in,O
polarized,O
,,O
brush,O
border,O
possessing,O
CaCo-2,O
cells,O
.,O
 , 
Loss,O
of,O
surface,O
microvilli,O
,,O
increased,O
formation,O
of,O
microvillus,O
inclusions,O
,,O
and,O
subapical,O
enrichment,O
of,O
PAS,O
-,O
positive,O
endomembrane,O
compartments,O
were,O
induced,O
in,O
polarized,O
,,O
filter,O
-,O
grown,O
CaCo-2,O
cells,O
,,O
following,O
MYO5B,B-Gene
knock,O
-,O
down,O
.,O
 , 
Our,O
data,O
indicate,O
that,O
MYO5B,O
mutations,B-Gene
are,O
a,O
major,O
cause,O
of,O
microvillus,O
inclusion,O
disease,O
and,O
that,O
MYO5B,B-Gene
knock,O
-,O
down,O
recapitulates,O
most,O
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
as,O
the,O
cause,O
of,O
microvillus,O
inclusion,O
disease,O
.,O
 , 
#15747259
No,O
convincing,O
evidence,O
of,O
linkage,O
for,O
restless,O
legs,O
syndrome,O
on,O
chromosome,O
9p,O
.,O
 , 
#1301933
Rapid,O
preparation,O
of,O
genomic,O
DNA,O
from,O
dried,O
blood,O
and,O
saliva,O
spots,O
for,O
polymerase,O
chain,O
reaction,O
.,O
 , 
#19944400
Deletions,O
and,O
point,O
mutations,O
of,O
LRRC50,B-Gene
cause,O
primary,O
ciliary,O
dyskinesia,O
due,O
to,O
dynein,O
arm,O
defects,O
.,O
 , 
Genetic,O
defects,O
affecting,O
motility,O
of,O
cilia,O
and,O
flagella,O
cause,O
chronic,O
destructive,O
airway,O
disease,O
,,O
randomization,O
of,O
left,O
-,O
right,O
body,O
asymmetry,O
,,O
and,O
,,O
frequently,O
,,O
male,O
infertility,O
in,O
primary,O
ciliary,O
dyskinesia,O
(,O
PCD,O
),O
.,O
 , 
The,O
most,O
frequent,O
defects,O
involve,O
outer,O
and,O
inner,O
dynein,O
arms,O
(,O
ODAs,O
and,O
IDAs,O
),O
that,O
are,O
large,O
multiprotein,O
complexes,O
responsible,O
for,O
cilia,O
-,O
beat,O
generation,O
and,O
regulation,O
,,O
respectively,O
.,O
 , 
Here,O
,,O
we,O
demonstrate,O
that,O
large,O
genomic,O
deletions,O
,,O
as,O
well,O
as,O
point,O
mutations,O
involving,O
LRRC50,B-Gene
,,I-Gene
are,O
responsible,O
for,O
a,O
distinct,O
PCD,O
variant,O
that,O
is,O
characterized,O
by,O
a,O
combined,O
defect,O
involving,O
assembly,O
of,O
the,O
ODAs,O
and,O
IDAs,O
.,O
 , 
Functional,O
analyses,O
showed,O
that,O
LRRC50,B-Gene
deficiency,O
disrupts,O
assembly,O
of,O
distally,O
and,O
proximally,O
DNAH5-,B-Gene
and,O
DNAI2,B-Gene
-,I-Gene
containing,O
ODA,O
complexes,O
,,O
as,O
well,O
as,O
DNALI1,B-Gene
-,I-Gene
containing,O
IDA,O
complexes,O
,,O
resulting,O
in,O
immotile,O
cilia,O
.,O
 , 
On,O
the,O
basis,O
of,O
these,O
findings,O
,,O
we,O
assume,O
that,O
LRRC50,B-Gene
plays,O
a,O
role,O
in,O
assembly,O
of,O
distinct,O
dynein,O
-,O
arm,O
complexes,O
.,O
 , 
#7977348
Familial,O
site,O
-,O
specific,O
ovarian,O
cancer,O
is,O
linked,O
to,O
BRCA1,B-Gene
on,O
17q12,O
-,O
21,O
.,O
 , 
In,O
a,O
study,O
of,O
nine,O
families,O
with,O
",O
site,O
-,O
specific,O
",O
ovarian,O
cancer,O
(,O
criterion,O
:,O
three,O
or,O
more,O
cases,O
of,O
epithelial,O
ovarian,O
cancer,O
and,O
no,O
cases,O
of,O
breast,O
cancer,O
diagnosed,O
at,O
age,O
<,O
50,O
years,O
),O
we,O
have,O
obtained,O
evidence,O
of,O
linkage,O
to,O
the,O
breast,O
-,O
ovarian,O
cancer,O
susceptibility,O
gene,O
,,O
BRCA1,B-Gene
on,O
17q12,O
-,O
21,O
.,O
 , 
If,O
the,O
risk,O
of,O
cancer,O
in,O
these,O
families,O
is,O
assumed,O
to,O
be,O
restricted,O
to,O
the,O
ovary,O
,,O
the,O
best,O
estimate,O
of,O
the,O
proportion,O
of,O
families,O
linked,O
to,O
BRCA1,B-Gene
is,O
.78,O
(,O
95,O
%,O
confidence,O
interval,O
.32,O
-,O
1.0,O
),O
.,O
 , 
If,O
predisposition,O
to,O
both,O
breast,O
and,O
ovarian,O
cancer,O
is,O
assumed,O
,,O
the,O
proportion,O
linked,O
is,O
1.0,O
(,O
95,O
%,O
confidence,O
interval,O
.46,O
-,O
1.0,O
),O
.,O
 , 
The,O
linkage,O
of,O
familial,O
site,O
-,O
specific,O
ovarian,O
cancer,O
to,O
BRCA1,B-Gene
indicates,O
the,O
possibility,O
of,O
predictive,O
testing,O
in,O
such,O
families,O
;,O
however,O
,,O
this,O
is,O
only,O
appropriate,O
in,O
families,O
where,O
the,O
evidence,O
for,O
linkage,O
to,O
BRCA1,B-Gene
is,O
conclusive,O
.,O
 , 
#11139239
Jagged1,B-Gene
mutations,O
in,O
alagille,O
syndrome,O
.,O
 , 
We,O
have,O
summarized,O
data,O
on,O
233,O
Alagille,O
syndrome,O
patients,O
reported,O
with,O
mutations,O
in,O
Jagged1,B-Gene
(,B-Gene
JAG1,I-Gene
),I-Gene
.,O
 , 
This,O
data,O
has,O
been,O
published,O
by,O
seven,O
different,O
laboratories,O
in,O
Europe,O
,,O
the,O
United,O
States,O
,,O
Australia,O
,,O
and,O
Japan,O
.,O
 , 
Mutations,O
have,O
been,O
demonstrated,O
in,O
60,O
-,O
75,O
%,O
of,O
patients,O
with,O
a,O
clinically,O
confirmed,O
diagnosis,O
of,O
Alagille,O
syndrome,O
.,O
 , 
Total,O
gene,O
deletions,O
have,O
been,O
reported,O
in,O
3,O
-,O
7,O
%,O
of,O
patients,O
,,O
and,O
the,O
remainder,O
have,O
intragenic,O
mutations,O
.,O
 , 
Seventy,O
two,O
percent,O
(,O
168/233,O
),O
of,O
the,O
reported,O
mutations,O
lead,O
to,O
frameshifts,O
that,O
cause,O
a,O
premature,O
termination,O
codon,O
.,O
 , 
These,O
mutations,O
will,O
either,O
lead,O
to,O
a,O
prematurely,O
truncated,O
protein,O
,,O
or,O
alternatively,O
,,O
nonsense,O
mediated,O
decay,O
might,O
lead,O
to,O
lack,O
of,O
a,O
product,O
from,O
that,O
allele,O
.,O
 , 
Twenty,O
three,O
unique,O
missense,O
mutations,O
were,O
identified,O
(,O
13,O
%,O
of,O
mutations,O
),O
.,O
 , 
These,O
were,O
clustered,O
in,O
conserved,O
regions,O
at,O
the,O
5,O
',O
end,O
of,O
the,O
gene,O
,,O
or,O
in,O
the,O
EGF,O
repeats,O
.,O
 , 
Splicing,O
consensus,O
sequence,O
changes,O
were,O
identified,O
in,O
15,O
%,O
of,O
patients,O
.,O
 , 
A,O
high,O
frequency,O
of,O
de,O
novo,O
mutations,O
(,O
60,O
-,O
70,O
%,O
),O
has,O
been,O
reported,O
.,O
 , 
The,O
spectrum,O
of,O
mutations,O
identified,O
is,O
consistent,O
with,O
haploinsufficiency,O
for,O
JAG1,B-Gene
being,O
a,O
mechanism,O
for,O
Alagille,O
syndrome,O
.,O
 , 
#12938095
Molecular,O
analysis,O
in,O
Fabry,O
disease,O
in,O
Spain,O
:,O
fifteen,O
novel,O
GLA,O
mutations,O
and,O
identification,O
of,O
a,O
homozygous,O
female,O
.,O
 , 
Fabry,O
disease,O
,,O
an,O
X,O
-,O
linked,O
inborn,O
error,O
of,O
glycosphingolipid,O
catabolism,O
,,O
results,O
from,O
mutations,O
in,O
the,O
alpha,B-Gene
-,I-Gene
galactosidase,I-Gene
A,I-Gene
gene,I-Gene
(,B-Gene
GLA,I-Gene
),I-Gene
.,O
 , 
Here,O
we,O
report,O
molecular,O
studies,O
in,O
22,O
unrelated,O
Spanish,O
patients,O
with,O
Fabry,O
disease,O
(,O
20,O
males,O
and,O
two,O
females,O
),O
.,O
 , 
Fifteen,O
novel,O
mutations,O
were,O
identified,O
.,O
 , 
In,O
addition,O
7,O
previously,O
described,O
mutations,O
and,O
two,O
previously,O
reported,O
polymorphisms,O
were,O
detected,O
.,O
 , 
The,O
15,O
novel,O
mutations,O
comprise,O
:,O
eight,O
missense,O
E48,B-SNP
K,I-SNP
(,B-SNP
c.142G,I-SNP
>,I-SNP
A,I-SNP
),I-SNP
,,O
W81S,B-SNP
(,B-SNP
c.242G,I-SNP
>,I-SNP
C,I-SNP
),I-SNP
,,O
 , 
D170H,B-SNP
(,B-SNP
c.508G,I-SNP
>,I-SNP
C,I-SNP
),I-SNP
,,O
W226C,B-SNP
(,B-SNP
c.678G,I-SNP
>,I-SNP
T,I-SNP
),I-SNP
,,O
Q279R,B-SNP
 , 
(,B-SNP
c.836A,I-SNP
>,I-SNP
G,I-SNP
),I-SNP
,,O
C382Y,B-SNP
(,B-SNP
c.1145G,I-SNP
>,I-SNP
A,I-SNP
),I-SNP
,,O
I407,B-SNP
K,I-SNP
(,B-SNP
c.1220T,I-SNP
>,I-SNP
A,I-SNP
),I-SNP
,,O
L414S,B-SNP
(,B-SNP
c.1241T,I-SNP
>,I-SNP
C,I-SNP
),I-SNP
;,O
one,O
nonsense,O
W95X,B-SNP
(,B-SNP
c.284G,I-SNP
>,I-SNP
A,I-SNP
),I-SNP
;,O
one,O
insertion,O
Y216fsX15,B-SNP
(,B-SNP
c.646_647insT,I-SNP
),I-SNP
;,O
two,O
small,O
deletions,O
G346fsX1,B-SNP
(,B-SNP
c.1037delG,I-SNP
),I-SNP
,,O
K426fsX23,B-SNP
(,B-SNP
c.1277_1278delAA,I-SNP
),I-SNP
;,O
one,O
gross,O
deletion,O
comprising,O
exons,O
5,O
,,O
6,O
,,O
7,O
;,O
one,O
complex,O
mutation,O
(,O
insertion,O
and,O
deletion,O
),O
A368fsX24,B-SNP
(,B-SNP
c.1102delGinsTTATAC,I-SNP
),I-SNP
,,O
and,O
one,O
splice,O
-,O
site,O
mutation,O
IVS4,B-SNP
+,I-SNP
1G,I-SNP
>,I-SNP
A,I-SNP
(,B-SNP
c.639,I-SNP
+,I-SNP
1G,I-SNP
>,I-SNP
A,I-SNP
),I-SNP
.,O
 , 
One,O
of,O
the,O
females,O
was,O
found,O
homozygous,O
for,O
Q279R,B-SNP
mutation,O
and,O
she,O
presented,O
with,O
the,O
classic,O
phenotype,O
since,O
the,O
age,O
of,O
8,O
years,O
,,O
this,O
case,O
extending,O
into,O
women,O
the,O
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
to,O
inhibit,O
the,O
initial,O
folding,O
of,O
the,O
subunit,O
.,O
 , 
#9375854
Analysis,O
of,O
multiple,O
mitochondrial,O
DNA,O
deletions,O
in,O
inclusion,O
body,O
myositis,O
.,O
 , 
Inclusion,O
body,O
myositis,O
(,O
IBM,O
),O
is,O
a,O
sporadic,O
progressive,O
myopathy,O
,,O
which,O
is,O
morphologically,O
characterized,O
by,O
inflammatory,O
cell,O
infiltrates,O
and,O
rimmed,O
vacuoles,O
in,O
muscle,O
fibers,O
.,O
 , 
Mitochondrial,O
changes,O
are,O
regularly,O
present,O
with,O
ragged,O
-,O
red,O
fibers,O
showing,O
deficiency,O
of,O
cytochrome,O
c,O
oxidase,O
.,O
 , 
In,O
these,O
muscle,O
fiber,O
segments,O
,,O
there,O
is,O
accumulation,O
of,O
mitochondria,O
with,O
mitochondrial,O
DNA,O
(,O
mtDNA,O
),O
deletions,O
.,O
 , 
There,O
are,O
different,O
deletions,O
in,O
different,O
muscle,O
fibers,O
.,O
 , 
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
 , 
The,O
deletion,O
breakpoints,O
were,O
sequenced,O
from,O
cloned,O
polymerase,O
chain,O
reaction,O
(,O
PCR)-amplified,O
mtDNA,O
fragments,O
.,O
 , 
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
 , 
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
breakpoints,O
in,O
certain,O
regions,O
of,O
mtDNA,O
.,O
 , 
These,O
predominant,O
breakpoint,O
regions,O
are,O
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
dominant,O
progressive,O
external,O
ophthalmoplegia,O
(,O
adPEO,O
),O
and,O
normal,O
aging,O
,,O
but,O
different,O
from,O
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
adPEO,O
,,O
and,O
aging,O
.,O
 , 
#9222768
Novel,O
mutation,O
(,B-SNP
A141D,I-SNP
),I-SNP
in,O
exon,O
4,O
of,O
the,O
CFTR,B-Gene
gene,O
identified,O
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
 , 
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
with,O
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
an,O
additional,O
missense,O
mutation,O
(,B-SNP
Gly122,I-SNP
>,I-SNP
Ser,I-SNP
),I-SNP
.,O
 , 
The,O
splice,O
donor,O
site,O
mutation,O
and,O
the,O
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
was,O
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
P<.05,O
),O
.,O
 , 
The,O
same,O
region,O
is,O
known,O
to,O
be,O
the,O
site,O
of,O
a,O
neuropeptide,B-Gene
Y,I-Gene
receptor,I-Gene
gene,O
,,O
NPY1R,B-Gene
(,O
4q31,O
-,O
q32,O
),O
,,O
that,O
was,O
recently,O
connected,O
to,O
anxiolytic,O
-,O
like,O
effects,O
in,O
rats,O
.,O
 , 
Several,O
other,O
regions,O
on,O
four,O
chromosomes,O
(,O
4q21.21,O
-,O
22.3,O
,,O
5q14.2,O
-,O
14.3,O
,,O
8p23.1,O
,,O
and,O
14q22.3,O
-,O
23.3,O
),O
met,O
criteria,O
for,O
suggestive,O
linkage,O
(,O
multipoint,O
nominal,O
P,O
values,O
<,O
.01,O
),O
.,O
 , 
Family,O
-,O
by,O
-,O
family,O
analysis,O
did,O
not,O
show,O
any,O
strong,O
evidence,O
of,O
heterogeneity,O
.,O
 , 
Our,O
findings,O
support,O
the,O
notion,O
that,O
the,O
major,O
anxiety,O
disorders,O
,,O
including,O
phobias,O
and,O
panic,O
disorder,O
,,O
are,O
complex,O
traits,O
that,O
share,O
at,O
least,O
one,O
susceptibility,O
locus,O
.,O
 , 
This,O
method,O
could,O
be,O
applied,O
to,O
other,O
complex,O
traits,O
for,O
which,O
shared,O
genetic,O
-,O
liability,O
factors,O
are,O
thought,O
to,O
be,O
important,O
,,O
such,O
as,O
substance,O
dependencies,O
.,O
 , 
#17024664
Genotype,O
-,O
phenotype,O
correlations,O
in,O
von,O
Hippel,O
-,O
Lindau,O
disease,O
.,O
 , 
von,O
Hippel,O
-,O
Lindau,O
(,O
VHL,O
),O
disease,O
is,O
a,O
dominantly,O
inherited,O
familial,O
cancer,O
syndrome,O
resulting,O
from,O
mutations,O
in,O
the,O
VHL,O
tumor,O
suppressor,O
gene,O
.,O
 , 
VHL,O
disease,O
displays,O
marked,O
variation,O
in,O
expression,O
and,O
the,O
presence,O
of,O
pheochromocytoma,O
has,O
been,O
linked,O
to,O
missense,O
VHL,O
mutations,O
.,O
 , 
We,O
analyzed,O
genotype,O
-,O
phenotype,O
correlations,O
in,O
573,O
individuals,O
with,O
VHL,O
disease,O
.,O
 , 
Routine,O
clinical,O
and,O
radiological,O
surveillance,O
of,O
VHL,O
patients,O
and,O
at,O
-,O
risk,O
relatives,O
was,O
associated,O
with,O
increased,O
detection,O
of,O
retinal,O
angiomatosis,O
(,O
73,O
vs.,O
59,O
%,O
of,O
cases,O
),O
and,O
a,O
reduction,O
in,O
age,O
at,O
diagnosis,O
of,O
renal,O
cell,O
carcinoma,O
(,O
RCC,O
),O
(,O
44.0+/-10.9,O
vs.,O
39.7+/-10.3,O
years,O
),O
.,O
 , 
We,O
confirmed,O
the,O
association,O
of,O
pheochromocytoma,O
with,O
missense,O
mutations,O
described,O
previously,O
,,O
but,O
stratifying,O
missense,O
mutations,O
into,O
those,O
that,O
resulted,O
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
at,O
first,O
manifestation,O
of,O
VHL,O
disease,O
was,O
significantly,O
earlier,O
(,O
P=0.001,O
),O
,,O
and,O
age,O
-,O
related,O
risks,O
of,O
retinal,O
angiomas,O
and,O
RCC,O
were,O
higher,O
(,O
P=0.022,O
and,O
P=0.0008,O
,,O
respectively,O
),O
in,O
individuals,O
with,O
a,O
nonsense,O
or,O
frameshift,O
mutation,O
than,O
in,O
those,O
with,O
deletions,O
or,O
missense,O
mutations,O
that,O
disrupted,O
the,O
structural,O
integrity,O
of,O
the,O
VHL,O
gene,O
product,O
(,O
pVHL,O
),O
.,O
 , 
These,O
results,O
extend,O
genotype,O
-,O
phenotype,O
-,O
protein,O
structure,O
correlations,O
in,O
VHL,O
disease,O
and,O
provide,O
a,O
baseline,O
for,O
future,O
chemoprevention,O
studies,O
in,O
VHL,O
disease,O
.,O
 , 
#23084292
Unraveling,O
multiple,O
MHC,O
gene,O
associations,O
with,O
systemic,O
lupus,O
erythematosus,O
:,O
model,O
choice,O
indicates,O
a,O
role,O
for,O
HLA,O
alleles,O
and,O
non,O
-,O
HLA,O
genes,O
in,O
Europeans,O
.,O
 , 
We,O
have,O
performed,O
a,O
meta,O
-,O
analysis,O
of,O
the,O
major,O
-,O
histocompatibility,O
-,O
complex,O
(,O
MHC,O
),O
region,O
in,O
systemic,O
lupus,O
erythematosus,O
(,O
SLE,O
),O
to,O
determine,O
the,O
association,O
with,O
both,O
SNPs,O
and,O
classical,O
human,O
-,O
leukocyte,O
-,O
antigen,O
(,O
HLA,O
),O
alleles,O
.,O
 , 
More,O
specifically,O
,,O
we,O
combined,O
results,O
from,O
six,O
studies,O
and,O
well,O
-,O
known,O
out,O
-,O
of,O
-,O
study,O
control,O
data,O
sets,O
,,O
providing,O
us,O
with,O
3,701,O
independent,O
SLE,O
cases,O
and,O
12,110,O
independent,O
controls,O
of,O
European,O
ancestry,O
.,O
 , 
This,O
study,O
used,O
genotypes,O
for,O
7,199,O
SNPs,O
within,O
the,O
MHC,O
region,O
and,O
for,O
classical,O
HLA,O
alleles,O
(,O
typed,O
and,O
imputed,O
),O
.,O
 , 
Our,O
results,O
from,O
conditional,O
analysis,O
and,O
model,O
choice,O
with,O
the,O
use,O
of,O
the,O
Bayesian,O
information,O
criterion,O
show,O
that,O
the,O
best,O
model,O
for,O
SLE,O
association,O
includes,O
both,O
classical,O
loci,O
(,B-Gene
HLA,I-Gene
-,I-Gene
DRB1(∗)03:01,I-Gene
,,O
HLA,B-Gene
-,I-Gene
DRB1(∗)08:01,I-Gene
,,O
and,O
HLA,B-Gene
-,I-Gene
DQA1(∗)01:02,I-Gene
),O
and,O
two,O
SNPs,O
,,O
rs8192591,O
(,O
in,O
class,O
III,O
and,O
upstream,O
of,O
NOTCH4,B-Gene
),I-Gene
and,O
rs2246618,O
(,B-Gene
MICB,I-Gene
in,O
class,O
I,O
),O
.,O
 , 
Our,O
approach,O
was,O
to,O
perform,O
a,O
stepwise,O
search,O
from,O
multiple,O
baseline,O
models,O
deduced,O
from,O
a,O
priori,O
evidence,O
on,O
HLA,B-Gene
-,I-Gene
DRB1,I-Gene
lupus,O
-,O
associated,O
alleles,O
,,O
a,O
stepwise,O
regression,O
on,O
SNPs,O
alone,O
,,O
and,O
a,O
stepwise,O
regression,O
on,O
HLA,O
alleles,O
.,O
 , 
With,O
this,O
approach,O
,,O
we,O
were,O
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
one,O
identified,O
by,O
simple,O
stepwise,O
regression,O
either,O
on,O
SNPs,O
alone,O
(,O
Bayes,O
factor,O
[,O
BF,O
],O
>,O
50,O
),O
or,O
on,O
classical,O
HLA,O
alleles,O
alone,O
(,O
BF,O
>,O
1,000,O
),O
.,O
 , 
#11799475
Evidence,O
for,O
a,O
susceptibility,O
gene,O
for,O
anorexia,O
nervosa,O
on,O
chromosome,O
1,O
.,O
 , 
Eating,O
disorders,O
,,O
such,O
as,O
anorexia,O
nervosa,O
(,O
AN,O
),O
,,O
have,O
a,O
significant,O
genetic,O
component,O
.,O
 , 
In,O
the,O
current,O
study,O
,,O
a,O
genomewide,O
linkage,O
analysis,O
of,O
192,O
families,O
with,O
at,O
least,O
one,O
affected,O
relative,O
pair,O
with,O
AN,O
and,O
related,O
eating,O
disorders,O
,,O
including,O
bulimia,O
nervosa,O
,,O
was,O
performed,O
,,O
resulting,O
in,O
only,O
modest,O
evidence,O
for,O
linkage,O
,,O
with,O
the,O
highest,O
nonparametric,O
linkage,O
(,O
NPL,O
),O
score,O
,,O
1.80,O
,,O
at,O
marker,O
D4S2367,O
on,O
chromosome,O
4,O
.,O
 , 
Since,O
the,O
reduction,O
of,O
sample,O
heterogeneity,O
would,O
increase,O
power,O
to,O
detect,O
linkage,O
,,O
we,O
performed,O
linkage,O
analysis,O
in,O
a,O
subset,O
(,O
n=37,O
),O
of,O
families,O
in,O
which,O
at,O
least,O
two,O
affected,O
relatives,O
had,O
diagnoses,O
of,O
restricting,O
AN,O
,,O
a,O
clinically,O
defined,O
subtype,O
of,O
AN,O
characterized,O
by,O
severe,O
limitation,O
of,O
food,O
intake,O
without,O
the,O
presence,O
of,O
binge,O
-,O
eating,O
or,O
purging,O
behavior,O
.,O
 , 
When,O
we,O
limited,O
the,O
linkage,O
analysis,O
to,O
this,O
clinically,O
more,O
homogeneous,O
subgroup,O
,,O
the,O
highest,O
multipoint,O
NPL,O
score,O
observed,O
was,O
3.03,O
,,O
at,O
marker,O
D1S3721,O
on,O
chromosome,O
1p,O
.,O
 , 
The,O
genotyping,O
of,O
additional,O
markers,O
in,O
this,O
region,O
led,O
to,O
a,O
peak,O
multipoint,O
NPL,O
score,O
of,O
3.45,O
,,O
thereby,O
providing,O
suggestive,O
evidence,O
for,O
the,O
presence,O
of,O
an,O
AN,O
-,O
susceptibility,O
locus,O
on,O
chromosome,O
1p,O
.,O
 , 
#9452048
Identification,O
of,O
three,O
novel,O
mutations,O
in,O
the,O
CFTR,B-Gene
gene,O
,,O
R117P,B-SNP
,,I-SNP
deltaD192,B-SNP
,,I-SNP
and,O
3121,B-SNP
-,I-SNP
1G-->A,I-SNP
in,O
four,O
French,O
patients,O
.,O
 , 
#11781875
2001,O
ASHG,O
Award,O
for,O
Excellence,O
in,O
Education,O
.,O
 , 
Introductory,O
speech,O
for,O
Charles,O
Scriver,O
.,O
 , 
#16138310
Molecular,O
diagnosis,O
of,O
inherited,O
disorders,O
:,O
lessons,O
from,O
hemoglobinopathies,O
.,O
 , 
Hemoglobinopathies,O
constitute,O
a,O
major,O
health,O
problem,O
worldwide,O
,,O
with,O
a,O
high,O
carrier,O
frequency,O
,,O
particularly,O
in,O
certain,O
regions,O
where,O
malaria,O
has,O
been,O
endemic,O
.,O
 , 
These,O
disorders,O
are,O
characterized,O
by,O
a,O
vast,O
clinical,O
and,O
hematological,O
phenotypic,O
heterogeneity,O
.,O
 , 
Over,O
1,200,O
different,O
genetic,O
alterations,O
that,O
affect,O
the,O
DNA,O
sequence,O
of,O
the,O
human,O
alpha,O
-,O
like,O
(,B-Gene
HBZ,I-Gene
,,I-Gene
HBA2,B-Gene
,,I-Gene
HBA1,B-Gene
,,I-Gene
and,O
HBQ1,B-Gene
),I-Gene
and,O
beta,O
-,O
like,O
(,B-Gene
HBE1,I-Gene
,,I-Gene
HBG2,B-Gene
,,I-Gene
HBG1,B-Gene
,,I-Gene
HBD,B-Gene
,,I-Gene
and,O
HBB,B-Gene
),I-Gene
globin,B-Gene
genes,O
are,O
mainly,O
responsible,O
for,O
the,O
observed,O
clinical,O
heterogeneity,O
.,O
 , 
These,O
mutations,O
,,O
together,O
with,O
detailed,O
information,O
about,O
the,O
resulting,O
phenotype,O
,,O
are,O
documented,O
in,O
the,O
globin,O
locus,O
-,O
specific,O
HbVar,O
database,O
.,O
 , 
Family,O
studies,O
and,O
comprehensive,O
hematological,O
analyses,O
provide,O
useful,O
insights,O
for,O
accurately,O
diagnosing,O
thalassemia,O
at,O
the,O
DNA,O
level,O
.,O
 , 
For,O
this,O
purpose,O
,,O
numerous,O
techniques,O
can,O
provide,O
accurate,O
,,O
rapid,O
,,O
and,O
cost,O
-,O
effective,O
identification,O
of,O
the,O
underlying,O
genetic,O
defect,O
in,O
affected,O
individuals,O
.,O
 , 
The,O
aim,O
of,O
this,O
article,O
is,O
to,O
review,O
the,O
diverse,O
methodological,O
and,O
technical,O
platforms,O
available,O
for,O
the,O
molecular,O
diagnosis,O
of,O
inherited,O
disorders,O
,,O
using,O
thalassemia,O
and,O
hemoglobinopathies,O
as,O
a,O
model,O
.,O
 , 
This,O
article,O
also,O
attempts,O
to,O
shed,O
light,O
on,O
issues,O
closely,O
related,O
to,O
thalassemia,O
diagnostics,O
,,O
such,O
as,O
prenatal,O
and,O
preimplantation,O
genetic,O
diagnoses,O
and,O
genetic,O
counseling,O
,,O
for,O
better,O
-,O
quality,O
disease,O
management,O
.,O
 , 
#15338459
",O
Bias,O
toward,O
the,O
null,O
",O
means,O
reduced,O
power,O
.,O
 , 
#18429048
Haplotype,O
analysis,O
suggests,O
a,O
single,O
Balkan,O
origin,O
for,O
the,O
Gaucher,O
disease,O
[,B-SNP
D409H;H255Q,B-SNP
],I-SNP
double,O
mutant,O
allele,O
.,O
 , 
Gaucher,O
disease,O
is,O
an,O
autosomal,O
recessive,O
lysosomal,O
storage,O
disease,O
that,O
is,O
mainly,O
due,O
to,O
mutations,O
in,O
the,O
GBA,O
gene,O
.,O
 , 
Most,O
of,O
the,O
mutant,O
alleles,O
described,O
so,O
far,O
bear,O
a,O
single,O
mutation,O
.,O
 , 
However,O
,,O
there,O
are,O
a,O
few,O
alleles,O
bearing,O
two,O
or,O
more,O
DNA,O
changes,O
.,O
 , 
It,O
has,O
been,O
reported,O
that,O
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
and,O
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
affecting,O
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
 , 
As,O
a,O
consequence,O
,,O
a,O
high,O
number,O
of,O
cases,O
(,O
up,O
to,O
50,O
%,O
),O
are,O
sporadic,O
.,O
 , 
Mutation,O
detection,O
is,O
complex,O
due,O
to,O
the,O
large,O
size,O
of,O
NF1,B-Gene
gene,O
,,O
the,O
presence,O
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
unrelated,O
subjects,O
affected,O
by,O
NF1,B-Gene
.,I-Gene
 , 
For,O
each,O
patient,O
,,O
the,O
whole,O
coding,O
sequence,O
and,O
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
or,O
,,O
most,O
often,O
,,O
by,O
denaturing,O
high,O
performance,O
liquid,O
chromatography,O
(,O
DHPLC,O
),O
.,O
 , 
Mutations,O
were,O
identified,O
in,O
75,O
(,O
68,O
%,O
),O
patients,O
.,O
 , 
Twenty,O
-,O
two,O
mutations,O
were,O
found,O
to,O
be,O
novel,O
.,O
 , 
The,O
detection,O
rate,O
for,O
the,O
different,O
methods,O
was,O
7/18,O
(,O
39,O
%,O
),O
for,O
PTT,O
,,O
and,O
68/103,O
(,O
66,O
%,O
),O
for,O
DHPLC,O
.,O
 , 
The,O
mutations,O
were,O
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
harbour,O
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
was,O
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
patients,O
with,O
the,O
hyperornithinemia,O
,,O
hyperammonemia,O
,,O
and,O
homocitrullinuria,O
(,O
HHH,O
),O
syndrome,O
were,O
analyzed,O
for,O
mutations,O
in,O
the,O
ORNT1,B-Gene
gene,O
.,O
 , 
Seven,O
novel,O
mutations,O
were,O
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
and,O
IVS5,B-SNP
+,I-SNP
1G-->A,I-SNP
),I-SNP
.,O
 , 
Other,O
previously,O
described,O
variants,O
were,O
a,O
heterozygous,O
deletion,O
of,O
a,O
phenylalanine,O
residue,O
(,B-SNP
F188del,I-SNP
),I-SNP
in,O
one,O
allele,O
and,O
the,O
R179X,B-SNP
in,O
two,O
.,O
 , 
The,O
G27R,B-SNP
mutation,O
was,O
carried,O
by,O
two,O
patients,O
.,O
 , 
Analyses,O
of,O
ORNT1,B-Gene
mRNA,O
in,O
four,O
patients,O
showed,O
that,O
mutant,O
alleles,O
were,O
stable,O
and,O
of,O
the,O
predicted,O
size,O
.,O
 , 
The,O
current,O
study,O
expands,O
the,O
spectrum,O
of,O
mutations,O
in,O
ORNT1,B-Gene
gene,O
.,O
 , 
#8981970
Expression,O
of,O
DAZ,B-Gene
,,I-Gene
an,O
azoospermia,O
factor,O
candidate,O
,,O
in,O
human,O
spermatogonia,O
.,O
 , 
#8723698
Simple,O
detection,O
of,O
a,O
(,O
Finnish,O
),O
hereditary,O
tyrosinemia,B-Gene
type,I-Gene
1,I-Gene
mutation,O
.,O
 , 
#8102508
Genetic,O
heterogeneity,O
in,O
benign,O
familial,O
neonatal,O
convulsions,O
:,O
identification,O
of,O
a,O
new,O
locus,O
on,O
chromosome,O
8q,O
.,O
 , 
The,O
syndrome,O
of,O
benign,O
familial,O
neonatal,O
convulsions,O
(,O
BFNC,O
),O
is,O
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
has,O
been,O
mapped,O
to,O
chromosome,O
20,O
in,O
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
dinucleotide,O
repeat,O
markers,O
distributed,O
throughout,O
the,O
genome,O
were,O
used,O
to,O
screen,O
this,O
family,O
.,O
 , 
Maximum,O
pairwise,O
LOD,O
scores,O
of,O
4.43,O
were,O
obtained,O
with,O
markers,O
D8S284,O
and,O
D8S256,O
on,O
chromosome,O
8q,O
.,O
 , 
Multipoint,O
analysis,O
placed,O
the,O
BFNC,B-Gene
locus,O
in,O
the,O
interval,O
spanned,O
by,O
D8S198,O
-,O
D8S274,O
.,O
 , 
This,O
study,O
establishes,O
the,O
presence,O
of,O
a,O
new,O
BFNC,B-Gene
locus,O
and,O
confirms,O
genetic,O
heterogeneity,O
of,O
this,O
disorder,O
.,O
 , 
#15726498
Position,O
effects,O
due,O
to,O
chromosome,O
breakpoints,O
that,O
map,O
approximately,O
900,O
Kb,O
upstream,O
and,O
approximately,O
1.3,O
Mb,O
downstream,O
of,O
SOX9,B-Gene
in,O
two,O
patients,O
with,O
campomelic,O
dysplasia,O
.,O
 , 
Campomelic,O
dysplasia,O
(,O
CD,O
),O
is,O
a,O
semilethal,O
skeletal,O
malformation,O
syndrome,O
with,O
or,O
without,O
XY,O
sex,O
reversal,O
.,O
 , 
In,O
addition,O
to,O
the,O
multiple,O
mutations,O
found,O
within,O
the,O
sex,O
-,O
determining,O
region,O
Y,O
-,O
related,O
high,O
-,O
mobility,O
group,O
box,O
gene,O
(,B-Gene
SOX9,I-Gene
),I-Gene
on,O
17q24.3,O
,,O
several,O
chromosome,O
anomalies,O
(,O
translocations,O
,,O
inversions,O
,,O
and,O
deletions,O
),O
with,O
breakpoints,O
scattered,O
over,O
1,O
Mb,O
upstream,O
of,O
SOX9,B-Gene
have,O
been,O
described,O
.,O
 , 
Here,O
,,O
we,O
present,O
a,O
balanced,O
translocation,O
,,O
t(4;17)(q28.3;q24.3,O
),O
,,O
segregating,O
in,O
a,O
family,O
with,O
a,O
mild,O
acampomelic,O
CD,O
with,O
Robin,O
sequence,O
.,O
 , 
Both,O
chromosome,O
breakpoints,O
have,O
been,O
identified,O
by,O
fluorescence,O
in,O
situ,O
hybridization,O
and,O
have,O
been,O
sequenced,O
using,O
a,O
somatic,O
cell,O
hybrid,O
.,O
 , 
The,O
17q24.3,O
breakpoint,O
maps,O
approximately,O
900,O
kb,O
upstream,O
of,O
SOX9,B-Gene
,,I-Gene
which,O
is,O
within,O
the,O
same,O
bacterial,O
artificial,O
chromosome,O
clone,O
as,O
the,O
breakpoints,O
of,O
two,O
other,O
reported,O
patients,O
with,O
mild,O
CD,O
.,O
 , 
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
sex,O
reversal,O
in,O
a,O
fetus,O
with,O
a,O
de,O
novo,O
balanced,O
complex,O
karyotype,O
,,O
46,XY,O
,,O
t(4;7;8;17)(4qter-->4p15.1::17q25.1,O
-,O
->17qter;7qter-->7p15.3::4p15.1,O
-,O
->4pter;8pter-->8q12.1::7p15.3,O
-,O
->7pter;17pter-->17q25.1::8q12.1,O
-,O
->8qter,O
),O
.,O
 , 
Surprisingly,O
,,O
the,O
17q,O
breakpoint,O
maps,O
approximately,O
1.3,O
Mb,O
downstream,O
of,O
SOX9,B-Gene
,,I-Gene
making,O
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
using,O
the,O
Regulatory,O
Potential,O
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
the,O
interphase,O
nucleus,O
,,O
despite,O
being,O
located,O
1.1,O
Mb,O
upstream,O
and,O
1.3,O
Mb,O
downstream,O
of,O
it,O
,,O
respectively,O
.,O
 , 
The,O
potential,O
molecular,O
mechanism,O
responsible,O
for,O
the,O
position,O
effect,O
is,O
discussed,O
.,O
 , 
#19462467
Molecular,O
profiling,O
of,O
the,O
",O
plexinome,O
",O
in,O
melanoma,O
and,O
pancreatic,O
cancer,O
.,O
 , 
Plexins,O
are,O
transmembrane,O
high,O
-,O
affinity,O
receptors,O
for,O
semaphorins,O
,,O
regulating,O
cell,O
guidance,O
,,O
motility,O
,,O
and,O
invasion,O
.,O
 , 
Functional,O
evidences,O
implicate,O
semaphorin,O
signals,O
in,O
cancer,O
progression,O
and,O
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
or,O
the,O
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
truncated,O
dystrophin,O
lacking,O
the,O
C,O
-,O
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
 , 
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
markers,O
within,O
and,O
flanking,O
the,O
TP53,B-Gene
gene,O
were,O
studied,O
.,O
 , 
Haplotype,O
analysis,O
using,O
five,O
markers,O
revealed,O
an,O
identical,O
haplotype,O
shared,O
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
lip,O
with,O
or,O
without,O
cleft,O
palate,O
(,O
CL,O
+,O
/-,O
 , 
P,O
),O
is,O
traditionally,O
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
 , 
P,O
has,O
been,O
reported,O
.,O
 , 
To,O
assess,O
the,O
potential,O
for,O
major,O
-,O
gene,O
involvement,O
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
were,O
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
or,O
a,O
generalized,O
single,O
-,O
major,O
-,O
locus,O
(,O
gSML,O
),O
trait,O
.,O
 , 
The,O
use,O
of,O
multiple,O
thresholds,O
based,O
on,O
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
 , 
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
was,O
reported,O
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
and,O
fusions,O
occur,O
frequently,O
in,O
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
aberrant,O
),O
loci,O
in,O
single,O
cells,O
.,O
 , 
Paternal,O
as,O
well,O
as,O
maternal,O
alleles,O
were,O
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
variants,O
.,O
 , 
The,O
parent,O
-,O
of,O
-,O
origin,O
analyses,O
together,O
with,O
microarray,O
-,O
guided,O
FISH,O
analyses,O
demonstrate,O
the,O
presence,O
of,O
inv,O
dup,O
del,O
chromosomes,O
as,O
well,O
as,O
more,O
complex,O
rearrangements,O
.,O
 , 
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
 , 
mtDNA,O
sequences,O
were,O
determined,O
from,O
241,O
individuals,O
from,O
nine,O
ethnic,O
groups,O
in,O
Africa,O
.,O
 , 
When,O
they,O
were,O
compared,O
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
do,O
between,O
one,O
other,O
.,O
 , 
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
not,O
are,O
hunters,O
and,O
gatherers,O
.,O
 , 
#10486315
Tissue,O
-,O
specific,O
somatic,O
mosaicism,O
in,O
spinal,O
and,O
bulbar,O
muscular,O
atrophy,O
is,O
dependent,O
on,O
CAG,O
-,O
repeat,O
length,O
and,O
androgen,O
receptor,O
--,O
gene,O
expression,O
level,O
.,O
 , 
The,O
factors,O
influencing,O
the,O
tissue,O
-,O
specific,O
pattern,O
of,O
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
 , 
We,O
performed,O
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
and,O
bulbar,O
muscular,O
atrophy,O
(,O
SBMA,O
),O
,,O
including,O
4,O
who,O
were,O
deceased,O
.,O
 , 
The,O
most,O
outstanding,O
feature,O
was,O
the,O
prominent,O
somatic,O
mosaicism,O
observed,O
in,O
the,O
cardiac,O
and,O
skeletal,O
muscles,O
,,O
composed,O
predominantly,O
of,O
postmitotic,O
cells,O
,,O
and,O
in,O
the,O
skin,O
,,O
prostate,O
,,O
and,O
testis,O
.,O
 , 
The,O
CNS,O
tissues,O
,,O
liver,O
,,O
and,O
spleen,O
showed,O
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
(,O
HD,O
),O
and,O
from,O
that,O
in,O
patients,O
with,O
dentatorubral,O
-,O
pallidoluysian,O
atrophy,O
(,O
DRPLA,O
),O
.,O
 , 
The,O
degree,O
of,O
somatic,O
mosaicism,O
correlated,O
with,O
the,O
CAG,O
-,O
repeat,O
number,O
but,O
not,O
with,O
age,O
at,O
examination,O
.,O
 , 
Furthermore,O
,,O
tissues,O
with,O
a,O
higher,O
mosaicism,O
level,O
corresponded,O
well,O
to,O
those,O
with,O
a,O
higher,O
expression,O
level,O
of,O
androgen,O
receptor,O
protein,O
.,O
 , 
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
with,O
iron,O
,,O
and,O
serum,O
ferritin,O
),O
,,O
which,O
are,O
important,O
in,O
iron,O
overload,O
(,O
e.g.,O
,,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
of,O
TF,B-Gene
,,I-Gene
was,O
significantly,O
associated,O
with,O
serum,O
transferrin,O
(,O
p,O
total,O
association,O
test,O
=,O
1.0,O
x,O
10(-9,O
),O
;,O
p,O
within,O
-,O
family,O
test,O
=,O
2.2,O
x,O
10(-5,O
),O
),O
.,O
 , 
In,O
the,O
second,O
GWAS,O
on,O
an,O
independent,O
sample,O
of,O
459,O
female,O
monozygotic,O
(,O
MZ,O
),O
twin,O
pairs,O
genotyped,O
with,O
300,O
K,O
SNPs,O
,,O
we,O
found,O
rs3811647,O
(,O
within,O
intron,O
11,O
of,O
TF,B-Gene
,,I-Gene
HapMap,O
CEU,O
r(2,O
),O
with,O
rs1830084,O
=,O
0.86,O
),O
was,O
significantly,O
associated,O
with,O
serum,O
transferrin,O
(,O
p,O
=,O
3.0,O
x,O
10(-15,O
),O
),O
.,O
 , 
In,O
the,O
second,O
GWAS,O
,,O
we,O
found,O
two,O
additional,O
and,O
independent,O
SNPs,O
on,O
TF,B-Gene
(,O
rs1799852,O
and,O
rs2280673,O
),O
and,O
confirmed,O
the,O
known,O
C282Y,B-SNP
mutation,O
in,O
HFE,B-Gene
to,O
be,O
independently,O
associated,O
with,O
serum,O
transferrin,O
.,O
 , 
The,O
three,O
variants,O
in,O
TF,B-Gene
(,O
rs3811647,O
,,O
rs1799852,O
and,O
rs2280673,O
),O
plus,O
the,O
HFE,B-Gene
C282Y,B-SNP
mutation,O
explained,O
approximately,O
40,O
%,O
of,O
genetic,O
variation,O
in,O
serum,O
transferrin,O
(,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
may,O
be,O
simpler,O
than,O
that,O
of,O
disease,O
.,O
 , 
#10094554
A,O
simple,O
multiplex,O
FRAXA,O
,,O
FRAXE,O
,,O
and,O
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
are,O
folate,O
-,O
sensitive,O
fragile,O
sites,O
originally,O
discovered,O
in,O
patients,O
with,O
X,O
-,O
linked,O
mental,O
retardation,O
.,O
 , 
The,O
FMR1,B-Gene
gene,O
,,O
whose,O
first,O
exon,O
includes,O
the,O
FRAXA,O
site,O
on,O
Xq27.3,O
,,O
accounts,O
for,O
15,O
-,O
20,O
%,O
of,O
all,O
X,O
-,O
linked,O
forms,O
of,O
mental,O
retardation,O
.,O
 , 
Loss,O
of,O
expression,O
of,O
FMR2,B-Gene
,,I-Gene
a,O
gene,O
adjacent,O
to,O
the,O
FRAXE,O
site,O
on,O
Xq28,O
,,O
is,O
correlated,O
with,O
FRAXE,O
expansion,O
in,O
some,O
mild,O
mentally,O
retarded,O
patients,O
.,O
 , 
FRAXF,O
is,O
a,O
fragile,O
site,O
whose,O
expression,O
has,O
not,O
been,O
associated,O
with,O
any,O
pathological,O
phenotype,O
.,O
 , 
The,O
fragility,O
in,O
all,O
three,O
sites,O
is,O
caused,O
by,O
expansions,O
of,O
CGG,O
repeats,O
adjacent,O
to,O
hypermethylated,O
CpG,O
islands,O
.,O
 , 
The,O
prevalence,O
of,O
FRAXA,O
,,O
FRAXE,O
,,O
and,O
FRAXF,O
remains,O
uncertain,O
because,O
of,O
the,O
lack,O
of,O
a,O
simple,O
and,O
cost,O
-,O
effective,O
test,O
allowing,O
wide,O
screening,O
programs,O
.,O
 , 
For,O
the,O
same,O
reason,O
,,O
the,O
real,O
phenotype,O
-,O
genotype,O
correlations,O
in,O
FRAXE,O
and,O
FRAXF,O
are,O
uncertain,O
as,O
well,O
.,O
 , 
We,O
have,O
developed,O
a,O
rapid,O
multiplex,O
polymerase,O
chain,O
reaction,O
(,O
PCR,O
),O
assay,O
in,O
which,O
hypermethylated,O
CpG,O
islands,O
adjacent,O
to,O
FRAXA,O
,,O
FRAXE,O
,,O
and,O
FRAXF,O
are,O
displayed,O
.,O
 , 
The,O
test,O
is,O
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
retarded,O
males,O
and,O
newborn,O
boys,O
.,O
 , 
#7887433
Prenatal,O
genetic,O
counseling,O
for,O
hemoglobinopathy,O
carriers,O
:,O
a,O
comparison,O
of,O
primary,O
providers,O
of,O
prenatal,O
care,O
and,O
professional,O
genetic,O
counselors,O
.,O
 , 
Health,O
personnel,O
trained,O
in,O
medical,O
genetics,O
are,O
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
themselves,O
.,O
 , 
In,O
our,O
recently,O
reported,O
community,O
-,O
wide,O
prenatal,O
screening,O
program,O
for,O
hemoglobinopathies,O
,,O
36,O
%,O
of,O
women,O
detected,O
to,O
have,O
a,O
hemoglobinopathy,O
did,O
not,O
come,O
to,O
a,O
tertiary,O
center,O
for,O
counseling,O
and,O
thus,O
may,O
have,O
not,O
benefited,O
from,O
testing,O
.,O
 , 
To,O
determine,O
whether,O
the,O
efficiency,O
of,O
the,O
program,O
could,O
be,O
increased,O
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
we,O
developed,O
a,O
pilot,O
training,O
program,O
on,O
the,O
basis,O
of,O
our,O
experience,O
in,O
offering,O
such,O
services,O
and,O
enlisted,O
68,O
%,O
of,O
regional,O
prenatal,O
care,O
providers,O
to,O
participate,O
.,O
 , 
The,O
proportion,O
of,O
patients,O
detected,O
to,O
have,O
a,O
hemoglobinopathy,O
who,O
received,O
counseling,O
was,O
similar,O
in,O
the,O
primary,O
and,O
tertiary,O
provider,O
groups,O
:,O
59,O
%,O
versus,O
50,O
%,O
,,O
respectively,O
,,O
for,O
sickle,O
trait,O
,,O
and,O
69,O
%,O
versus,O
66,O
%,O
,,O
respectively,O
,,O
for,O
beta,O
-,O
thalassemia,O
trait,O
.,O
 , 
Knowledge,O
after,O
counseling,O
was,O
also,O
similar,O
for,O
the,O
primary,O
and,O
tertiary,O
provider,O
groups,O
:,O
64,O
%,O
versus,O
66,O
%,O
(,O
mean,O
%,O
correct,O
),O
,,O
respectively,O
,,O
for,O
sickle,O
trait,O
,,O
and,O
79,O
%,O
versus,O
78,O
%,O
,,O
respectively,O
,,O
for,O
beta,O
-,O
thalassemia,O
trait,O
.,O
 , 
However,O
,,O
the,O
two,O
provider,O
groups,O
significantly,O
differed,O
with,O
regard,O
to,O
whether,O
or,O
not,O
the,O
patient,O
had,O
her,O
partner,O
tested,O
.,O
 , 
For,O
sickle,O
trait,O
,,O
it,O
was,O
25,O
%,O
for,O
the,O
primary,O
providers,O
but,O
49,O
%,O
for,O
the,O
tertiary,O
providers,O
(,O
P,O
<,O
.001,O
),O
.,O
 , 
For,O
beta,O
-,O
thalassemia,O
trait,O
,,O
it,O
was,O
47,O
%,O
for,O
the,O
primary,O
providers,O
but,O
78,O
%,O
for,O
the,O
tertiary,O
providers,O
(,O
P,O
<,O
.001).(ABSTRACT,O
TRUNCATED,O
AT,O
250,O
WORDS,O
),O
 , 
#9067759
Three,O
novel,O
PAX3,B-Gene
mutations,O
observed,O
in,O
patients,O
with,O
Waardenburg,O
syndrome,O
type,O
1,O
.,O
 , 
#9399882
Inherited,O
interstitial,O
duplications,O
of,O
proximal,O
15q,O
:,O
genotype,O
-,O
phenotype,O
correlations,O
.,O
 , 
We,O
present,O
the,O
cytogenetic,O
,,O
molecular,O
cytogenetic,O
,,O
and,O
molecular,O
genetic,O
results,O
on,O
20,O
unrelated,O
patients,O
with,O
an,O
interstitial,O
duplication,O
of,O
the,O
proximal,O
long,O
arm,O
of,O
chromosome,O
15,O
.,O
 , 
Multiple,O
probes,O
showed,O
that,O
the,O
Prader,O
-,O
Willi,O
/,O
Angelman,O
critical,O
region,O
(,O
PWACR,O
),O
was,O
included,O
in,O
the,O
duplication,O
in,O
4/20,O
patients,O
,,O
each,O
ascertained,O
with,O
developmental,O
delay,O
.,O
 , 
The,O
duplication,O
was,O
also,O
found,O
in,O
two,O
affected,O
but,O
not,O
in,O
three,O
unaffected,O
sibs,O
of,O
one,O
of,O
these,O
patients,O
.,O
 , 
All,O
four,O
probands,O
had,O
inherited,O
their,O
duplication,O
from,O
their,O
mothers,O
,,O
three,O
of,O
whom,O
were,O
also,O
affected,O
.,O
 , 
Two,O
of,O
the,O
affected,O
mothers,O
also,O
carried,O
a,O
maternally,O
inherited,O
duplication,O
,,O
whereas,O
the,O
duplication,O
in,O
the,O
unaffected,O
mother,O
and,O
in,O
an,O
unaffected,O
grandmother,O
was,O
paternal,O
in,O
origin,O
,,O
raising,O
the,O
possibility,O
of,O
a,O
parental,O
-,O
origin,O
effect,O
.,O
 , 
The,O
PWACR,O
was,O
not,O
duplicated,O
in,O
the,O
remaining,O
16,O
patients,O
,,O
of,O
whom,O
4,O
were,O
referred,O
with,O
developmental,O
delay,O
.,O
 , 
In,O
the,O
14,O
families,O
for,O
which,O
parental,O
samples,O
were,O
available,O
,,O
the,O
duplication,O
was,O
inherited,O
with,O
equal,O
frequency,O
from,O
a,O
phenotypically,O
normal,O
parent,O
,,O
mother,O
or,O
father,O
.,O
 , 
Comparative,O
genomic,O
hybridization,O
undertaken,O
on,O
two,O
patients,O
suggested,O
that,O
proximal,O
15q,O
outside,O
the,O
PWACR,O
was,O
the,O
origin,O
of,O
the,O
duplicated,O
material,O
.,O
 , 
The,O
use,O
of,O
PWACR,O
probes,O
discriminates,O
between,O
a,O
large,O
group,O
of,O
duplications,O
of,O
no,O
apparent,O
clinical,O
significance,O
and,O
a,O
smaller,O
group,O
,,O
in,O
which,O
a,O
maternally,O
derived,O
PWACR,O
duplication,O
is,O
consistently,O
associated,O
with,O
developmental,O
delay,O
and,O
speech,O
difficulties,O
but,O
not,O
with,O
overt,O
features,O
of,O
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
-,O
q21.33,O
(,B-Gene
LGMD2D),4q12,I-Gene
(,B-Gene
LGMD2E,I-Gene
),I-Gene
,,I-Gene
and,O
5q33,O
-,O
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
,,O
mildly,O
elevated,O
serum,O
CK,O
levels,O
,,O
and,O
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
nucleotide,O
polymorphisms,O
(,O
SNPs,O
),O
were,O
identified,O
in,O
ELN,B-Gene
,,I-Gene
and,O
no,O
obvious,O
allelic,O
association,O
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
nonsense,O
mutations,O
c.712C,B-SNP
>,I-SNP
T,I-SNP
and,O
c.2115ins35bp,B-SNP
,,I-SNP
the,O
splice,O
site,O
mutations,O
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
>,I-SNP
C,I-SNP
and,O
c.4101,B-SNP
+,I-SNP
2T,I-SNP
>,I-SNP
C,I-SNP
,,I-SNP
and,O
a,O
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
syndrome,O
(,O
www.wernersyndrome.org,O
),O
has,O
been,O
providing,O
molecular,O
diagnosis,O
of,O
the,O
Werner,O
syndrome,O
(,O
WS,O
),O
for,O
the,O
past,O
decade,O
.,O
 , 
The,O
present,O
communication,O
summarizes,O
,,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
were,O
seen,O
in,O
more,O
than,O
95,O
%,O
of,O
the,O
cases,O
.,O
 , 
The,O
median,O
age,O
of,O
death,O
,,O
previously,O
reported,O
to,O
be,O
in,O
the,O
range,O
of,O
46,O
-,O
48,O
years,O
,,O
is,O
54,O
years,O
.,O
 , 
Lymphoblastoid,O
cell,O
lines,O
(,O
LCLs,O
),O
have,O
been,O
cryopreserved,O
from,O
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
citrullinemia,O
.,O
 , 
Classical,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,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
),O
,,O
IVS-13(+5,B-SNP
),I-SNP
(,O
delta,O
Ex13,O
),O
,,O
and,O
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
-,I-Gene
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
is,O
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
3,O
,,O
4,O
,,O
8,O
,,O
9,O
,,O
11,O
,,O
12,O
,,O
and,O
18,O
control,O
variation,O
in,O
levels,O
of,O
T,O
and,O
B,O
lymphocyte,O
subpopulations,O
.,O
 , 
Lymphocyte,O
subpopulation,O
levels,O
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
was,O
performed,O
in,O
15,O
of,O
the,O
CEPH,O
families,O
that,O
form,O
the,O
main,O
human,O
genome,O
genetic,O
project,O
mapping,O
resource,O
.,O
 , 
Quantitative,O
-,O
trait,O
loci,O
(,O
QTLs,O
),O
that,O
account,O
for,O
significant,O
proportions,O
of,O
the,O
phenotypic,O
variance,O
of,O
lymphocyte,O
subpopulations,O
were,O
detected,O
on,O
chromosomes,O
1,O
,,O
2,O
,,O
3,O
,,O
4,O
,,O
8,O
,,O
9,O
,,O
11,O
,,O
12,O
,,O
and,O
18,O
.,O
 , 
The,O
most,O
significant,O
QTL,O
found,O
was,O
for,O
CD4,O
levels,O
on,O
chromosome,O
8,O
(,O
empirical,O
P=.00005,O
),O
.,O
 , 
Two,O
regions,O
of,O
chromosome,O
4,O
showed,O
significant,O
linkage,O
to,O
CD4,O
:,O
CD8,O
ratio,O
(,O
empirical,O
P=.00007,O
and,O
P=.003,O
),O
.,O
 , 
A,O
QTL,O
for,O
the,O
highly,O
correlated,O
measures,O
of,O
CD4,O
and,O
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
phosphate,O
wasting,O
results,O
from,O
a,O
heterogeneous,O
group,O
of,O
disorders,O
.,O
 , 
Hereditary,O
hypophosphatemic,O
rickets,O
with,O
hypercalciuria,O
(,O
HHRH,O
),O
is,O
an,O
autosomal,O
recessive,O
form,O
that,O
is,O
characterized,O
by,O
reduced,O
renal,O
phosphate,O
reabsorption,O
,,O
hypophosphatemia,O
,,O
and,O
rickets,O
.,O
 , 
It,O
can,O
be,O
distinguished,O
from,O
other,O
forms,O
of,O
hypophosphatemia,O
by,O
increased,O
serum,O
levels,O
of,O
1,25,O
-,O
dihydroxyvitamin,O
D,O
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
),O
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
for,O
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
were,O
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
three,O
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
mutations,O
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
complete,O
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
x,O
in,O
Altaians,O
from,O
South,O
Siberia,O
.,O
 , 
#10533067
Analysis,O
of,O
both,O
TSC1,B-Gene
and,O
TSC2,B-Gene
for,O
germline,O
mutations,O
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
are,O
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
including,O
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
followed,O
by,O
direct,O
sequencing,O
.,O
 , 
Mutations,O
were,O
identified,O
in,O
a,O
total,O
of,O
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
conformational,O
polymorphism,O
(,O
SSCP,O
),O
analysis,O
.,O
 , 
The,O
aim,O
of,O
this,O
study,O
was,O
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
of,O
the,O
SSCP,O
technique,O
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
can,O
be,O
deleterious,O
by,O
affecting,O
normal,O
pre,O
-,O
mRNA,O
splicing,O
via,O
disruption,O
/,O
creation,O
of,O
splice,O
site,O
consensus,O
sequences,O
.,O
 , 
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
defect,O
in,O
order,O
to,O
restrict,O
transcript,O
analyses,O
to,O
the,O
most,O
appropriate,O
cases,O
.,O
 , 
Web,O
-,O
based,O
tools,O
designed,O
to,O
provide,O
such,O
predictions,O
are,O
available,O
.,O
 , 
We,O
evaluated,O
the,O
performance,O
of,O
six,O
of,O
these,O
tools,O
(,O
Splice,O
Site,O
Prediction,O
by,O
Neural,O
Network,O
[,O
NNSplice,O
],O
,,O
Splice,O
-,O
Site,O
Finder,O
 , 
[,O
SSF,O
],O
,,O
MaxEntScan,O
[,O
MES,O
],O
,,O
Automated,O
Splice,O
-,O
Site,O
Analyses,O
 , 
[,O
ASSA,O
],O
,,O
Exonic,O
Splicing,O
Enhancer,O
[,O
ESE,O
],O
Finder,O
,,O
and,O
Relative,O
Enhancer,O
and,O
Silencer,O
Classification,O
by,O
Unanimous,O
Enrichment,O
[,O
RESCUE]-ESE,O
),O
using,O
39,O
unrelated,O
retinoblastoma,O
patients,O
carrying,O
different,O
RB1,O
variants,O
(,O
31,O
intronic,O
and,O
eight,O
exonic,O
),O
.,O
 , 
These,O
39,O
patients,O
were,O
screened,O
for,O
abnormal,O
splicing,O
using,O
puromycin,O
-,O
treated,O
cell,O
lines,O
and,O
the,O
results,O
were,O
compared,O
to,O
the,O
predictions,O
.,O
 , 
As,O
expected,O
,,O
17,O
variants,O
impacting,O
canonical,O
AG,O
/,O
GT,O
splice,O
sites,O
were,O
correctly,O
predicted,O
as,O
deleterious,O
.,O
 , 
A,O
total,O
of,O
22,O
variations,O
occurring,O
at,O
loosely,O
defined,O
positions,O
(,O
+,O
/-60,O
nucleotides,O
from,O
an,O
AG,O
/,O
GT,O
site,O
),O
led,O
to,O
a,O
splice,O
defect,O
in,O
19,O
cases,O
and,O
16,O
of,O
them,O
were,O
classified,O
as,O
deleterious,O
by,O
at,O
least,O
one,O
tool,O
(,O
84,O
%,O
sensitivity,O
),O
.,O
 , 
In,O
other,O
words,O
,,O
three,O
variants,O
escaped,O
in,O
silico,O
detection,O
and,O
the,O
remaining,O
three,O
were,O
correctly,O
predicted,O
as,O
neutral,O
.,O
 , 
Overall,O
our,O
results,O
suggest,O
that,O
a,O
combination,O
of,O
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
analysis,O
and,O
the,O
risk,O
of,O
missing,O
a,O
deleterious,O
mutation,O
),O
because,O
the,O
weaknesses,O
of,O
one,O
in,O
silico,O
tool,O
may,O
be,O
overcome,O
by,O
the,O
results,O
of,O
another,O
tool,O
.,O
 , 
#8981969
Prevalence,O
and,O
parental,O
origin,O
of,O
de,O
novo,O
RET,B-Gene
mutations,O
in,O
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
characterization,O
of,O
phenylalanine,O
hydroxylase,O
deficiency,O
in,O
Chile,O
.,O
 , 
Mutations,O
in,O
brief,O
no,O
.,O
243,O
.,O
 , 
Online,O
.,O
 , 
Both,O
the,O
haplotype,O
distribution,O
and,O
the,O
mutational,O
spectrum,O
of,O
the,O
phenylalanine,B-Gene
hydroxylase,I-Gene
(,B-Gene
PAH,I-Gene
),I-Gene
gene,O
has,O
been,O
defined,O
for,O
the,O
Chilean,O
phenylketonuria,O
(,O
PKU,O
),O
population,O
.,O
 , 
Mutation,O
analysis,O
was,O
performed,O
using,O
a,O
combined,O
approach,O
of,O
screening,O
for,O
common,O
European,O
and,O
Oriental,O
mutations,O
and,O
application,O
of,O
the,O
DGGE,O
scanning,O
method,O
in,O
the,O
remaining,O
uncharacterized,O
alleles,O
.,O
 , 
A,O
total,O
of,O
16,O
different,O
mutations,O
have,O
been,O
identified,O
,,O
including,O
two,O
novel,O
ones,O
,,O
Q232X,B-SNP
and,O
IVS11nt5,B-SNP
.,I-SNP
 , 
The,O
most,O
frequent,O
mutations,O
were,O
IVS10nt-11,B-SNP
and,O
V388,B-SNP
M,I-SNP
present,O
both,O
in,O
the,O
13,O
%,O
of,O
the,O
mutant,O
chromosomes,O
.,O
 , 
The,O
rest,O
of,O
the,O
mutations,O
are,O
rare,O
.,O
 , 
The,O
haplotype,O
association,O
including,O
VNTR,O
and,O
STR,O
alleles,O
,,O
was,O
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
in,O
each,O
population,O
both,O
for,O
diagnostic,O
and,O
prognostic,O
purposes,O
.,O
 , 
The,O
correlation,O
between,O
the,O
genotypes,O
and,O
the,O
phenotypes,O
is,O
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
the,O
BRWD3,B-Gene
gene,O
cause,O
X,O
-,O
linked,O
mental,O
retardation,O
associated,O
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
sequences,O
in,O
250,O
families,O
with,O
nonsyndromic,O
X,O
-,O
linked,O
mental,O
retardation,O
(,O
XLMR,O
),O
,,O
two,O
families,O
were,O
identified,O
with,O
truncating,O
mutations,O
in,O
BRWD3,B-Gene
,,I-Gene
a,O
gene,O
encoding,O
a,O
bromodomain,O
and,O
WD,O
-,O
repeat,O
domain,O
-,O
containing,O
protein,O
.,O
 , 
In,O
both,O
families,O
,,O
the,O
mutation,O
segregates,O
with,O
the,O
phenotype,O
in,O
affected,O
males,O
.,O
 , 
Affected,O
males,O
have,O
macrocephaly,O
with,O
a,O
prominent,O
forehead,O
,,O
large,O
cupped,O
ears,O
,,O
and,O
mild,O
-,O
to,O
-,O
moderate,O
intellectual,O
disability,O
.,O
 , 
No,O
truncating,O
variants,O
were,O
found,O
in,O
520,O
control,O
X,O
chromosomes,O
.,O
 , 
BRWD3,B-Gene
is,O
therefore,O
a,O
new,O
gene,O
implicated,O
in,O
the,O
etiology,O
of,O
XLMR,O
associated,O
with,O
macrocephaly,O
and,O
may,O
cause,O
disease,O
by,O
altering,O
intracellular,O
signaling,O
pathways,O
affecting,O
cellular,O
proliferation,O
.,O
 , 
#21194677
Identification,O
of,O
a,O
systemic,O
lupus,O
erythematosus,O
susceptibility,O
locus,O
at,O
11p13,O
between,O
PDHX,B-Gene
and,O
CD44,B-Gene
in,O
a,O
multiethnic,O
study,O
.,O
 , 
Systemic,O
lupus,O
erythematosus,O
(,O
SLE,O
),O
is,O
considered,O
to,O
be,O
the,O
prototypic,O
autoimmune,O
disease,O
,,O
with,O
a,O
complex,O
genetic,O
architecture,O
influenced,O
by,O
environmental,O
factors,O
.,O
 , 
We,O
sought,O
to,O
replicate,O
a,O
putative,O
association,O
at,O
11p13,O
not,O
yet,O
exceeding,O
genome,O
-,O
wide,O
significance,O
(,O
p,O
<,O
5,O
×,O
10(-8,O
),O
),O
identified,O
in,O
a,O
genome,O
-,O
wide,O
association,O
study,O
(,O
GWAS,O
),O
.,O
 , 
Our,O
GWA,O
scan,O
identified,O
two,O
intergenic,O
SNPs,O
located,O
between,O
PDHX,B-Gene
and,O
CD44,B-Gene
showing,O
suggestive,O
evidence,O
of,O
association,O
with,O
SLE,O
in,O
cases,O
of,O
European,O
descent,O
(,O
rs2732552,O
,,O
p,O
=,O
0.004,O
,,O
odds,O
ratio,O
[,O
OR,O
],O
=,O
0.78,O
;,O
rs387619,O
,,O
p,O
=,O
0.003,O
,,O
OR,O
=,O
0.78,O
),O
.,O
 , 
The,O
replication,O
cohort,O
consisted,O
of,O
>,O
15,000,O
subjects,O
,,O
including,O
3562,O
SLE,O
cases,O
and,O
3491,O
controls,O
of,O
European,O
ancestry,O
,,O
1527,O
cases,O
and,O
1811,O
controls,O
of,O
African,O
American,O
(,O
AA,O
),O
descent,O
,,O
and,O
1265,O
cases,O
and,O
1260,O
controls,O
of,O
Asian,O
origin,O
.,O
 , 
We,O
observed,O
robust,O
association,O
at,O
both,O
rs2732552,O
(,O
p,O
=,O
9.03,O
×,O
10(-8,O
),O
,,O
OR,O
=,O
0.83,O
),O
and,O
rs387619,O
(,O
p,O
=,O
7.7,O
×,O
10(-7,O
),O
,,O
OR,O
=,O
0.83,O
),O
in,O
the,O
European,O
samples,O
with,O
p(meta,O
),O
=,O
 , 
1.82,O
×,O
10(-9,O
),O
for,O
rs2732552,O
.,O
 , 
The,O
AA,O
and,O
Asian,O
SLE,O
cases,O
also,O
demonstrated,O
association,O
at,O
rs2732552,O
(,O
p,O
=,O
5,O
×,O
10(-3,O
),O
,,O
OR,O
=,O
0.81,O
 , 
and,O
p,O
=,O
4.3,O
×,O
10(-4,O
),O
,,O
OR,O
=,O
0.80,O
,,O
respectively,O
),O
.,O
 , 
A,O
meta,O
-,O
analysis,O
of,O
rs2732552,O
for,O
all,O
racial,O
and,O
ethnic,O
groups,O
studied,O
produced,O
p(meta,O
),O
 , 
=,O
2.36,O
×,O
10(-13,O
),O
.,O
 , 
This,O
locus,O
contains,O
multiple,O
regulatory,O
sites,O
that,O
could,O
potentially,O
affect,O
expression,O
and,O
functions,O
of,O
CD44,B-Gene
,,I-Gene
a,O
cell,O
-,O
surface,O
glycoprotein,O
influencing,O
immunologic,O
,,O
inflammatory,O
,,O
and,O
oncologic,O
phenotypes,O
,,O
or,O
PDHX,B-Gene
,,I-Gene
a,O
subunit,O
of,O
the,O
pyruvate,O
dehydrogenase,O
complex,O
.,O
 , 
#14722921
Context,O
of,O
deletions,O
and,O
insertions,O
in,O
human,O
coding,O
sequences,O
.,O
 , 
We,O
studied,O
the,O
dependence,O
of,O
the,O
rate,O
of,O
short,O
deletions,O
and,O
insertions,O
on,O
their,O
contexts,O
using,O
the,O
data,O
on,O
mutations,O
within,O
coding,O
exons,O
at,O
19,O
human,O
loci,O
that,O
cause,O
mendelian,O
diseases,O
.,O
 , 
We,O
confirm,O
that,O
periodic,O
sequences,O
consisting,O
of,O
three,O
to,O
five,O
or,O
more,O
nucleotides,O
are,O
mutagenic,O
.,O
 , 
Mutability,O
of,O
sequences,O
with,O
strongly,O
biased,O
nucleotide,O
composition,O
is,O
also,O
elevated,O
,,O
even,O
when,O
mutations,O
within,O
homonucleotide,O
runs,O
longer,O
than,O
three,O
nucleotides,O
are,O
ignored,O
.,O
 , 
In,O
contrast,O
,,O
no,O
elevated,O
mutation,O
rates,O
have,O
been,O
detected,O
for,O
imperfect,O
direct,O
or,O
inverted,O
repeats,O
.,O
 , 
Among,O
known,O
candidate,O
contexts,O
,,O
the,O
indel,O
context,O
GTAAGT,O
and,O
regions,O
with,O
purine,O
-,O
pyrimidine,O
imbalance,O
between,O
the,O
two,O
DNA,O
strands,O
are,O
mutagenic,O
in,O
our,O
sample,O
,,O
and,O
many,O
others,O
are,O
not,O
mutagenic,O
.,O
 , 
Data,O
on,O
mutation,O
hot,O
spots,O
suggest,O
two,O
novel,O
contexts,O
that,O
increase,O
the,O
deletion,O
rate,O
.,O
 , 
Comprehensive,O
analysis,O
of,O
mutability,O
of,O
all,O
possible,O
contexts,O
of,O
lengths,O
four,O
,,O
six,O
,,O
and,O
eight,O
indicates,O
a,O
substantially,O
elevated,O
deletion,O
rate,O
within,O
YYYTG,O
and,O
similar,O
sequences,O
,,O
which,O
is,O
one,O
of,O
the,O
two,O
contexts,O
revealed,O
by,O
the,O
hot,O
spots,O
.,O
 , 
Possible,O
contexts,O
that,O
increase,O
the,O
insertion,O
rate,O
(,O
AT(A,O
/,O
C)(A,O
/,O
C)GCC,O
and,O
TACCRC,O
),O
and,O
decrease,O
deletion,O
(,O
TATCGC,O
),O
or,O
insertion,O
(,O
GCGG,O
),O
rates,O
have,O
also,O
been,O
identified,O
.,O
 , 
Two,O
-,O
thirds,O
of,O
deletions,O
remove,O
a,O
repeat,O
,,O
and,O
over,O
80,O
%,O
of,O
insertions,O
create,O
a,O
repeat,O
,,O
i.e.,O
,,O
they,O
are,O
duplications,O
.,O
 , 
#12325018
rSNP_Guide,O
:,O
an,O
integrated,O
database,O
-,O
tools,O
system,O
for,O
studying,O
SNPs,O
and,O
site,O
-,O
directed,O
mutations,O
in,O
transcription,O
factor,O
binding,O
sites,O
.,O
 , 
Since,O
the,O
human,O
genome,O
was,O
sequenced,O
in,O
draft,O
,,O
single,O
nucleotide,O
polymorphism,O
(,O
SNP,O
),O
analysis,O
has,O
become,O
one,O
of,O
the,O
keynote,O
fields,O
of,O
bioinformatics,O
.,O
 , 
We,O
have,O
developed,O
an,O
integrated,O
database,O
-,O
tools,O
system,O
,,O
rSNP_Guide,O
(,O
http://wwwmgs.bionet.nsc.ru/mgs/systems/rsnp/,O
),O
,,O
devoted,O
to,O
prediction,O
of,O
transcription,O
factor,O
(,O
TF,O
),O
binding,O
sites,O
,,O
alterations,O
of,O
which,O
could,O
be,O
associated,O
with,O
disease,O
phenotype,O
.,O
 , 
By,O
inputting,O
data,O
on,O
alterations,O
in,O
DNA,O
sequence,O
and,O
in,O
DNA,O
binding,O
pattern,O
of,O
an,O
unknown,O
TF,O
,,O
rSNP_Guide,O
searches,O
for,O
a,O
known,O
TF,O
with,O
alterations,O
in,O
the,O
recognition,O
score,O
calculated,O
on,O
the,O
basis,O
of,O
TF,O
site,O
's,O
sequence,O
and,O
consistent,O
with,O
the,O
input,O
alterations,O
in,O
DNA,O
binding,O
to,O
the,O
unknown,O
TF,O
.,O
 , 
Our,O
system,O
has,O
been,O
tested,O
on,O
many,O
relationships,O
between,O
known,O
TF,O
sites,O
and,O
diseases,O
,,O
as,O
well,O
as,O
on,O
site,O
-,O
directed,O
mutagenesis,O
data,O
.,O
 , 
Experimental,O
verification,O
of,O
rSNP_Guide,O
system,O
was,O
made,O
on,O
functionally,O
important,O
SNPs,O
in,O
human,O
TDO2and,B-Gene
mouse,O
K,B-Gene
-,I-Gene
ras,I-Gene
genes,O
.,O
 , 
Additional,O
examples,O
of,O
analysis,O
are,O
reported,O
involving,O
variants,O
in,O
the,O
human,O
gammaA,B-Gene
-,I-Gene
globin,I-Gene
(,B-Gene
HBG1,I-Gene
),I-Gene
,,O
hsp70(HSPA1A,B-Gene
),I-Gene
,,O
and,O
Factor,B-Gene
IX,I-Gene
(,B-Gene
F9,I-Gene
),I-Gene
gene,O
promoters,O
.,O
 , 
#16380905
Bipolar,O
I,O
disorder,O
and,O
schizophrenia,O
:,O
a,O
440,O
-,O
single,O
-,O
nucleotide,O
polymorphism,O
screen,O
of,O
64,O
candidate,O
genes,O
among,O
Ashkenazi,O
Jewish,O
case,O
-,O
parent,O
trios,O
.,O
 , 
Bipolar,O
,,O
schizophrenia,O
,,O
and,O
schizoaffective,O
disorders,O
are,O
common,O
,,O
highly,O
heritable,O
psychiatric,O
disorders,O
,,O
for,O
which,O
familial,O
coaggregation,O
,,O
as,O
well,O
as,O
epidemiological,O
and,O
genetic,O
evidence,O
,,O
suggests,O
overlapping,O
etiologies,O
.,O
 , 
No,O
definitive,O
susceptibility,O
genes,O
have,O
yet,O
been,O
identified,O
for,O
any,O
of,O
these,O
disorders,O
.,O
 , 
Genetic,O
heterogeneity,O
,,O
combined,O
with,O
phenotypic,O
imprecision,O
and,O
poor,O
marker,O
coverage,O
,,O
has,O
contributed,O
to,O
the,O
difficulty,O
in,O
defining,O
risk,O
variants,O
.,O
 , 
We,O
focused,O
on,O
families,O
of,O
Ashkenazi,O
Jewish,O
descent,O
,,O
to,O
reduce,O
genetic,O
heterogeneity,O
,,O
and,O
,,O
as,O
a,O
precursor,O
to,O
genomewide,O
association,O
studies,O
,,O
we,O
undertook,O
a,O
single,O
-,O
nucleotide,O
polymorphism,O
(,O
SNP,O
),O
genotyping,O
screen,O
of,O
64,O
candidate,O
genes,O
(,O
440,O
SNPs,O
),O
chosen,O
on,O
the,O
basis,O
of,O
previous,O
linkage,O
or,O
of,O
association,O
and/or,O
biological,O
relevance,O
.,O
 , 
We,O
genotyped,O
an,O
average,O
of,O
6.9,O
SNPs,O
per,O
gene,O
,,O
with,O
an,O
average,O
density,O
of,O
1,O
SNP,O
per,O
11.9,O
kb,O
in,O
323,O
bipolar,O
I,O
disorder,O
and,O
274,O
schizophrenia,O
or,O
schizoaffective,O
Ashkenazi,O
case,O
-,O
parent,O
trios,O
.,O
 , 
Using,O
single,O
-,O
SNP,O
and,O
haplotype,O
-,O
based,O
transmission,O
/,O
disequilibrium,O
tests,O
,,O
we,O
ranked,O
genes,O
on,O
the,O
basis,O
of,O
strength,O
of,O
association,O
(,O
P<.01,O
),O
.,O
 , 
Six,O
genes,O
(,B-Gene
DAO,I-Gene
,,I-Gene
GRM3,B-Gene
,,I-Gene
GRM4,B-Gene
,,I-Gene
GRIN2B,B-Gene
,,I-Gene
IL2RB,B-Gene
,,I-Gene
and,O
TUBA8,B-Gene
),I-Gene
met,O
this,O
criterion,O
for,O
bipolar,O
I,O
disorder,O
;,O
only,O
DAO,B-Gene
has,O
been,O
previously,O
associated,O
with,O
bipolar,O
disorder,O
.,O
 , 
Six,O
genes,O
(,B-Gene
RGS4,I-Gene
,,I-Gene
SCA1,B-Gene
,,I-Gene
GRM4,B-Gene
,,I-Gene
DPYSL2,B-Gene
,,I-Gene
NOS1,B-Gene
,,I-Gene
and,O
GRID1,B-Gene
),I-Gene
met,O
this,O
criterion,O
for,O
schizophrenia,O
or,O
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
 , 
In,O
addition,O
,,O
six,O
genes,O
(,B-Gene
DPYSL2,I-Gene
,,I-Gene
DTNBP1,B-Gene
,,I-Gene
G30,B-Gene
/,I-Gene
G72,I-Gene
,,I-Gene
GRID1,B-Gene
,,I-Gene
GRM4,B-Gene
,,I-Gene
and,O
NOS1,B-Gene
),I-Gene
showed,O
overlapping,O
suggestive,O
evidence,O
of,O
association,O
in,O
both,O
disorders,O
.,O
 , 
These,O
results,O
may,O
help,O
to,O
prioritize,O
candidate,O
genes,O
for,O
future,O
study,O
from,O
among,O
the,O
many,O
suspected,O
/,O
proposed,O
for,O
schizophrenia,O
and,O
bipolar,O
disorders,O
.,O
 , 
They,O
provide,O
further,O
support,O
for,O
shared,O
genetic,O
susceptibility,O
between,O
these,O
two,O
disorders,O
that,O
involve,O
glutamate,O
-,O
signaling,O
pathways,O
.,O
 , 
#14691730
The,O
PARK8,B-Gene
locus,O
in,O
autosomal,O
dominant,O
parkinsonism,O
:,O
confirmation,O
of,O
linkage,O
and,O
further,O
delineation,O
of,O
the,O
disease,O
-,O
containing,O
interval,O
.,O
 , 
Recently,O
,,O
a,O
new,O
locus,O
(,B-Gene
PARK8,I-Gene
),I-Gene
for,O
autosomal,O
dominant,O
parkinsonism,O
has,O
been,O
identified,O
in,O
one,O
large,O
Japanese,O
family,O
.,O
 , 
Linkage,O
has,O
been,O
shown,O
to,O
a,O
16,O
-,O
cM,O
centromeric,O
region,O
of,O
chromosome,O
12,O
,,O
between,O
markers,O
D12S1631,O
and,O
D12S339,O
.,O
 , 
We,O
tested,O
21,O
white,O
families,O
with,O
Parkinson,O
disease,O
and,O
an,O
inheritance,O
pattern,O
compatible,O
with,O
autosomal,O
dominant,O
transmission,O
for,O
linkage,O
in,O
this,O
region,O
.,O
 , 
Criteria,O
for,O
inclusion,O
were,O
at,O
least,O
three,O
affected,O
individuals,O
in,O
more,O
than,O
one,O
generation,O
.,O
 , 
A,O
total,O
of,O
29,O
markers,O
were,O
used,O
to,O
saturate,O
the,O
candidate,O
region,O
.,O
 , 
One,O
hundred,O
sixty,O
-,O
seven,O
family,O
members,O
were,O
tested,O
(,O
84,O
affected,O
and,O
83,O
unaffected,O
),O
.,O
 , 
Under,O
the,O
assumption,O
of,O
heterogeneity,O
and,O
through,O
use,O
of,O
an,O
affecteds,O
-,O
only,O
model,O
,,O
a,O
maximum,O
multipoint,O
LOD,O
score,O
of,O
2.01,O
was,O
achieved,O
in,O
the,O
total,O
sample,O
,,O
with,O
an,O
estimated,O
proportion,O
of,O
families,O
with,O
linkage,O
of,O
0.32,O
.,O
 , 
This,O
LOD,O
score,O
is,O
significant,O
for,O
linkage,O
in,O
a,O
replication,O
study,O
and,O
corresponds,O
to,O
a,O
P,O
value,O
of.0047,O
.,O
 , 
Two,O
families,O
(,O
family,O
A,O
[,O
German,O
Canadian,O
],O
and,O
family,O
D,O
[,O
from,O
western,O
Nebraska,O
],O
),O
reached,O
significant,O
linkage,O
on,O
their,O
own,O
,,O
with,O
a,O
combined,O
maximum,O
multipoint,O
LOD,O
score,O
of,O
3.33,O
,,O
calculated,O
with,O
an,O
affecteds,O
-,O
only,O
model,O
(,O
family,O
A,O
:,O
LOD,O
score,O
1.67,O
,,O
P=.0028,O
;,O
family,O
D,O
:,O
LOD,O
score,O
1.67,O
,,O
P=.0028,O
),O
.,O
 , 
When,O
a,O
penetrance,O
-,O
dependent,O
model,O
was,O
calculated,O
,,O
the,O
combined,O
multipoint,O
LOD,O
score,O
achieved,O
was,O
3.92,O
(,O
family,O
A,O
:,O
LOD,O
score,O
1.68,O
,,O
P=.0027,O
;,O
family,O
D,O
:,O
LOD,O
score,O
2.24,O
,,O
P=.0007,O
),O
.,O
 , 
On,O
the,O
basis,O
of,O
the,O
multipoint,O
analysis,O
for,O
the,O
combined,O
families,O
A,O
and,O
D,O
,,O
the,O
1,O
-,O
LOD,O
support,O
interval,O
suggests,O
that,O
the,O
most,O
likely,O
disease,O
location,O
is,O
between,O
a,O
CA,O
repeat,O
polymorphism,O
on,O
genomic,O
clone,O
AC025253,O
(,O
44.5,O
Mb,O
),O
and,O
marker,O
D12S1701,O
(,O
47.7,O
Mb,O
),O
.,O
 , 
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
common,O
locus,O
.,O
 , 
#18179903
Mutation,O
analysis,O
of,O
CHRNA1,B-Gene
,,I-Gene
CHRNB1,B-Gene
,,I-Gene
CHRND,B-Gene
,,I-Gene
and,O
RAPSN,B-Gene
genes,O
in,O
multiple,O
pterygium,O
syndrome,O
/,O
fetal,O
akinesia,O
patients,O
.,O
 , 
Multiple,O
pterygium,O
syndromes,O
(,O
MPS,O
),O
comprise,O
a,O
group,O
of,O
multiple,O
congenital,O
anomaly,O
disorders,O
characterized,O
by,O
webbing,O
(,O
pterygia,O
),O
of,O
the,O
neck,O
,,O
elbows,O
,,O
and/or,O
knees,O
and,O
joint,O
contractures,O
(,O
arthrogryposis,O
),O
.,O
 , 
MPS,O
are,O
phenotypically,O
and,O
genetically,O
heterogeneous,O
but,O
are,O
traditionally,O
divided,O
into,O
prenatally,O
lethal,O
and,O
nonlethal,O
(,O
Escobar,O
),O
types,O
.,O
 , 
Previously,O
,,O
we,O
and,O
others,O
reported,O
that,O
recessive,O
mutations,O
in,O
the,O
embryonal,B-Gene
acetylcholine,I-Gene
receptor,I-Gene
g,I-Gene
subunit,O
(,B-Gene
CHRNG,I-Gene
),I-Gene
can,O
cause,O
both,O
lethal,O
and,O
nonlethal,O
MPS,O
,,O
thus,O
demonstrating,O
that,O
pterygia,O
resulted,O
from,O
fetal,O
akinesia,O
.,O
 , 
We,O
hypothesized,O
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
MPS,O
/,O
fetal,O
akinesia,O
phenotype,O
and,O
so,O
we,O
analyzed,O
15,O
cases,O
of,O
lethal,O
MPS,O
/,O
fetal,O
akinesia,O
without,O
CHRNG,B-Gene
mutations,O
for,O
mutations,O
in,O
the,O
CHRNA1,B-Gene
,,I-Gene
CHRNB1,B-Gene
,,I-Gene
CHRND,B-Gene
,,I-Gene
and,O
rapsyn,B-Gene
(,B-Gene
RAPSN,I-Gene
),I-Gene
genes,O
.,O
 , 
No,O
CHRNA1,B-Gene
,,I-Gene
CHRNB1,B-Gene
,,I-Gene
or,O
CHRND,B-Gene
mutations,O
were,O
detected,O
,,O
but,O
a,O
homozygous,O
RAPSN,B-Gene
frameshift,O
mutation,O
,,O
c.1177,B-SNP
-,I-SNP
1178delAA,I-SNP
,,I-SNP
was,O
identified,O
in,O
a,O
family,O
with,O
three,O
children,O
affected,O
with,O
lethal,O
fetal,O
akinesia,O
sequence,O
.,O
 , 
Previously,O
,,O
RAPSN,B-Gene
mutations,O
have,O
been,O
reported,O
in,O
congenital,O
myasthenia,O
.,O
 , 
Functional,O
studies,O
were,O
consistent,O
with,O
the,O
hypothesis,O
that,O
whereas,O
incomplete,O
loss,O
of,O
rapsyn,O
function,O
may,O
cause,O
congenital,O
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
combined,O
analysis,O
of,O
19,O
studies,O
.,O
 , 
RAD51,B-Gene
is,O
an,O
important,O
component,O
of,O
double,O
-,O
stranded,O
DNA,O
-,O
repair,O
mechanisms,O
that,O
interacts,O
with,O
both,O
BRCA1,B-Gene
and,O
BRCA2,B-Gene
.,I-Gene
 , 
A,O
single,O
-,O
nucleotide,O
polymorphism,O
(,O
SNP,O
),O
in,O
the,O
5,O
',O
untranslated,O
region,O
(,O
UTR,O
),O
of,O
RAD51,B-Gene
,,I-Gene
135G-->C,B-SNP
,,I-SNP
has,O
been,O
suggested,O
as,O
a,O
possible,O
modifier,O
of,O
breast,O
cancer,O
risk,O
in,O
BRCA1,B-Gene
and,O
BRCA2,B-Gene
mutation,O
carriers,O
.,O
 , 
We,O
pooled,O
genotype,O
data,O
for,O
8,512,O
female,O
mutation,O
carriers,O
from,O
19,O
studies,O
for,O
the,O
RAD51,B-Gene
135G-->C,B-SNP
SNP,O
.,O
 , 
We,O
found,O
evidence,O
of,O
an,O
increased,O
breast,O
cancer,O
risk,O
in,O
CC,O
homozygotes,O
(,O
hazard,O
ratio,O
[,O
HR,O
],O
1.92,O
[,O
95,O
%,O
confidence,O
interval,O
{,O
CI,O
},O
1.25,O
-,O
2.94,O
),O
but,O
not,O
in,O
heterozygotes,O
(,O
HR,O
0.95,O
 , 
[,O
95,O
%,O
CI,O
0.83,O
-,O
1.07,O
],O
;,O
P=.002,O
,,O
by,O
heterogeneity,O
test,O
with,O
2,O
degrees,O
of,O
freedom,O
[,O
df,O
],O
),O
.,O
 , 
When,O
BRCA1,B-Gene
and,O
BRCA2,B-Gene
mutation,O
carriers,O
were,O
analyzed,O
separately,O
,,O
the,O
increased,O
risk,O
was,O
statistically,O
significant,O
only,O
among,O
BRCA2,B-Gene
mutation,O
carriers,O
,,O
in,O
whom,O
we,O
observed,O
HRs,O
of,O
1.17,O
(,O
95,O
%,O
CI,O
0.91,O
-,O
1.51,O
),O
among,O
heterozygotes,O
and,O
3.18,O
(,O
95,O
%,O
CI,O
1.39,O
-,O
7.27,O
),O
among,O
rare,O
homozygotes,O
(,O
P=.0007,O
,,O
by,O
heterogeneity,O
test,O
with,O
2,O
df,O
),O
.,O
 , 
In,O
addition,O
,,O
we,O
determined,O
that,O
the,O
135G-->C,B-SNP
variant,O
affects,O
RAD51,B-Gene
splicing,O
within,O
the,O
5,O
',O
UTR,O
.,O
 , 
Thus,O
,,O
135G-->C,B-SNP
may,O
modify,O
the,O
risk,O
of,O
breast,O
cancer,O
in,O
BRCA2,B-Gene
mutation,O
carriers,O
by,O
altering,O
the,O
expression,O
of,O
RAD51,B-Gene
.,I-Gene
 , 
RAD51,B-Gene
is,O
the,O
first,O
gene,O
to,O
be,O
reliably,O
identified,O
as,O
a,O
modifier,O
of,O
risk,O
among,O
BRCA1/2,B-Gene
mutation,O
carriers,O
.,O
 , 
#8651297
Mutations,O
and,O
phenotype,O
in,O
isolated,O
glycerol,O
kinase,O
deficiency,O
.,O
 , 
We,O
demonstrate,O
that,O
isolated,O
glycerol,B-Gene
kinase,I-Gene
(,B-Gene
GK,I-Gene
),I-Gene
deficiency,O
in,O
three,O
families,O
results,O
from,O
mutation,O
of,O
the,O
Xp21,O
GK,B-Gene
gene,O
.,O
 , 
GK,B-Gene
mutations,O
were,O
detected,O
in,O
four,O
patients,O
with,O
widely,O
differing,O
phenotypes,O
.,O
 , 
Patient,O
1,O
had,O
a,O
splice,O
-,O
site,O
mutation,O
causing,O
premature,O
termination,O
.,O
 , 
His,O
general,O
health,O
was,O
good,O
despite,O
absent,O
GK,B-Gene
activity,O
,,O
indicating,O
that,O
isolated,O
GK,B-Gene
deficiency,O
can,O
be,O
silent,O
.,O
 , 
Patient,O
2,O
had,O
GK,B-Gene
deficiency,O
and,O
a,O
severe,O
phenotype,O
involving,O
psychomotor,O
retardation,O
and,O
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
the,O
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
 , 
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
 , 
Systemic,O
lupus,O
erythematosus,O
is,O
a,O
prototypic,O
autoimmune,O
disease,O
.,O
 , 
Apart,O
from,O
rare,O
monogenic,O
deficiencies,O
of,O
complement,O
factors,O
,,O
where,O
lupuslike,O
disease,O
may,O
occur,O
in,O
association,O
with,O
other,O
autoimmune,O
diseases,O
or,O
high,O
susceptibility,O
to,O
bacterial,O
infections,O
,,O
its,O
etiology,O
is,O
multifactorial,O
in,O
nature,O
.,O
 , 
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
European,O
ancestry,O
informative,O
markers,O
),O
for,O
ancestry,O
estimation,O
and,O
correction,O
.,O
 , 
The,O
Coriell,O
Caucasian,O
and,O
CEPH,O
(,O
Centre,O
d'Etude,O
du,O
Polymorphisme,O
Humain,O
),O
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
with,O
mitochondrial,O
structural,O
abnormalities,O
caused,O
by,O
defective,O
de,O
novo,O
phosphatidylcholine,O
biosynthesis,O
.,O
 , 
Congenital,O
muscular,O
dystrophy,O
is,O
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
is,O
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
were,O
compound,O
heterozygotes,O
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
is,O
associated,O
with,O
protection,O
from,O
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
and,O
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
we,O
identified,O
nine,O
CD36,B-Gene
polymorphisms,O
with,O
a,O
high,O
-,O
frequency,O
(,O
>,O
15,O
%,O
),O
minor,O
allele,O
.,O
 , 
Of,O
these,O
,,O
the,O
frequencies,O
of,O
the,O
-14T-->C,B-SNP
allele,O
in,O
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
were,O
significantly,O
decreased,O
in,O
patients,O
with,O
cerebral,O
malaria,O
compared,O
to,O
those,O
with,O
mild,O
malaria,O
(,O
P=.016,O
for,O
-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
between,O
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
and,O
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
may,O
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
have,O
examined,O
the,O
records,O
of,O
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
in,O
the,O
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
),I-Gene
locus,O
to,O
pericentromeric,O
chromosome,O
11,O
.,O
 , 
Best,O
vitelliform,O
macular,O
dystrophy,O
(,B-Gene
VMD2,I-Gene
),I-Gene
has,O
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
at,O
D11S903,O
and,O
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
used,O
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
of,O
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
studies,O
have,O
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
with,O
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
wide,O
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
x,O
10(-3,O
),O
.,O
 , 
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
a,O
gene,O
strongly,O
implicated,O
in,O
SZ,O
.,O
 , 
These,O
biological,O
properties,O
together,O
with,O
our,O
linkage,O
and,O
association,O
results,O
strongly,O
support,O
NRG3,B-Gene
as,O
a,O
gene,O
involved,O
in,O
SZ,O
.,O
 , 
#21376301
Estimating,O
missing,O
heritability,O
for,O
disease,O
from,O
genome,O
-,O
wide,O
association,O
studies,O
.,O
 , 
Genome,O
-,O
wide,O
association,O
studies,O
are,O
designed,O
to,O
discover,O
SNPs,O
that,O
are,O
associated,O
with,O
a,O
complex,O
trait,O
.,O
 , 
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
were,O
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
 , 
Six,O
pathogenic,O
mutations,O
,,O
of,O
which,O
five,O
were,O
novel,O
,,O
were,O
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
are,O
a,O
nonsense,O
mutation,O
(,B-SNP
p.,I-SNP
Y317X,I-SNP
),I-SNP
and,O
four,O
missense,O
mutations,O
.,O
 , 
Three,O
missense,O
mutations,O
(,B-SNP
p.,I-SNP
G87R,I-SNP
,,I-SNP
p.,B-SNP
P390L,I-SNP
,,I-SNP
and,O
p.,B-SNP
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
),I-Gene
sequence,O
variants,O
using,O
a,O
metabolic,O
assay,O
in,O
immortalized,O
B,O
-,O
lymphocytes,O
.,O
 , 
Mutations,O
in,O
the,O
RYR1,B-Gene
gene,O
are,O
linked,O
to,O
malignant,O
hyperthermia,O
(,O
MH,O
),O
,,O
central,O
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
 , 
Immortalized,O
lymphoblastoid,O
cell,O
lines,O
from,O
patients,O
with,O
RYR1,B-Gene
variants,O
and,O
from,O
controls,O
were,O
stimulated,O
with,O
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
was,O
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
an,O
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
based,O
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
has,O
been,O
subjected,O
to,O
a,O
selective,O
sweep,O
in,O
African,O
populations,O
,,O
the,O
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
allele,O
with,O
obesity,O
and,O
type,O
2,O
diabetes,O
,,O
dietary,O
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
susceptible,O
to,O
spurious,O
association,O
arising,O
from,O
population,O
stratification,O
.,O
 , 
Parental,O
controls,O
are,O
popular,O
,,O
since,O
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
of,O
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
is,O
more,O
appealing,O
because,O
it,O
uses,O
the,O
probability,O
of,O
genotype,O
configurations,O
across,O
the,O
strata,O
as,O
evidence,O
for,O
global,O
departures,O
from,O
HWE,O
.,O
 , 
We,O
developed,O
an,O
exact,O
stratified,O
test,O
for,O
HWE,O
for,O
diallelic,O
markers,O
,,O
such,O
as,O
single,O
-,O
nucleotide,O
polymorphisms,O
(,O
SNPs,O
),O
,,O
and,O
an,O
exact,O
test,O
for,O
homogeneity,O
of,O
Hardy,O
-,O
Weinberg,O
disequilibrium,O
.,O
 , 
By,O
applying,O
our,O
methods,O
to,O
data,O
from,O
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
or,O
approximate,O
stratified,O
tests,O
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
useful,O
for,O
samples,O
composed,O
of,O
multiple,O
ethnic,O
groups,O
.,O
 , 
#16532395
Spread,O
of,O
an,O
inactive,O
form,O
of,O
caspase-12,B-Gene
in,O
humans,O
is,O
due,O
to,O
recent,O
positive,O
selection,O
.,O
 , 
The,O
human,O
caspase-12,B-Gene
gene,O
is,O
polymorphic,O
for,O
the,O
presence,O
or,O
absence,O
of,O
a,O
stop,O
codon,O
,,O
which,O
results,O
in,O
the,O
occurrence,O
of,O
both,O
active,O
(,O
ancestral,O
),O
and,O
inactive,O
(,O
derived,O
),O
forms,O
of,O
the,O
gene,O
in,O
the,O
population,O
.,O
 , 
It,O
has,O
been,O
shown,O
elsewhere,O
that,O
carriers,O
of,O
the,O
inactive,O
gene,O
are,O
more,O
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
has,O
spread,O
because,O
of,O
neutral,O
drift,O
or,O
positive,O
selection,O
.,O
 , 
We,O
determined,O
its,O
distribution,O
in,O
a,O
worldwide,O
sample,O
of,O
52,O
populations,O
and,O
resequenced,O
the,O
gene,O
in,O
77,O
individuals,O
from,O
the,O
HapMap,O
Yoruba,O
,,O
Han,O
Chinese,O
,,O
and,O
European,O
populations,O
.,O
 , 
There,O
is,O
strong,O
evidence,O
of,O
positive,O
selection,O
from,O
low,O
diversity,O
,,O
skewed,O
allele,O
-,O
frequency,O
spectra,O
,,O
and,O
the,O
predominance,O
of,O
a,O
single,O
haplotype,O
.,O
 , 
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
and,O
was,O
initially,O
neutral,O
or,O
almost,O
neutral,O
but,O
that,O
positive,O
selection,O
beginning,O
approximately,O
60,O
-,O
100,O
KYA,O
drove,O
it,O
to,O
near,O
fixation,O
.,O
 , 
We,O
further,O
propose,O
that,O
its,O
selective,O
advantage,O
was,O
sepsis,O
resistance,O
in,O
populations,O
that,O
experienced,O
more,O
infectious,O
diseases,O
as,O
population,O
sizes,O
and,O
densities,O
increased,O
.,O
 , 
#7728151
Germline,O
mutations,O
in,O
the,O
von,O
Hippel,O
-,O
Lindau,O
disease,O
tumor,O
suppressor,O
gene,O
:,O
correlations,O
with,O
phenotype,O
.,O
 , 
von,O
Hippel,O
-,O
Lindau,O
disease,O
(,O
VHL,O
),O
is,O
an,O
inherited,O
neoplastic,O
disease,O
characterized,O
by,O
a,O
predisposition,O
to,O
develop,O
retinal,O
angiomas,O
,,O
central,O
nervous,O
system,O
hemangioblastomas,O
,,O
renal,O
cell,O
carcinomas,O
,,O
pancreatic,O
cysts,O
,,O
and,O
pheochromocytomas,O
.,O
 , 
The,O
VHL,B-Gene
gene,O
was,O
recently,O
isolated,O
by,O
positional,O
cloning,O
.,O
 , 
The,O
cDNA,O
encodes,O
852,O
nucleotides,O
in,O
3,O
exons,O
.,O
 , 
The,O
VHL,B-Gene
gene,O
is,O
unrelated,O
to,O
any,O
known,O
gene,O
families,O
.,O
 , 
We,O
identified,O
germline,O
mutations,O
in,O
85/114,O
(,O
75,O
%,O
),O
of,O
VHL,O
families,O
.,O
 , 
Clinical,O
heterogeneity,O
is,O
a,O
well,O
-,O
known,O
feature,O
of,O
VHL,O
.,O
 , 
VHL,O
families,O
were,O
classified,O
into,O
2,O
types,O
based,O
on,O
the,O
presence,O
or,O
absence,O
of,O
pheochromocytoma,O
.,O
 , 
The,O
types,O
of,O
mutations,O
responsible,O
for,O
VHL,O
without,O
pheochromocytoma,O
(,O
VHL,O
type,O
1,O
),O
differed,O
from,O
those,O
responsible,O
for,O
VHL,O
with,O
pheochromocytoma,O
(,O
VHL,O
type,O
2,O
),O
.,O
 , 
Fifty,O
-,O
six,O
%,O
of,O
the,O
mutations,O
responsible,O
for,O
VHL,O
type,O
1,O
were,O
microdeletions,O
/,O
insertions,O
,,O
nonsense,O
mutations,O
,,O
or,O
deletions,O
;,O
96,O
%,O
of,O
the,O
mutations,O
responsible,O
for,O
VHL,O
type,O
2,O
were,O
missense,O
mutations,O
.,O
 , 
Specific,O
mutations,O
in,O
codon,O
238,O
accounted,O
for,O
43,O
%,O
of,O
the,O
mutations,O
responsible,O
for,O
VHL,O
type,O
2,O
.,O
 , 
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
of,O
fundamental,O
genetic,O
mechanisms,O
of,O
VHL,O
disease,O
.,O
 , 
#19853236
Sequence,O
variants,O
in,O
three,O
loci,O
influence,O
monocyte,O
counts,O
and,O
erythrocyte,O
volume,O
.,O
 , 
Blood,O
cells,O
participate,O
in,O
vital,O
physiological,O
processes,O
,,O
and,O
their,O
numbers,O
are,O
tightly,O
regulated,O
so,O
that,O
homeostasis,O
is,O
maintained,O
.,O
 , 
Disruption,O
of,O
key,O
regulatory,O
mechanisms,O
underlies,O
many,O
blood,O
-,O
related,O
Mendelian,O
diseases,O
but,O
also,O
contributes,O
to,O
more,O
common,O
disorders,O
,,O
including,O
atherosclerosis,O
.,O
 , 
We,O
searched,O
for,O
quantitative,O
trait,O
loci,O
(,O
QTL,O
),O
for,O
hematology,O
traits,O
through,O
a,O
whole,O
-,O
genome,O
association,O
study,O
,,O
because,O
these,O
could,O
provide,O
new,O
insights,O
into,O
both,O
hemopoeitic,O
and,O
disease,O
mechanisms,O
.,O
 , 
We,O
tested,O
1.8,O
million,O
variants,O
for,O
association,O
with,O
13,O
hematology,O
traits,O
measured,O
in,O
6015,O
individuals,O
from,O
the,O
Australian,O
and,O
Dutch,O
populations,O
.,O
 , 
These,O
traits,O
included,O
hemoglobin,O
composition,O
,,O
platelet,O
counts,O
,,O
and,O
red,O
blood,O
cell,O
and,O
white,O
blood,O
cell,O
indices,O
.,O
 , 
We,O
identified,O
three,O
regions,O
of,O
strong,O
association,O
that,O
,,O
to,O
our,O
knowledge,O
,,O
have,O
not,O
been,O
previously,O
reported,O
in,O
the,O
literature,O
.,O
 , 
The,O
first,O
was,O
located,O
in,O
an,O
intergenic,O
region,O
of,O
chromosome,O
9q31,O
near,O
LPAR1,B-Gene
,,I-Gene
explaining,O
1.5,O
%,O
of,O
the,O
variation,O
in,O
monocyte,O
counts,O
(,O
best,O
SNP,O
rs7023923,O
,,O
p=8.9x10(-14,O
),O
),O
.,O
 , 
The,O
second,O
locus,O
was,O
located,O
on,O
chromosome,O
6p21,O
and,O
associated,O
with,O
mean,O
cell,O
erythrocyte,O
volume,O
(,O
rs12661667,O
,,O
p=1.2x10(-9,O
),O
,,O
0.7,O
%,O
variance,O
explained,O
),O
in,O
a,O
region,O
that,O
spanned,O
five,O
genes,O
,,O
including,O
CCND3,B-Gene
,,I-Gene
a,O
member,O
of,O
the,O
D,O
-,O
cyclin,O
gene,O
family,O
that,O
is,O
involved,O
in,O
hematopoietic,O
stem,O
cell,O
expansion,O
.,O
 , 
The,O
third,O
region,O
was,O
also,O
associated,O
with,O
erythrocyte,O
volume,O
and,O
was,O
located,O
in,O
an,O
intergenic,O
region,O
on,O
chromosome,O
6q24,O
(,O
rs592423,O
,,O
p=5.3x10(-9,O
),O
,,O
0.6,O
%,O
variance,O
explained,O
),O
.,O
 , 
All,O
three,O
loci,O
replicated,O
in,O
an,O
independent,O
panel,O
of,O
1543,O
individuals,O
(,O
p,O
values=0.001,O
,,O
9.9x10(-5,O
),O
,,O
and,O
7x10(-5,O
),O
,,O
respectively,O
),O
.,O
 , 
The,O
identification,O
of,O
these,O
QTL,O
provides,O
new,O
opportunities,O
for,O
furthering,O
our,O
understanding,O
of,O
the,O
mechanisms,O
regulating,O
hemopoietic,O
cell,O
fate,O
.,O
 , 
#16116623
Whole,O
genome,O
SNP,O
arrays,O
using,O
DNA,O
derived,O
from,O
formalin,O
-,O
fixed,O
,,O
paraffin,O
-,O
embedded,O
ovarian,O
tumor,O
tissue,O
.,O
 , 
Array,O
-,O
based,O
genotyping,O
platforms,O
,,O
such,O
as,O
the,O
Affymetrix,O
mapping,O
array,O
,,O
have,O
been,O
validated,O
as,O
reliable,O
methods,O
for,O
obtaining,O
high,O
-,O
resolution,O
copy,O
number,O
and,O
allele,O
status,O
information,O
when,O
using,O
DNA,O
derived,O
from,O
fresh,O
tissue,O
sources,O
.,O
 , 
However,O
,,O
the,O
suitability,O
of,O
such,O
systems,O
for,O
the,O
examination,O
of,O
DNA,O
derived,O
from,O
formalin,O
-,O
fixed,O
,,O
paraffin,O
-,O
embedded,O
(,O
FFPE,O
),O
tissues,O
has,O
not,O
been,O
tested,O
.,O
 , 
Therefore,O
,,O
we,O
analyzed,O
DNA,O
derived,O
from,O
five,O
matching,O
fresh,O
frozen,O
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
Mapping,O
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
and,O
Chromosome,O
Copy,O
Number,O
Tool,O
.,O
 , 
The,O
average,O
SNP,O
call,O
rate,O
(,O
rate,O
of,O
successful,O
genotype,O
identification,O
),O
of,O
the,O
fresh,O
samples,O
was,O
89.44,O
%,O
(,O
range,O
78.72,O
-,O
96.22,O
%,O
,,O
median,O
92.72,O
%,O
),O
and,O
was,O
only,O
slightly,O
lower,O
for,O
the,O
matching,O
FFPE,O
samples,O
at,O
83.48,O
%,O
(,O
range,O
76.93,O
-,O
93.17,O
%,O
,,O
median,O
82.60,O
%,O
),O
.,O
 , 
The,O
average,O
concordance,O
(,O
rate,O
of,O
agreement,O
between,O
successful,O
genotype,O
calls,O
),O
between,O
the,O
fresh,O
and,O
matching,O
FFPE,O
samples,O
was,O
97.06,O
%,O
(,O
range,O
92.70,O
-,O
99.41,O
%,O
,,O
median,O
97.52,O
%,O
),O
.,O
 , 
Loss,O
of,O
heterozygosity,O
(,O
LOH,O
),O
profiles,O
of,O
the,O
fresh,O
and,O
FFPE,O
samples,O
were,O
essentially,O
identical,O
across,O
all,O
chromosomes,O
.,O
 , 
Copy,O
number,O
data,O
was,O
also,O
comparable,O
,,O
although,O
the,O
quantification,O
of,O
copy,O
number,O
changes,O
appears,O
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
was,O
a,O
heterozygous,O
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
transcriptional,O
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
 , 
(,O
iii,O
),O
 , 
The,O
promoter,O
-,O
enhancer,O
interaction,O
contributes,O
to,O
tissue,O
specific,O
expression,O
of,O
OTC,B-Gene
in,O
the,O
liver,O
.,O
 , 
We,O
conclude,O
that,O
mutations,O
in,O
the,O
regulatory,O
regions,O
of,O
OTC,B-Gene
can,O
lead,O
to,O
OTCD,O
and,O
should,O
be,O
included,O
in,O
genetic,O
testing,O
.,O
 , 
#7599640
Mutations,O
of,O
the,O
iduronate-2,O
-,O
sulfatase,O
gene,O
on,O
a,O
T146,O
T,O
background,O
in,O
three,O
patients,O
with,O
Hunter,O
syndrome,O
.,O
 , 
#15372378
A,O
mutation,O
in,O
the,O
vesicle,B-Gene
-,I-Gene
trafficking,I-Gene
protein,I-Gene
VAPB,B-Gene
causes,O
late,O
-,O
onset,O
spinal,O
muscular,O
atrophy,O
and,O
amyotrophic,O
lateral,O
sclerosis,O
.,O
 , 
Motor,O
neuron,O
diseases,O
(,O
MNDs,O
),O
are,O
a,O
group,O
of,O
neurodegenerative,O
disorders,O
with,O
involvement,O
of,O
upper,O
and/or,O
lower,O
motor,O
neurons,O
,,O
such,O
as,O
amyotrophic,O
lateral,O
sclerosis,O
(,O
ALS,O
),O
,,O
spinal,O
muscular,O
atrophy,O
(,O
SMA,O
),O
,,O
progressive,O
bulbar,O
palsy,O
,,O
and,O
primary,O
lateral,O
sclerosis,O
.,O
 , 
Recently,O
,,O
we,O
have,O
mapped,O
a,O
new,O
locus,O
for,O
an,O
atypical,O
form,O
of,O
ALS,O
/,O
MND,O
(,O
atypical,O
amyotrophic,O
lateral,O
sclerosis,O
[,O
ALS8,O
],O
),O
at,O
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
associated,I-Gene
membrane,I-Gene
protein,I-Gene
/,I-Gene
synaptobrevin,I-Gene
-,I-Gene
associated,I-Gene
membrane,I-Gene
protein,I-Gene
B,I-Gene
(,B-Gene
VAPB,I-Gene
),I-Gene
gene,O
in,O
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
DNMs,O
in,O
this,O
disorder,O
.,O
 , 
#9973288
Hyperparathyroidism,O
-,O
jaw,O
tumor,O
syndrome,O
:,O
the,O
HRPT2,B-Gene
locus,O
is,O
within,O
a,O
0.7,O
-,O
cM,O
region,O
on,O
chromosome,O
1q,O
.,O
 , 
Hyperparathyroidism,O
-,O
jaw,O
tumor,O
syndrome,O
(,O
HPT,O
-,O
JT,O
),O
is,O
an,O
autosomal,O
dominant,O
disease,O
characterized,O
by,O
the,O
development,O
of,O
multiple,O
parathyroid,O
adenomas,O
and,O
multiple,O
fibro,O
-,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
and,O
hamartomas,O
.,O
 , 
The,O
HPT,O
-,O
JT,O
gene,O
(,B-Gene
HRPT2,I-Gene
),I-Gene
maps,O
to,O
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
and,O
K3349,O
),O
identified,O
through,O
the,O
literature,O
.,O
 , 
These,O
two,O
expanded,O
families,O
and,O
two,O
previously,O
reported,O
families,O
were,O
investigated,O
jointly,O
for,O
linkage,O
with,O
21,O
new,O
,,O
closely,O
linked,O
markers,O
.,O
 , 
Multipoint,O
linkage,O
analysis,O
resulted,O
in,O
a,O
maximum,O
LOD,O
score,O
of,O
7.83,O
(,O
at,O
recombination,O
fraction,O
0,O
),O
for,O
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
two,O
of,O
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
length,O
of,O
their,O
(,O
expanded,O
),O
affected,O
haplotype,O
,,O
indicating,O
a,O
possible,O
common,O
origin,O
.,O
 , 
Combining,O
the,O
linkage,O
data,O
and,O
shared,O
-,O
haplotype,O
data,O
,,O
we,O
propose,O
a,O
0.7,O
-,O
cM,O
candidate,O
region,O
for,O
HRPT2,B-Gene
.,I-Gene
 , 
#7825598
Evidence,O
for,O
an,O
association,O
between,O
RFLPs,O
at,O
the,O
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
of,O
hMSH3,B-Gene
and,O
hMSH6,B-Gene
mismatch,O
repair,O
genes,O
in,O
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
of,O
repeat,O
units,O
,,O
are,O
known,O
as,O
the,O
replication,O
/,O
repair,O
error,O
positive,O
(,O
RER+,O
),O
phenotype,O
or,O
micorsatellite,O
instability,O
(,O
MI,O
),O
.,O
 , 
Microsatellite,O
instability,O
has,O
been,O
demonstrated,O
in,O
hereditary,O
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
of,O
MI,O
have,O
been,O
identified,O
thus,O
far,O
.,O
 , 
Using,O
PCR,O
,,O
we,O
amplified,O
regions,O
encompassing,O
(,O
A)8,O
and,O
(,O
C)8,O
microsatellite,O
tracts,O
within,O
hMSH3,B-Gene
and,O
hMSH6,B-Gene
from,O
31,O
RER+,O
sporadic,O
colorectal,O
tumors,O
,,O
8,O
hereditary,O
colon,O
cancers,O
,,O
23,O
RER+,O
gastric,O
carcinomas,O
,,O
and,O
32,O
RER-,O
gastric,O
tumors,O
.,O
 , 
Mutations,O
were,O
found,O
in,O
11,O
(,O
36,O
%,O
),O
of,O
31,O
sporadic,O
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
.,O
 , 
#7981721
A,O
tandem,O
CC-->TT,O
transition,O
in,O
the,O
p53,B-Gene
gene,O
of,O
a,O
breast,O
cancer,O
.,O
 , 
#19718767
NR2E3,B-Gene
mutations,O
in,O
enhanced,O
S,O
-,O
cone,O
sensitivity,O
syndrome,O
(,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
and,O
retinitis,O
pigmentosa,O
(,O
RP,O
),O
.,O
 , 
NR2E3,B-Gene
,,I-Gene
also,O
called,O
photoreceptor,B-Gene
-,I-Gene
specific,I-Gene
nuclear,I-Gene
receptor,I-Gene
(,B-Gene
PNR,I-Gene
),I-Gene
,,O
is,O
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
different,O
mutations,O
in,O
NR2E3,B-Gene
have,O
been,O
identified,O
in,O
either,O
homozygous,O
or,O
compound,O
heterozygous,O
state,O
in,O
the,O
recessively,O
inherited,O
enhanced,O
S,O
-,O
cone,O
sensitivity,O
syndrome,O
(,O
ESCS,O
),O
,,O
Goldmann,O
-,O
Favre,O
syndrome,O
(,O
GFS,O
),O
,,O
and,O
clumped,O
pigmentary,O
retinal,O
degeneration,O
(,O
CPRD,O
),O
.,O
 , 
The,O
clinical,O
phenotype,O
common,O
to,O
all,O
these,O
patients,O
is,O
night,O
blindness,O
,,O
rudimental,O
or,O
absent,O
rod,O
function,O
,,O
and,O
hyperfunction,O
of,O
the,O
",O
blue,O
",O
S,O
-,O
cones,O
.,O
 , 
A,O
single,O
p.,B-SNP
G56R,I-SNP
mutation,O
is,O
inherited,O
in,O
a,O
dominant,O
manner,O
and,O
causes,O
retinitis,O
pigmentosa,O
(,O
RP,O
),O
.,O
 , 
We,O
have,O
established,O
a,O
new,O
locus,O
-,O
specific,O
database,O
for,O
NR2E3,B-Gene
(,O
www.LOVD.nl/eye,O
),O
,,O
containing,O
all,O
reported,O
mutations,O
,,O
polymorphisms,O
,,O
and,O
unclassified,O
sequence,O
variants,O
,,O
including,O
novel,O
ones,O
.,O
 , 
A,O
high,O
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
),O
and,O
ligand,O
-,O
binding,O
domains,O
(,O
LBDs,O
),O
of,O
NR2E3,B-Gene
.,I-Gene
 , 
Based,O
on,O
homology,O
modeling,O
of,O
these,O
NR2E3,B-Gene
domains,O
,,O
we,O
propose,O
a,O
structural,O
localization,O
of,O
mutated,O
residues,O
.,O
 , 
The,O
high,O
variability,O
of,O
clinical,O
phenotypes,O
observed,O
in,O
patients,O
affected,O
by,O
NR2E3,B-Gene
-,I-Gene
linked,O
retinal,O
degenerations,O
may,O
be,O
caused,O
by,O
different,O
disease,O
mechanisms,O
,,O
including,O
absence,O
of,O
DNA,O
-,O
binding,O
,,O
altered,O
interactions,O
with,O
transcriptional,O
coregulators,O
,,O
and,O
differential,O
activity,O
of,O
modifier,O
genes,O
.,O
 , 
#15272417
A,O
major,O
lung,O
cancer,O
susceptibility,O
locus,O
maps,O
to,O
chromosome,O
6q23,O
-,O
25,O
.,O
 , 
Lung,O
cancer,O
is,O
a,O
major,O
cause,O
of,O
death,O
in,O
the,O
United,O
States,O
and,O
other,O
countries,O
.,O
 , 
The,O
risk,O
of,O
lung,O
cancer,O
is,O
greatly,O
increased,O
by,O
cigarette,O
smoking,O
and,O
by,O
certain,O
occupational,O
exposures,O
,,O
but,O
familial,O
factors,O
also,O
clearly,O
play,O
a,O
major,O
role,O
.,O
 , 
To,O
identify,O
susceptibility,O
genes,O
for,O
familial,O
lung,O
cancer,O
,,O
we,O
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
under,O
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
yielded,O
a,O
maximum,O
heterogeneity,O
LOD,O
score,O
(,O
HLOD,O
),O
of,O
2.79,O
at,O
155,O
cM,O
on,O
chromosome,O
6q,O
(,O
marker,O
D6S2436,O
),O
.,O
 , 
A,O
subset,O
of,O
38,O
pedigrees,O
with,O
four,O
or,O
more,O
affected,O
individuals,O
yielded,O
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
multigenerational,O
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
 , 
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
,,O
which,O
results,O
from,O
mutations,O
of,O
the,O
P,B-Gene
gene,I-Gene
,,I-Gene
is,O
the,O
most,O
frequent,O
type,O
of,O
albinism,O
in,O
African,O
and,O
African,O
-,O
American,O
patients,O
.,O
 , 
OCA2,O
is,O
especially,O
frequent,O
in,O
Tanzania,O
,,O
where,O
it,O
occurs,O
with,O
an,O
incidence,O
of,O
approximately,O
1/1,400,O
.,O
 , 
We,O
have,O
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
with,O
OCA2,O
from,O
Tanzania,O
.,O
 , 
One,O
of,O
these,O
,,O
a,O
deletion,O
of,O
exon,O
7,O
,,O
is,O
strongly,O
predominant,O
,,O
accounting,O
for,O
approximately,O
77,O
%,O
of,O
mutant,O
alleles,O
in,O
this,O
group,O
of,O
patients,O
.,O
 , 
#12515255
The,O
ABCA4,B-Gene
gene,O
in,O
autosomal,O
recessive,O
cone,O
-,O
rod,O
dystrophies,O
.,O
 , 
#12687497
A,O
family,O
-,O
based,O
test,O
for,O
correlation,O
between,O
gene,O
expression,O
and,O
trait,O
values,O
.,O
 , 
Advances,O
in,O
microarray,O
technology,O
have,O
made,O
it,O
attractive,O
to,O
combine,O
information,O
on,O
clinical,O
traits,O
,,O
marker,O
genotypes,O
,,O
and,O
comprehensive,O
gene,O
expression,O
from,O
family,O
studies,O
to,O
dissect,O
complex,O
disease,O
genetics,O
.,O
 , 
Without,O
accounting,O
for,O
family,O
structure,O
,,O
methods,O
that,O
test,O
for,O
association,O
between,O
a,O
trait,O
and,O
gene,O
-,O
expression,O
levels,O
can,O
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
the,O
utility,O
of,O
the,O
FEXAT,O
via,O
simulation,O
and,O
an,O
application,O
to,O
gene,O
-,O
expression,O
data,O
from,O
lymphoblastoid,O
cell,O
lines,O
from,O
four,O
CEPH,O
families,O
.,O
 , 
The,O
FEXAT,O
has,O
a,O
smaller,O
estimated,O
false,O
-,O
discovery,O
rate,O
than,O
the,O
standard,O
test,O
when,O
within,O
-,O
family,O
correlations,O
are,O
of,O
interest,O
,,O
and,O
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
that,O
the,O
standard,O
test,O
does,O
not,O
.,O
 , 
#15759212
Identifying,O
candidate,O
Hirschsprung,O
disease,O
-,O
associated,O
RET,B-Gene
variants,O
.,O
 , 
Patients,O
with,O
sporadic,O
Hirschsprung,O
disease,O
(,O
HSCR,O
),O
show,O
increased,O
allele,O
sharing,O
at,O
markers,O
in,O
the,O
5,O
',O
region,O
of,O
the,O
RET,B-Gene
locus,O
,,O
indicating,O
the,O
presence,O
of,O
a,O
common,O
ancestral,O
RET,B-Gene
mutation,O
.,O
 , 
In,O
a,O
previous,O
study,O
,,O
we,O
found,O
a,O
haplotype,O
of,O
six,O
SNPs,O
that,O
was,O
transmitted,O
to,O
55.6,O
%,O
of,O
our,O
patients,O
,,O
whereas,O
it,O
was,O
present,O
in,O
only,O
16.2,O
%,O
of,O
the,O
controls,O
we,O
used,O
.,O
 , 
Among,O
the,O
patients,O
with,O
that,O
haplotype,O
,,O
90.8,O
%,O
had,O
it,O
on,O
both,O
chromosomes,O
,,O
which,O
led,O
to,O
a,O
much,O
higher,O
risk,O
of,O
developing,O
HSCR,O
than,O
when,O
the,O
haplotype,O
occurred,O
heterozygously,O
.,O
 , 
To,O
more,O
precisely,O
define,O
the,O
HSCR,O
-,O
associated,O
region,O
and,O
to,O
identify,O
candidate,O
disease,O
-,O
associated,O
variant(s,O
),O
,,O
we,O
sequenced,O
the,O
shared,O
common,O
haplotype,O
region,O
from,O
10,O
kb,O
upstream,O
of,O
the,O
RET,B-Gene
gene,O
through,O
intron,O
1,O
and,O
exon,O
2,O
(,O
in,O
total,O
,,O
33,O
kb,O
),O
in,O
a,O
patient,O
homozygous,O
for,O
the,O
common,O
risk,O
haplotype,O
and,O
in,O
a,O
control,O
individual,O
homozygous,O
for,O
the,O
most,O
common,O
nonrisk,O
haplotype,O
.,O
 , 
A,O
comparison,O
of,O
these,O
sequences,O
revealed,O
86,O
sequence,O
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
presence,O
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
association,O
with,O
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
and,O
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
strategies,O
for,O
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
-,O
based,O
replication,O
,,O
wherein,O
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
and,O
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
the,O
power,O
gain,O
is,O
small,O
(,O
1,O
),O
for,O
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
can,O
be,O
observed,O
and,O
(,O
2,O
),O
for,O
small-,O
to,O
medium,O
-,O
scale,O
studies,O
with,O
a,O
few,O
hundred,O
samples,O
,,O
because,O
a,O
large,O
proportion,O
of,O
the,O
locus,O
population,O
attributable,O
risk,O
can,O
be,O
explained,O
by,O
the,O
uncovered,O
variants,O
.,O
 , 
Therefore,O
,,O
genotyping,O
can,O
be,O
a,O
temporal,O
solution,O
for,O
replicating,O
genetic,O
studies,O
if,O
stage,O
1,O
and,O
2,O
samples,O
are,O
drawn,O
from,O
the,O
same,O
population,O
.,O
 , 
However,O
,,O
sequence,O
-,O
based,O
replication,O
is,O
advantageous,O
if,O
the,O
stage,O
1,O
sample,O
is,O
small,O
or,O
novel,O
variants,O
discovery,O
is,O
also,O
of,O
interest,O
.,O
 , 
It,O
is,O
shown,O
that,O
currently,O
attainable,O
levels,O
of,O
sequencing,O
error,O
only,O
minimally,O
affect,O
the,O
comparison,O
,,O
and,O
the,O
advantage,O
of,O
sequence,O
-,O
based,O
replication,O
remains,O
.,O
 , 
#8488834
Insurance,O
commissioners,O
and,O
genetic,O
discrimination,O
.,O
 , 
#8081391
Mutations,O
in,O
steroid,B-Gene
21,I-Gene
-,I-Gene
hydroxylase,I-Gene
(,B-Gene
CYP21,I-Gene
),I-Gene
.,O
 , 
The,O
inherited,O
inability,O
to,O
synthesize,O
cortisol,O
is,O
termed,O
congenital,O
adrenal,O
hyperplasia,O
.,O
 , 
More,O
than,O
90,O
%,O
of,O
cases,O
are,O
caused,O
by,O
21,O
-,O
hydroxylase,O
deficiency,O
.,O
 , 
This,O
syndrome,O
is,O
characterized,O
by,O
signs,O
of,O
androgen,O
excess,O
and,O
often,O
mineralocorticoid,O
deficiency,O
.,O
 , 
Steroid,B-Gene
21,I-Gene
-,I-Gene
hydroxylase,I-Gene
(,B-Gene
P450c21,I-Gene
),I-Gene
is,O
a,O
microsomal,O
enzyme,O
expressed,O
in,O
the,O
adrenal,O
gland,O
that,O
catalyzes,O
conversion,O
of,O
17,B-Gene
-,I-Gene
hydroxyprogesterone,I-Gene
and,O
progesterone,B-Gene
to,O
11,B-Gene
-,I-Gene
deoxycortisol,I-Gene
and,I-Gene
deoxycorticosterone,I-Gene
respectively,O
.,O
 , 
In,O
man,O
,,O
this,O
enzyme,O
is,O
encoded,O
by,O
the,O
CYP21,B-Gene
(,B-Gene
CYP21B,I-Gene
),I-Gene
gene,O
which,O
is,O
located,O
in,O
the,O
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
in,O
CYP21,B-Gene
causing,O
congenital,O
adrenal,O
hyperplasia,O
are,O
almost,O
all,O
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
mutations,O
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
 , 
Mutations,O
at,O
the,O
myocilin,B-Gene
(,B-Gene
MYOC,I-Gene
),I-Gene
gene,O
within,O
the,O
GLC1A,O
locus,O
have,O
been,O
revealed,O
in,O
2,O
-,O
4,O
%,O
of,O
patients,O
suffering,O
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
study,O
diagnosed,O
either,O
with,O
juvenile,O
OAG,O
(,O
JOAG,O
),O
,,O
POAG,O
,,O
ocular,O
hypertension,O
(,O
OHT,O
),O
or,O
normal,O
tension,O
glaucoma,O
(,O
NTG,O
),O
plus,O
22,O
cases,O
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
with,O
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
is,O
the,O
most,O
frequent,O
autosomal,O
recessive,O
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
gene,O
:,O
a,O
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
were,O
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
susceptibility,O
specificities,O
in,O
multiple,O
sclerosis,O
.,O
 , 
#11023809
Major,O
genes,O
regulating,O
total,O
serum,O
immunoglobulin,O
E,O
levels,O
in,O
families,O
with,O
asthma,O
.,O
 , 
Immunoglobulin,B-Gene
E,I-Gene
(,B-Gene
IgE,I-Gene
),I-Gene
has,O
a,O
major,O
role,O
in,O
the,O
pathogenesis,O
of,O
allergic,O
disorders,O
and,O
asthma,O
.,O
 , 
Previous,O
data,O
from,O
92,O
families,O
,,O
each,O
identified,O
through,O
a,O
proband,O
with,O
asthma,O
,,O
showed,O
evidence,O
for,O
two,O
major,O
genes,O
regulating,O
total,O
serum,O
IgE,B-Gene
levels,O
.,O
 , 
One,O
of,O
these,O
genes,O
mapped,O
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
of,O
108,O
probands,O
and,O
their,O
families,O
,,O
ascertained,O
in,O
the,O
same,O
manner,O
.,O
 , 
A,O
mixed,O
recessive,O
model,O
(,O
i.e.,O
,,O
major,O
recessive,O
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
parsimonious,O
one,O
-,O
locus,O
model,O
of,O
the,O
segregation,O
analysis,O
.,O
 , 
A,O
mixed,O
two,O
-,O
major,O
-,O
gene,O
model,O
(,O
i.e.,O
,,O
two,O
major,O
genes,O
and,O
residual,O
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
with,O
the,O
genotype,O
aaBB,O
(,O
homozygous,O
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
had,O
normal,O
IgE,B-Gene
levels,O
(,O
mean,O
23,O
IU,O
/,O
ml,O
),O
,,O
and,O
only,O
individuals,O
with,O
genotypes,O
aaBb,O
and,O
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
genomewide,O
screening,O
was,O
performed,O
using,O
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
 , 
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
P=.0002,O
),O
and,O
2.46,O
(,O
P=.0004,O
),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
atypical,O
),O
cases,O
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
10%-30,O
%,O
of,O
patients,O
with,O
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
terminal,O
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
and,O
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
will,O
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
missense,O
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
prevalent,O
in,O
pyridoxine,O
-,O
responsive,O
homocystinuria,O
and,O
associated,O
with,O
mild,O
clinical,O
phenotype,O
.,O
 , 
Cystathionine,B-Gene
beta,I-Gene
-,I-Gene
synthase,I-Gene
(,B-Gene
CBS,I-Gene
),I-Gene
deficiency,O
is,O
an,O
autosomal,O
recessive,O
disorder,O
characterized,O
by,O
homocystinuria,O
and,O
multisystem,O
clinical,O
disease,O
.,O
 , 
Patients,O
responsive,O
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
in,O
exon,O
8,O
causing,O
a,O
substitution,O
of,O
threonine,B-SNP
for,I-SNP
isoleucine,I-SNP
at,I-SNP
codon,I-SNP
278,I-SNP
(,B-SNP
I278,I-SNP
T,I-SNP
),I-SNP
.,O
 , 
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
homozygous,O
and,O
five,O
are,O
heterozygous,O
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
Alzheimer,O
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
polymorphism,O
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
with,O
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
involved,O
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
or,O
age,O
at,O
breast,O
cancer,O
onset,O
.,O
 , 
#8460646
BRCA1,B-Gene
maps,O
proximal,O
to,O
D17S579,O
on,O
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
and,O
ovarian,O
cancer,O
and,O
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
appears,O
to,O
be,O
inherited,O
as,O
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
appear,O
to,O
be,O
linked,O
to,O
BRCA1,B-Gene
.,I-Gene
 , 
One,O
apparently,O
linked,O
family,O
contains,O
critical,O
recombinants,O
,,O
suggesting,O
that,O
the,O
gene,O
is,O
proximal,O
to,O
the,O
marker,O
D17S579,O
(,O
Mfd188,O
),O
.,O
 , 
These,O
findings,O
are,O
consistent,O
with,O
the,O
maximum,O
-,O
likelihood,O
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
was,O
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
of,O
the,O
two,O
families,O
with,O
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
and,O
susceptibility,O
to,O
schizophrenia,O
.,O
 , 
The,O
cause,O
of,O
schizophrenia,O
is,O
unknown,O
,,O
but,O
it,O
has,O
a,O
significant,O
genetic,O
component,O
.,O
 , 
Pharmacologic,O
studies,O
,,O
studies,O
of,O
gene,O
expression,O
in,O
man,O
,,O
and,O
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
of,O
the,O
8p,O
locus,O
and,O
haplotype,O
-,O
association,O
analysis,O
,,O
supplemented,O
by,O
a,O
transmission,O
/,O
disequilibrium,O
test,O
,,O
identifies,O
neuregulin,B-Gene
1,I-Gene
(,B-Gene
NRG1,I-Gene
),I-Gene
as,O
a,O
candidate,O
gene,O
for,O
schizophrenia,O
.,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
heterozygous,O
for,O
either,O
NRG1,B-Gene
or,O
its,O
receptor,O
,,O
ErbB4,O
,,O
show,O
a,O
behavioral,O
phenotype,O
that,O
overlaps,O
with,O
mouse,O
models,O
for,O
schizophrenia,O
.,O
 , 
Furthermore,O
,,O
NRG1,B-Gene
hypomorphs,O
have,O
fewer,O
functional,O
NMDA,O
receptors,O
than,O
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
 ,