Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Deficits in phonological processing are known to play a major role in the aetiology of dyslexia, and speech perception is a prerequisite condition for phonological processing. Significant group differences between dyslexics and controls have been found in the categorical perception of synthetic speech stimuli. In a previous work, we have demonstrated that these group differences are already present at an early pre-attentive stage of signal processing in dyslexic children: the late component of the MMN elicited by passive speech perception was attenuated in comparison to a control group. In this study, 12 dyslexic adults and 13 controls were assessed using a passive oddball paradigm. Mismatch negativity (MMN) was determined for both tone and speech stimuli. The tone stimuli yielded two MMN components, but no group differences. Three components were found for the speech stimuli. Multivariate testing for group differences yielded a significant result, and univariate P values revealed significant differences between dyslexics and controls in two of the three time windows. This suggests that speech perception as measured on an early, pre-attentive level plays a major role in dyslexia not only in children (as shown in our previous study) but also in adults. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia is a neurofunctional disorder characterised by an unexpected difficulty in learning to read and write despite adequate intelligence, motivation, and education. Previous studies have suggested mostly quantitative susceptibility loci for dyslexia on chromosomes 1, 2, 6, and 15, but no genes have been identified yet. We studied a large pedigree, ascertained from 140 families considered, segregating pronounced dyslexia in an autosomal dominant fashion. Affected status and the subtype of dyslexia were determined by neuropsychological tests. A genome scan with 320 markers showed a novel dominant locus linked to dyslexia in the pericentromeric region of chromosome 3 with a multipoint lod score of 3.84. Nineteen out of 21 affected pedigree members shared this region identical by descent (corrected p<0.001). Previously implicated genomic regions showed no evidence for linkage. Sequencing of two positional candidate genes, 5HT1F and DRD3, did not support their role in dyslexia. The new locus on chromosome 3 is associated with deficits in all three essential components involved in the reading process, namely phonological awareness, rapid naming, and verbal short term memory. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Process extension is a most marked and characteristic neuronal feature that is observed during the development, regeneration and plasticity of nervous system tissues. Neuro-p24, a novel membranous protein with a molecular weight of 24 kDa, is specifically localized in neurons, particularly in the neurites. Based on its molecular structure and distribution pattern in the brain we proposed that Neuro-p24 plays a role in neurite extension. In the present study we have made several findings that support this hypothesis; first, Neuro-p24 was abundant in motor axonal fibers, neurites of dorsal root ganglia neurons and apical dendrites of cerebral cortex neurons when their extension or arborization was proceeding very actively. Secondly, when COS-7 epithelial cells were transfected with either wild-type or deletion-mutated Neuro-p24 cDNAs, ectopic expression of wild-type cDNA caused morphological alterations resulting in a neuron-like appearance. These observations firmly support our proposal and indicate that Neuro-p24 plays an important role in the nervous tissue. # 2002 Elsevier Science Ireland Ltd. and the Japan Neuroscience Society. All rights reserved. <s> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Slit proteins have previously been shown to regulate axon guidance, branching, and neural migration. Here we report that, in addition to acting as a chemorepellant for cortical axons, Slit1 regulates dendritic development. Slit1 is expressed in the developing cortex, and exposure to Slit1 leads to increased dendritic growth and branching. Conversely, inhibition of Slit-Robo interactions by Robo-Fc fusion proteins or by a dominant-negative Robo attenuates dendritic branching. Stimulation of neurons transfected with a Met-Robo chimeric receptor with Hepatocyte growth factor leads to a robust induction of dendritic growth and branching, suggesting that Robo-mediated signaling is sufficient to induce dendritic remodeling. These experiments indicate that Slit-Robo interactions may exert a significant influence over the specification of cortical neuron morphology by regulating both axon guidance and dendritic patterning. <s> BIB004 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia is defined as a specific and significant impairment in reading ability that cannot be explained by deficits in intelligence, learning opportunity, motivation or sensory acuity. It is one of the most frequently diagnosed disorders in childhood, representing a major educational and social problem. It is well established that dyslexia is a significantly heritable trait with a neurobiological basis. The etiological mechanisms remain elusive, however, despite being the focus of intensive multidisciplinary research. All attempts to map quantitative-trait loci (QTLs) influencing dyslexia susceptibility have targeted specific chromosomal regions, so that inferences regarding genetic etiology have been made on the basis of very limited information. Here we present the first two complete QTL-based genome-wide scans for this trait, in large samples of families from the United Kingdom and United States. Using single-point analysis, linkage to marker D18S53 was independently identified as being one of the most significant results of the genome in each scan (P< or =0.0004 for single word-reading ability in each family sample). Multipoint analysis gave increased evidence of 18p11.2 linkage for single-word reading, yielding top empirical P values of 0.00001 (UK) and 0.0004 (US). Measures related to phonological and orthographic processing also showed linkage at this locus. We replicated linkage to 18p11.2 in a third independent sample of families (from the UK), in which the strongest evidence came from a phoneme-awareness measure (most significant P value=0.00004). A combined analysis of all UK families confirmed that this newly discovered 18p QTL is probably a general risk factor for dyslexia, influencing several reading-related processes. This is the first report of QTL-based genome-wide scanning for a human cognitive trait. <s> BIB005 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Linkage between developmental dyslexia (DD) and chromosome 6p has been replicated in a number of independent samples. Recent attempts to identify the gene responsible for the linkage have produced inconsistent evidence for association of DD with a number of genes in a 575-kb region of chromosome 6p22.2, including VMP, DCDC2, KIAA0319, TTRAP, and THEM2. We aimed to identify the specific gene or genes involved by performing a systematic, high-density (approximately 2-3-kb intervals) linkage disequilibrium screen of these genes in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability. Using DNA pooling, we first observed evidence for association with 17 single-nucleotide polymorphisms (SNPs), 13 of which were located in the KIAA0319 gene (P<.01-.003). After redundant SNPs were excluded, 10 SNPs were individually genotyped in 223 subjects with DD and 273 controls. Those SNPs that were significant at P</=.05 were next genotyped in a semi-independent sample of 143 trios of probands with DD and their parents, to control for possible population stratification. Six SNPs showed significant evidence of association in both samples (P</=.04-.002), including a SNP (rs4504469) in exon 4 of the KIAA0319 gene that changes an amino acid (P=.002; odds ratio 1.5). Logistic regression analysis showed that two SNPs (rs4504469 and rs6935076) in the KIAA0319 gene best explained DD status. The haplotype composed of these two markers was significantly associated with DD (global P=.00001 in the case-control sample; P=.02 in trios). This finding was largely driven by underrepresentation of the most common haplotype in cases (P=.00003 in the case-control sample; P=.006 in trios; 1-degree-of-freedom tests). Our data strongly implicate KIAA0319 as a susceptibility gene for dyslexia. The gene product is expressed in brain, but its specific function is currently unknown. <s> BIB006 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples), the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans. <s> BIB007 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> The DYX2 locus on chromosome 6p22.2 is the most replicated region of linkage to developmental dyslexia (DD). Two candidate genes within this region have recently been implicated in the disorder: KIAA0319 and DCDC2. Variants within DCDC2 have shown association with DD in a US and a German sample. However, when we genotyped these specific variants in two large, independent UK samples, we obtained only weak, inconsistent evidence for their involvement in DD. Having previously found evidence that variation in the KIAA0319 gene confers susceptibility to DD, we sought to refine this genetic association by genotyping 36 additional SNPs in the gene. Nine SNPs, predominantly clustered around the first exon, showed the most significant association with DD in one or both UK samples, including rs3212236 in the 5' flanking region (P = 0.00003) and rs761100 in intron 1 (P = 0.0004). We have thus refined the region of association with developmental dyslexia to putative regulatory sequences around the first exon of the KIAA0319 gene, supporting the presence of functional mutations that could affect gene expression. Our data also suggests a possible interaction between KIAA0319 and DCDC2, which requires further testing. <s> BIB008 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Abstract Rodent homologues of two candidate dyslexia susceptibility genes, Kiaa0319 and Dcdc2, have been shown to play roles in neuronal migration in developing cerebral neocortex. This functional role is consistent with the hypothesis that dyslexia susceptibility is increased by interference with normal neural development. In this study we report that in utero RNA interference against the rat homolog of another candidate dyslexia susceptibility gene, DYX1C1, disrupts neuronal migration in developing neocortex. The disruption of migration can be rescued by concurrent overexpression of DYX1C1, indicating that the impairment is not due to off-target effects. Transfection of C- and N-terminal truncations of DYX1C1 shows that the C-terminal TPR domains determine DYX1C1 intracellular localization to cytoplasm and nucleus. RNAi rescue experiments using truncated versions of DYX1C1 further indicate that the C-terminus of DYX1C1 is necessary and sufficient to DYX1C1’s function in migration. In conclusion, DYX1C1, similar to two other candidate dyslexia susceptibility genes, functions in neuronal migration in rat neocortex. <s> BIB009 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> The Slit genes encode secreted ligands that regulate axon branching, commissural axon pathfinding and neuronal migration. The principal identified receptor for Slit is Robo (Roundabout in Drosophila). To investigate Slit signalling in forebrain development, we generated Robo1 knockout mice by targeted deletion of exon 5 of the Robo1 gene. Homozygote knockout mice died at birth, but prenatally displayed major defects in axon pathfinding and cortical interneuron migration. Axon pathfinding defects included dysgenesis of the corpus callosum and hippocampal commissure, and abnormalities in corticothalamic and thalamocortical targeting. Slit2 and Slit1/2 double mutants display malformations in callosal development, and in corticothalamic and thalamocortical targeting, as well as optic tract defects. In these animals, corticothalamic axons form large fasciculated bundles that aberrantly cross the midline at the level of the hippocampal and anterior commissures, and more caudally at the medial preoptic area. Such phenotypes of corticothalamic targeting were not observed in Robo1 knockout mice but, instead, both corticothalamic and thalamocortical axons aberrantly arrived at their respective targets at least 1 day earlier than controls. By contrast, in Slit mutants, fewer thalamic axons actually arrive in the cortex during development. Finally, significantly more interneurons (up to twice as many at E12.5 and E15.5) migrated into the cortex of Robo1 knockout mice, particularly in both rostral and parietal regions, but not caudal cortex. These results indicate that Robo1 mutants have distinct phenotypes, some of which are different from those described in Slit mutants, suggesting that additional ligands, receptors or receptor partners are likely to be involved in Slit/Robo signalling. <s> BIB010 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Dyslexia is a common heterogeneous disorder with a significant genetic component. Multiple studies have replicated the evidence for linkage between variously defined phenotypes of dyslexia and chromosomal regions on 15q21 (DYX1) and 6p22.2 (DYX2). Based on association studies and the possibility for functional significance of several polymorphisms, candidate genes responsible for the observed linkage signal have been proposed-DYX1C1 for 15q21, and KIAA0319 and DCDC2 for 6p22.2. We investigated the evidence for contribution of these candidate genes to dyslexia in our sample of multigenerational families. Our previous quantitative linkage analyses in this dataset provided supportive evidence for linkage of dyslexia to the locus on chromosome 15, but not to the locus on chromosome 6. In the current study, we used probands from 191 families for a case control analysis, and proband-parent trios for family-based TDT analyses. The observation of weak evidence for transmission disequilibrium for one of the two studied polymorphisms in DYX1C1 suggests involvement of this gene in dyslexia in our dataset. We did not find evidence for the association of KIAA0319 or DCDC2 alleles to dyslexia in our sample. We observed a slight tendency for an intronic deletion in DCDC2 to be associated with worse performance on some quantitative measures of dyslexia in the probands in our sample, but not in their parents. <s> BIB011 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Objective ::: The purpose of this investigation was to determine whether there is an association between the putative reading disability (RD) susceptibility gene Doublecortin Domain Containing 2 (DCDC2), and gray matter (GM) distribution in the brain, in a sample of healthy control individuals. <s> BIB012 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Background KIAA0319 (6p22.2) has recently been implicated as a susceptibility gene for dyslexia. We aimed to find further support for this gene by examining its association with reading and spelling ability in adolescent twins and their siblings unselected for dyslexia. Methods Ten single nucleotide polymorphisms (SNPs) in or near the KIAA0319 gene were typed in 440 families with up to five offspring who had been tested on reading and spelling tasks. Family-based association analyses were performed, including a univariate analysis of the principal component reading and spelling score derived from the Components of Reading Examination (CORE) test battery and a bivariate analysis of whole-word reading tests measured in a slightly larger sample. Results Significant association with rs2143340 ( TTRAP ) and rs6935076 ( KIAA0319 ) and with a three-SNP haplotype spanning KIAA0319 and TTRAP was observed. The association with rs2143340 was found in both analyses, although the effect was in the opposite direction to that previously reported. The effect of rs6935076 on the principal component was in the same direction as past findings. Two of the three significant individual haplotypes showed effects in the opposite direction to the two prior reports. Conclusions These results suggest that a multilocus effect in or near KIAA0319 may influence variation in reading ability. <s> BIB013 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental malformations of cortex have been shown to co-occur with language, learning, and other cognitive deficits in humans. Rodent models have repeatedly shown that animals with such developmental malformations have deficits related to auditory processing and learning. More specifically, freeze-lesion induced microgyria as well as molecular layer ectopias have been found to impair rapid auditory processing ability in rats and mice. In humans, deficits in rapid auditory processing appear to relate to later impairments of language. Recently, genetic variants of four different genes involved in early brain development have been proposed to associate with an elevated incidence of developmental dyslexia in humans. Three of these, DYX1C1, DCDC2, and KIAA0319, have been shown by in utero RNAi to play a role in neuronal migration in developing neocortex. The present study assessed the effects of in utero RNAi of Dyx1c1 on auditory processing and spatial learning in rats. Results indicate that RNAi of Dyx1c1 is associated with cortical heterotopia and is suggestive of an overall processing deficit of complex auditory stimuli in both juvenile and adult periods (p = .051, one-tail). In contrast, adult data alone reveal a significant processing impairment among RNAi treated subjects compared to shams, indicating an inability for RNAi treated subjects to improve detection of complex auditory stimuli over time (p = .022, one-tail). Further, a subset of RNAi treated rats exhibited hippocampal heterotopia centered in CA1 (in addition to cortical malformations). Malformations of hippocampus were associated with robust spatial learning impairment in this sub-group (p < .01, twotail). In conclusion, in utero RNAi of Dyx1c1 results in heterogeneous malformations that correspond to distinct behavioral impairments in auditory <s> BIB014 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> A substantial genetic contribution in the etiology of developmental dyslexia (DD) has been well documented with independent groups reporting a susceptibility locus on chromosome 15q. After the identification of the DYX1C1 gene as a potential candidate for DD, several independent association studies reported controversial results. We performed a family-based association study to determine whether the DYX1C1 single nucleotide polymorphisms (SNPs) that have been associated with DD before, that is SNPs '-3GA' and '1249GT', influence a broader phenotypic definition of DD. A significant linkage disequilibrium was observed with 'Single Letter Backward Span' (SLBS) in both single-marker and haplotype analyses. These results provide further support to the association between DD and DYX1C1 and it suggests that the linkage disequilibrium with DYX1C1 is more saliently explained in Italian dyslexics by short-term memory, as measured by 'SLBS', than by the categorical diagnosis of DD or other related phenotypes. <s> BIB015 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> The dyslexia susceptibility locus DYX2 (chr. 6p21-p22) harbours two candidate genes, DCDC2 and KIAA0319. In 2006, Harold et al. reported evidence for interaction between both genes. Having previously identified a risk haplotype for dyslexia in DCDC2, but not KIAA0319, in German families, we also tested for interaction between this risk haplotype and KIAA0319. We found a nominally significant association for the quantitative dimension “word reading”, the core phenotype in the study of Harold et al., which may be considered as supportive evidence. <s> BIB016 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Dyslexia is a complex reading and writing disorder with a strong genetic component. In a German case-control cohort, we studied the influence of the suspected dyslexia-associated gene DCDC2. For the first time in a German cohort, we describe association of a 2445 basepair deletion, first identified in an American study. Evidence of association for three DCDC2 single nucleotide polymorphisms (rs807724, rs793862, rs807701), previously identified in German or American cohorts, was replicated. A haplotype of these polymorphisms showed evidence for association as well. Thus, our data further corroborate association of DCDC2 with dyslexia. Analysis of functional subgroups suggests association of investigated DCDC2 variants mainly with nondysphonetic, nonsevere, but probably dyseidetic (surface) dyslexia. Based on the presumed function of DCDC2, our findings point to a role of impaired neuronal migration in the etiology of the disease. <s> BIB017 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Dyslexia (or reading disability) and specific language impairment (or SLI) are common childhood disorders that show considerable co-morbidity and diagnostic overlaps and have been suggested to share some genetic aetiology. Recently, genetic risk variants have been identified for SLI and dyslexia enabling the direct evaluation of possible shared genetic influences between these disorders. In this study we investigate the role of variants in these genes (namely MRPL19/C20RF3,ROBO1,DCDC2, KIAA0319, DYX1C1, CNTNAP2, ATP2C2 and CMIP) in the aetiology of SLI and dyslexia. We perform case–control and quantitative association analyses using measures of oral and written language skills in samples of SLI and dyslexic families and cases. We replicate association between KIAA0319 and DCDC2 and dyslexia and provide evidence to support a role for KIAA0319 in oral language ability. In addition, we find association between reading-related measures and variants in CNTNAP2 and CMIP in the SLI families. <s> BIB018 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Reading disabilities (RDs) have been associated with chromosome 6p with recent studies pointing to two genes, DCDC2 and KIAA0319. In this study, markers across the 6p region were tested for association with RD. Our strongest findings were for association with markers in KIAA0319, although with the opposite alleles compared with a previous study. We also found association with markers in VMP, but not with DCDC2. Current evidence indicates that differential regulation of KIAA0319 and DCDC2 contributes to RD, thus we used chromatin immunoprecipitation coupled with genomic tiling arrays (ChIP-chip) to map acetylated histones, a molecular marker for regulatory elements, across a 500 kb genomic region covering the RD locus on 6p. This approach identified several regions marked by acetylated histones that mapped near associated markers, including intron 7 of DCDC2 and the 5' region of KIAA0319. The latter is located within the 70 kb region previously associated with differential expression of KIAA0319. Interestingly, five markers associated with RD in independent studies were also located within the 2.7 kb acetylated region, and six additional associated markers, including the most significant one in this study, were located within a 22 kb haplotype block that encompassed this region. Our data indicates that this putative regulatory region is a likely site of genetic variation contributing to RD in our sample, further narrowing the candidate region. <s> BIB019 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Department of Physics, Harvard University,Cambridge, MA 02138, USAVeronica J. Peschansky, Timothy J. Burbridge, and Amy J. Volzcontributed equally to this manuscript.We investigated the postnatal effects of embryonic knockdown andoverexpression of the candidate dyslexia gene homolog Kiaa0319.We used in utero electroporation to transfect cells in E15/16 ratneocortical ventricular zone with either 1) small hairpin RNA(shRNA) vectors targeting Kiaa0319, 2) a KIAA0319 expressionconstruct, 3) Kiaa0319 shRNA along with KIAA0319 expressionconstruct (‘‘rescue’’), or 4) a scrambled version of Kiaa0319 shRNA.Knockdown, but not overexpression, of Kiaa0319 resulted inperiventricular heterotopias that contained large numbers of bothtransfected and non--transfected neurons. This suggested thatKiaa0319 shRNA disrupts neuronal migration by cell autonomous aswell as non--cell autonomous mechanisms. Of the Kiaa0319 shRNA--transfected neurons that migrated into the cortical plate, mostmigrated to their appropriate lamina. In contrast, neurons trans-fected with the KIAA0319 expression vector attained laminarpositions subjacent to their expected positions. Neurons trans-fected with Kiaa0319 shRNA exhibited apical, but not basal,dendrite hypertrophy, which was rescued by overexpression ofKIAA0319. The results provide additional supportive evidencelinking candidate dyslexia susceptibility genes to migrationaldisturbances during brain development, and extends the role ofKiaa0319 to include growth and differentiation of dendrites.Keywords: cerebral cortex, dendritic hypertrophy, heterotopias,malformation, RNAiIntroductionDevelopmental dyslexia is a language--based learning disabilitythat affects between 4% and 10% of the population, and hasa strong genetic component (Fisher and Francks 2006). Postmortem examination of the brains of developmental dyslexicsdemonstrated the presence of neuronal migration anomalies,including molecular layer ectopias, laminar dysplasia, andoccasional focal microgyria (Galaburda and Kemper 1979;Galaburda et al. 1985; Humphreys et al. 1990). More recently,an association between periventricular nodular heterotopiasand developmental dyslexia has been reported (Chang et al.2005; Sokol et al. 2006).Recent reports proposing candidate dyslexia susceptibilitygenes haveopenedupnew linesofinvestigation intothe geneticmodulation of this disorder. A number of these genes, inspeciﬁc—DCDC2 and KIAA0319 on Chr 6 (Francks et al. 2004;Cope et al. 2005; Meng et al. 2005; Harold et al. 2006; Paracchiniet al. 2006; Schumacher et al. 2006; Luciano et al. 2007;Paracchini et al. 2008), and DYX1C1 on Chr 15 (Taipale et al.2003; Brkanac et al. 2007; Marino et al. 2007)—have beenshownto have roles in neuronal migration. Thus, we have previouslydemonstrated that in utero electroporation of shRNA targetedagainst rat homologs of DCDC2, KIAA0319,orDYX1C1 in therat disrupts the process of neuronal migration to the cerebralcortex as assessed during the prenatal period (Meng et al. 2005;Paracchini et al. 2006; Wang et al. 2006). Further evaluationof the postnatal consequences of embryonic knockdown ofDyx1c1 and Dcdc2 function in rats revealed the presence ofa variety of neocortical malformations, including molecular layerectopias and periventricular heterotopias (PVHs) (Rosen et al.2007; Burbridge et al. 2008). In addition to these frankneuronal migration anomalies, we found evidence of moresubtle disruptions, with some transfected neurons migrating tothe cortical plate (CP), albeit past their expected laminarlocations (Rosen et al. 2007; Burbridge et al. 2008).As mentioned above, embryonic knockdown of Kiaa0319disrupted neuronal migration when assessed 4--7 days aftertransfection (Paracchini et al. 2006). Unknown were the long-term effects, both in terms of neuronal migration andsubsequent neuronal morphology, of embryonic knockdownor overexpression of this candidate dyslexia susceptibilitygene. In the current report, therefore, we examined the brainsof postnatal rats that were embryonically transfected by inutero electroporation with plasmids containing 1) shRNAtargeted against Kiaa0319 (knockdown), 2) a constructexpressing KIAA0319 protein (overexpression), or 3) a combi-nation of the shRNA and expression constructs (rescue). Wequalitatively assessed these brains for the presence or absenceof neuronal migration anomalies and the laminar disposition oftransfected and non--transfected neurons. In addition, wequantiﬁed migration distances and neuronal morphology ofthe transfected cells.Experimental ProceduresIn Situ HybridizationIn order to better interpret the knockdown and overexpres-sion ﬁndings, we ﬁrst determined the expression of Kiaa0319in the prenatal brain by in situ hybridization. We obtained time-mated pregnant females (Charles River Laboratory, Wilmington,MA) and sacriﬁced the litters on E14/15, E16/17, or E19/20.Three embryos from each litter were immediately frozen andthey were cut in either the horizontal, sagittal, or coronal planeon a cryostat at 18 lm, and the slides were processed for in situhybridization of Kiaa0319 as described below.The cDNAs prepared from frontal, parietal, and occipital lobesof human embryonic brain (20 weeks, Biochain Institute, <s> BIB020 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> To identify the putative interacting partners for Kiaa0319-like protein. KIAA0319-like, located near the dyslexia susceptibility locus, DYX8 in chromosome 1p34.3, has been suggested as a positional candidate for developmental dyslexia due to its homology with another gene, KIAA0319 which has been strongly established as a candidate gene for developmental dyslexia. Previous research has shown that a single marker, rs7523017 (P = 0.042) has been associated with developmental dyslexia by a Canadian group. There is little functional information about this gene and protein. In this article, we put forward further evidence that support Kiaa0319-like is a candidate for this disorder. A yeast-2-hybrid screen and co-immunopreciptiation assays were performed to find protein interacting partners of KIAA0319L. A human cortex immunohistochemistry assay was performed to show the colocalization of Kiaa0319-like and its specific interacting partner in cells. Nogo Receptor 1 (NgR1), an axon guidance receptor, was identified to have physical interactions with Kiaa0319-like protein. These two proteins interact predominantly in the cytoplasmic granules of cortical neurons in the human brain cortex. Based on this data, it can be concluded that Kiaa0319-like protein interacts with Nogo Receptor 1, supporting the idea that Kiaa0319-like protein participates in axon guidance. <s> BIB021 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> The KIAA0319 gene has been associated with reading disability in several studies. It encodes a plasma membrane protein with a large, highly glycosylated, extracellular domain. This protein is proposed to function in adhesion and attachment and thought to play an important role during neuronal migration in the developing brain. We have previously proposed that endocytosis of this protein could constitute an important mechanism to regulate its function. Here we show that KIAA0319 undergoes ectodomain shedding and intramembrane cleavage. At least five different cleavage events occur, four in the extracellular domain and one within the transmembrane domain. The ectodomain shedding processing cleaves the extracellular domain, generating several small fragments, including the N-terminal region with the Cys-rich MANEC domain. It is possible that these fragments are released to the extracellular medium and trigger cellular responses. The intramembrane cleavage releases the intracellular domain from its membrane attachment. Our results suggest that this cleavage event is not carried out by γ-secretase, the enzyme complex involved in similar processing in many other type I proteins. The soluble cytoplasmic domain of KIAA0319 is able to translocate to the nucleus, accumulating in nucleoli after overexpression. This fragment has an unknown role, although it could be involved in regulation of gene expression. The absence of DNA-interacting motifs indicates that such a function would most probably be mediated through interaction with other proteins, not by direct DNA binding. These results suggest that KIAA0319 not only has a direct role in neuronal migration but may also have additional signaling functions. <s> BIB022 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> It has been repeatedly shown that mismatch negativity (MMN), an event related potential measurement, reveals differences between dyslexic children and age-matched controls. MMN reflects the automatic detection of deviance between a stream of incoming sounds presented to the passive listener, and deficits in MMN (i.e. attenuated amplitudes) have been especially reported in dyslexia for detecting differences between speech sounds (e.g./ba/vs./da/). We performed an association analysis in 200 dyslexic children. This analysis focused on two MMN components, an early MMN (188–300 ms) and a late MMN (300–710 ms), and the dyslexia candidate genes KIAA0319 and DCDC2 on chromosome 6. Additionally, we imputed rare variants located in this region based on the 1000 genomes project. We identified four rare variants that were significantly associated with the late MMN component. For three of these variants, which were in high LD to each other, genotyping confirmed the association signal. Our results point to an association between late MMN and rare variants in a candidate gene region for dyslexia. <s> BIB023 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia is a language-based learning disability, and a number of candidate dyslexia susceptibility genes have been identified, including DYX1C1, KIAA0319, and DCDC2. Knockdown of function by embryonic transfection of small hairpin RNA (shRNA) of rat homologues of these genes dramatically disrupts neuronal migration to the cerebral cortex by both cell autonomous and non-cell autonomous effects. Here we sought to investigate the extent of non-cell autonomous effects following in utero disruption of the candidate dyslexia susceptibility gene homolog Dyx1c1 by assessing the effects of this disruption on GABAergic neurons. We transfected the ventricular zone of embryonic day (E) 15.5 rat pups with either Dyx1c1 shRNA, DYX1C1 expression construct, both Dyx1c1 shRNA and DYX1C1 expression construct, or a scrambled version of Dyx1c1 shRNA, and sacrificed them at postnatal day 21. The mothers of these rats were injected with BrdU at either E13.5, E15.5, or E17.5. Neurons transfected with Dyx1c1 shRNA were bi-modally distributed in the cerebral cortex with one population in heterotopic locations at the white matter border and another migrating beyond their expected location in the cerebral cortex. In contrast, there was no disruption of migration following transfection with the DYX1C1 expression construct. We found untransfected GABAergic neurons (parvalbumin, calretinin, and neuropeptide Y) in the heterotopic collections of neurons in Dyx1c1 shRNA treated animals, supporting the hypothesis of non-cell autonomous effects. In contrast, we found no evidence that the position of the GABAergic neurons that made it to the cerebral cortex was disrupted by the embryonic transfection with any of the constructs. Taken together, these results support the notion that neurons within heterotopias caused by transfection with Dyx1c1 shRNA result from both cell autonomous and non-cell autonomous effects, but there is no evidence to support non-cell autonomous disruption of neuronal position in the cerebral cortex itself. <s> BIB024 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Disruptions in the development of the neocortex are associated with cognitive deficits in humans and other mammals. Several genes contribute to neocortical development, and research into the behavioral phenotype associated with specific gene manipulations is advancing rapidly. Findings include evidence that variants in the human gene DYX1C1 may be associated with an increased risk of developmental dyslexia. Concurrent research has shown that the rat homolog for this gene modulates critical parameters of early cortical development, including neuronal migration. Moreover, recent studies have shown auditory processing and spatial learning deficits in rats following in utero transfection of an RNA interference (RNAi) vector of the rat homolog Dyx1c1 gene. The current study examined the effects of in utero RNAi of Dyx1c1 on working memory performance in Sprague‐Dawley rats. This task was chosen based on the evidence of short-term memory deficits in dyslexic populations, as well as more recent evidence of an association between memory deficits and DYX1C1 anomalies in humans. Working memory performance was assessed using a novel match-to-place radial water maze task that allows the evaluation of memory for a single brief (" 4‐10 seconds) swim to an ew goal location each day. A 10-min retention interval was used, followed by a test trial. Histology revealed migrational abnormalities and laminar disruption in Dyx1c1 RNAi-treated rats. Dyx1c1 RNAi-treated rats exhibited a subtle, but significant and persistent impairment in working memory as compared to Shams. These results provide further support for the role of Dyx1c1 in neuronal migration and working memory. <s> BIB025 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> BackgroundDyslexia is a learning disability that is characterized by difficulties in the acquisition of reading and spelling skills independent of intelligence, motivation or schooling. Studies of western populations have suggested that DYX1C1 is a candidate gene for dyslexia. In view of the different languages used in Caucasian and Chinese populations, it is therefore worthwhile to investigate whether there is an association of DYX1C1 in Chinese children with dyslexia.Method and ResultsEight single nucleotide polymorphisms (SNPs) were genotyped from three hundred and ninety three individuals from 131 Chinese families with two which have been reported in the literature and six tag SNPs at DYX1C1. Analysis for allelic and haplotypic associations was performed with the UNPHASED program and multiple testing was corrected using false discovery rates. We replicated the previously reported association of rs3743205 in Chinese children with dyslexia (pcorrected= 0.0072). This SNP was also associated with rapid naming, phonological memory and orthographic skills in quantitative trait analysis.ConclusionOur findings suggest that DYX1C1 is associated with dyslexia in people of Chinese ethnicity in Hong Kong. <s> BIB026 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> The region containing ROBO1 (Chromosome 3p12.3) has been implicated as a susceptibility gene for reading disorder and language deficit by translocation and linkage data. No association studies have yet been reported supporting any candidate gene. Here we report the first association of this gene with language deficits, specifically with phonological buffer deficits (a phenotype implicated in language acquisition, Specific Language Impairment and Speech Sound Disorder) and dyslexia (reading and spelling ability traits) in an unselected sample of adolescent twins and their siblings. Family-based analyses were performed on 144 tag SNPs in ROBO1, typed in 538 families with up to five offspring and tested for association with a developmental marker of language impairment (phonological buffer capacity, assessed using non word repetition).A reading and spelling ability measure—based on validated measures of lexical processing (irregular word) and grapheme–phoneme decoding (pseudo word)—and measures of short-term and working memory were also analysed. Significant association for phonological buffer capacity was observed for 21 of 144 SNPs tested, peaking at 8.70 × 10−05 and 9.30 × 10−05 for SNPs rs6803202 and rs4535189 respectively for nonword repetition, values that survive correction for multiple testing. Twenty-two SNPs showed significant associations for verbal storage (forward digit span)—a trait linked to phonological span. By contrast, just 5 SNPs reached nominal significance for working-memory, not surviving correction, and, importantly, only one SNP in the 144 tested reached nominal significance (0.04) for association with reading and spelling ability. These results provide strong support for ROBO1 as a gene involved in a core trait underpinning language acquisition, with a specific function in supporting a short-term buffer for arbitrary phonological strings. These effects of ROBO1 appear to be unrelated to brain mechanisms underpinning reading ability, at least by adolescence. While replication will be critical, the present results strongly support ROBO1 as the first gene discovered to be associated with language deficits affecting normal variation in language ability. Its functional role in neuronal migration underlying bilateral symmetry and lateralization of neuronal function further suggests a role in the evolution of human language ability. <s> BIB027 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Objective(s) ::: Developmental Dyslexia is a heritable condition, with genetic factors accounting for 44%–75% of the variance in performance tests of reading component subphenotypes. Compelling genetic linkage and association evidence supports a quantitative trait locus in the 6p21.3 region, which encodes a gene called DCDC2. In the present study, we explored the contribution of two DCDC2 markers to dyslexia, related reading and memory phenotypes in nuclear families of Italian origin. <s> BIB028 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Background Volume and integrity of white matter correlate with reading ability, but the underlying factors contributing to this variability are unknown. Methods We investigated single nucleotide polymorphisms in three genes previously associated with dyslexia and implicated in neuronal migration ( DYX1C1 , DCDC2 , KIAA0319 ) and white matter volume in a cohort of 76 children and young adults from the general population. Results We found that all three genes contained polymorphisms that were significantly associated with white matter volume in the left temporo-parietal region and that white matter volume influenced reading ability. Conclusions The identified region contained white matter pathways connecting the middle temporal gyrus with the inferior parietal lobe. The finding links previous neuroimaging and genetic results and proposes a mechanism underlying variability in reading ability in both normal and impaired readers. <s> BIB029 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Abstract Reading disability (RD) is a complex genetic disorder with unknown etiology. Genes on chromosome 6p22, including DCDC2, KIAA0319, and TTRAP, have been identified as RD associated genes. Imaging studies have shown both functional and structural differences between brains of individuals with and without RD. There are limited association studies performed between RD genes, specifically genes on 6p22, and regional brain activation during reading tasks. Using fourteen variants in DCDC2, KIAA0319, and TTRAP and exhaustive reading measures, we first tested for association with reading performance in 82 parent-offspring families (326 individuals). Next, we determined the association of these variants with activation of sixteen brain regions of interest during four functional magnetic resonance imaging-reading tasks. We nominally replicated associations between reading performance and variants of DCDC2 and KIAA0319. Furthermore, we observed a number of associations with brain activation patterns during imaging-reading tasks with all three genes. The strongest association occurred between activation of the left anterior inferior parietal lobe and complex tandem repeat BV677278 in DCDC2 (uncorrected p = 0.00003, q = 0.0442). Our results show that activation patterns across regions of interest in the brain are influenced by variants in the DYX2 locus. The combination of genetic and functional imaging data show a link between genes and brain functioning during reading tasks in subjects with RD. This study highlights the many advantages of imaging data as an endophenotype for discerning genetic risk factors for RD and other communication disorders and underscores the importance of integrating neurocognitive, imaging, and genetic data in future investigations. <s> BIB030 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Within the last decade several genes have been identified as candidate risk genes for developmental dyslexia. Recent research using animal models and embryonic RNA interference (RNAi) has shown that a subset of the candidate dyslexia risk genes--DYX1C1, ROBO1, DCDC2, KIAA0319--regulate critical parameters of neocortical development, such as neuronal migration. For example, embryonic disruption of the rodent homolog of DYX1C1 disrupts neuronal migration and produces deficits in rapid auditory processing (RAP) and working memory--phenotypes that have been reported to be associated with developmental dyslexia. In the current study we used a modified prepulse inhibition paradigm to assess acoustic discrimination abilities of male Wistar rats following in utero RNA interference targeting Kiaa0319. We also assessed spatial learning and working memory using a Morris water maze (MWM) and a radial arm water maze. We found that embryonic interference with this gene resulted in disrupted migration of neocortical neurons leading to formation of heterotopia in white matter, and to formation of hippocampal dysplasia in a subset of animals. These animals displayed deficits in processing complex acoustic stimuli, and those with hippocampal malformations exhibited impaired spatial learning abilities. No significant impairment in working memory was detected in the Kiaa0319 RNAi treated animals. Taken together, these results suggest that Kiaa0319 plays a role in neuronal migration during embryonic development, and that early interference with this gene results in an array of behavioral deficits including impairments in rapid auditory processing and simple spatial learning. <s> BIB031 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Several independent studies have supported the association of DYX1C1 with dyslexia, but its role in general reading development remains unclear. Here, we investigated the contribution of this gene to reading, with a focus on orthographic skills, in a sample of 284 unrelated Chinese children aged 5 to 11 years who were participating in the Chinese Longitudinal Study of Reading Development. We tested this association using a quantitative approach for Chinese character reading, Chinese character dictation, orthographic judgment, and visual skills. Significant or marginally significant associations were observed at the marker rs11629841 with children's orthographic judgments at ages 7 and 8 years (all P values<0.020). Significant associations with Chinese character dictation (all P values<0.013) were also observed for this single-nucleotide polymorphism (SNP) at ages 9, 10, and 11 years. Further analyses revealed that the association with orthographic skills was specific to the processing of specific components of characters (P values<0.046). No association was found at either SNP of rs3743205 or rs57809907. Our findings suggest that DYX1C1 influences reading development in the general Chinese population and supports a universal effect of this gene. <s> BIB032 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> In rodents, the Robo1 gene regulates midline crossing of major nerve tracts, a fundamental property of the mammalian CNS. However, the neurodevelopmental function of the human ROBO1 gene remains unknown, apart from a suggested role in dyslexia. We therefore studied axonal crossing with a functional approach, based on magnetoencephalography, in 10 dyslexic individuals who all share the same rare, weakly expressing haplotype of the ROBO1 gene. Auditory-cortex responses were recorded separately to left- and right-ear sounds that were amplitude modulated at different frequencies. We found impaired interaural interaction that depended on the ROBO1 in a dose-dependent manner. Our results indicate that normal crossing of the auditory pathways requires an adequate ROBO1 expression level. <s> BIB033 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Reading disability (RD) and language impairment (LI) are common learning disabilities that make acquisition and utilization of reading and verbal language skills, respectively, difficult for affected individuals. Both disorders have a substantial genetic component with complex inheritance. Despite decades of study, reading and language, like many other complex traits, consistently evade identification of causative and functional variants. We previously identified a putative functional risk variant, named BV677278 for its GenBank accession number, for RD in DCDC2. This variant consists of an intronic microdeletion and a highly polymorphic short tandem repeat (STR) within its breakpoints. We have also shown this STR to bind to an unknown nuclear protein with high specificity. Here, we replicate BV677278's association with RD, expand its association to LI, identify the BV677278-binding protein as the transcription factor ETV6, and provide compelling genetic evidence that BV677278 is a regulatory element that influences reading and language skills. We also provide evidence that BV677278 interacts nonadditively with KIAA0319, an RD-associated gene, to adversely affect several reading and cognitive phenotypes. On the basis of these data, we propose a new name for BV677278: "READ1" or "regulatory element associated with dyslexia 1." <s> BIB034 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia (DD) is a heritable, complex genetic disorder associated with impairment in reading and writing skills despite having normal intellectual ability and appropriate educational opportunities. Chromosome 6p23-21.3 at DYX2 locus has showed the most consistent evidence of linkage for DD and two susceptible genes KIAA0319 and DCDC2 for DD at DYX2 locus showed significant association. Specific candidate gene-association studies have identified variants, risk haplotypes and microsatellites of KIAA0319 and DCDC2 correlated with wide range of reading-related traits. In this study, we used a case-control approach for analyzing single-nucleotide polymorphisms (SNPs) in KIAA0319 and DCDC2. Our study demonstrated the association of DD with SNP rs4504469 of KIAA0319 and not with any SNPs of DCDC2. <s> BIB035 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia is a disorder characterized by a specific deficit in reading despite adequate overall intelligence and educational resources. The neurological substrate underlying these significant behavioral impairments is not known. Studies of post mortem brain tissue from male and female dyslexic individuals revealed focal disruptions of neuronal migration concentrated in the left hemisphere, along with aberrant symmetry of the right and left the planum temporale, and changes in cell size distribution within the medial geniculate nucleus of the thalamus (Galaburda et al., 1985; Humphreys et al., 1990). More recent neuroimaging studies have identified several changes in the brains of dyslexic individuals, including regional changes in gray matter, changes in white matter, and changes in patterns of functional activation. In a further effort to elucidate the etiology of dyslexia, epidemiological and genetic studies have identified several candidate dyslexia susceptibility genes. Some recent work has investigated associations between some of these genetic variants and structural changes in the brain. Variants of one candidate dyslexia susceptibility gene, KIAA0319, have been linked to morphological changes in the cerebellum and functional activational changes in the superior temporal sulcus (Jamadar et al., 2011; Pinel et al., 2012). Animal models have been used to create a knockdown of Kiaa0319 (the rodent homolog of the human gene) via in utero RNA interference in order to study the gene's effects on brain development and behavior. Studies using this animal model have demonstrated that knocking down the gene leads to focal disruptions of neuronal migration in the form of ectopias and heterotopias, similar to those observed in the brains of human dyslexics. However, further changes to the structure of the brain have not been studied following this genetic disruption. The current study sought to determine the effects of embryonic Kiaa0319 knockdown on volume of the cortex and hippocampus, as well as midsagittal area of the corpus callosum in male rats. Results demonstrate that Kiaa0319 knockdown did not change the volume of the cortex or hippocampus, but did result in a significant reduction in the midsagittal area of the corpus callosum. Taken in the context of previous reports of behavioral deficits following Kiaa0319 knockdown (Szalkowski et al., 2012), and reports that reductions of corpus callosum size are related to processing deficits in humans (Paul, 2011), these results suggest that Kiaa0319 has a specific involvement in neural systems important for temporal processing. <s> BIB036 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> DYX1C1 has been associated with dyslexia and neuronal migration in the developing neocortex. Unexpectedly, we found that deleting exons 2-4 of Dyx1c1 in mice caused a phenotype resembling primary ciliary dyskinesia (PCD), a disorder characterized by chronic airway disease, laterality defects and male infertility. This phenotype was confirmed independently in mice with a Dyx1c1 c.T2A start-codon mutation recovered from an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. Morpholinos targeting dyx1c1 in zebrafish also caused laterality and ciliary motility defects. In humans, we identified recessive loss-of-function DYX1C1 mutations in 12 individuals with PCD. Ultrastructural and immunofluorescence analyses of DYX1C1-mutant motile cilia in mice and humans showed disruptions of outer and inner dynein arms (ODAs and IDAs, respectively). DYX1C1 localizes to the cytoplasm of respiratory epithelial cells, its interactome is enriched for molecular chaperones, and it interacts with the cytoplasmic ODA and IDA assembly factor DNAAF2 (KTU). Thus, we propose that DYX1C1 is a newly identified dynein axonemal assembly factor (DNAAF4). <s> BIB037 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia (DD) is characterized by difficulties in reading and spelling independent of intelligence, educational backgrounds and neurological injuries. Increasing evidences supported DD as a complex genetic disorder and identified four DD candidate genes namely DYX1C1, DCDC2, KIAA0319 and ROBO1. As such, DCDC2 and KIAA0319 are located in DYX2, one of the most studied DD susceptibility loci. However, association of these two genes with DD was inconclusive across different populations. Given the linguistic and genetic differences between Chinese and other populations, it is worthwhile to investigate association of DCDC2 and KIAA0319 with Chinese dyslexic children. Here, we selected 60 tag SNPs covering DCDC2 and KIAA0319 followed by high density genotyping in a large unrelated Chinese cohort with 502 dyslexic cases and 522 healthy controls. Several SNPs (Pmin = 0.0192) of DCDC2 and KIAA0319 as well as a four-maker haplotype (Padjusted = 0.0289, Odds Ratio (OR) = 1.3400) of KIAA0319 showed nominal association with DD. However, none of these results survived Bonferroni correction for multiple comparisons. Thus, the association of DCDC2 and KIAA0319 with DD in Chinese population should be further validated and their contribution to DD etiology and pathology should be interpreted with caution. <s> BIB038 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Three genes, DYX1C1 , DCDC2 , and KIAA0319 , have been previously associated with dyslexia, neuronal migration, and ciliary function. Three polymorphisms within these genes, rs3743204 ( DYX1C1 ), rs793842 ( DCDC2 ), and rs6935076 ( KIAA0319 ) have also been linked to normal variability of left temporoparietal white matter volume connecting the middle temporal cortex to the angular and supramarginal gyri. Here, we assessed whether these polymorphisms are also related to the cortical thickness of the associated regions during childhood development using a longitudinal dataset of 76 randomly selected children and young adults who were scanned up to three times each, 2 years apart. rs793842 in DCDC2 was significantly associated with the thickness of left angular and supramarginal gyri as well as the left lateral occipital cortex. The cortex was significantly thicker for T-allele carriers, who also had lower white matter volume and lower reading comprehension scores. There was a negative correlation between white matter volume and cortical thickness, but only white matter volume predicted reading comprehension 2 years after scanning. These results show how normal variability in reading comprehension is related to gene, white matter volume, and cortical thickness in the inferior parietal lobe. Possibly, the variability of gray and white matter structures could both be related to the role of DCDC2 in ciliary function, which affects both neuronal migration and axonal outgrowth. <s> BIB039 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Abstract Introduction The DCDC2 gene is involved in neuronal migration. Heterotopias have been found within the white matter of DCDC2-knockdown rats. A deletion in DCDC2/intron 2 (DCDC2d), which encompasses a regulatory region named ‘regulatory element associated with dyslexia 1’ (READ1), increases the risk for dyslexia. We hypothesized that DCDC2d can be associated to alterations of the white matter structure in general and in dyslexic brains. Methods Based on a full-factorial analysis of covariance (ANCOVA) model, we investigated voxel-based diffusion tensor imaging (VB-DTI) data of four groups of subjects: dyslexia with/without DCDC2d, and normal readers with/without DCDC2d. We also tested DCDC2d effects upon correlation patterns between fractional anisotropy (FA) and reading scores. Results We found that FA was reduced in the left arcuate fasciculus and splenium of the corpus callosum in subjects with versus without DCDC2d, irrespective of dyslexia. Subjects with dyslexia and DCDC2d showed reduced FA, mainly in the left hemisphere and in the corpus callosum; their counterpart without DCDC2d showed similar FA alterations. Noteworthy, a conjunction analysis in impaired readers revealed common regions with lower FA mainly in the left hemisphere. When we compared subjects with dyslexia with versus without DCDC2d, we found lower FA in the inferior longitudinal fasciculus and genu of the corpus callosum, bilaterally. Normal readers with versus without DCDC2d had FA increases and decreases in both the right and left hemisphere. Discussion The major contribution of our study was to provide evidence relating genes, brain and behaviour. Overall, our findings support the hypothesis that DCDC2d is associated with altered FA. In normal readers, DCDC2-related anatomical patterns may mark some developmental cognitive vulnerability to learning disabilities. In subjects with dyslexia, DCDC2d accounted for both common – mainly located in the left hemisphere – and unique – a more severe and extended pattern – alterations of white matter fibre tracts. <s> BIB040 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Substantial heritability has been reported for developmental dyslexia (DD), and KIAA0319 and ROBO1 appear as more than plausible candidate susceptibility genes for this developmental disorder. Converging evidence indicates that developmental difficulties in oral language and mathematics can predate or co-occur with DD, and substantial genetic correlations have been found between these abilities and reading traits. In this study, we explored the role of eight single-nucleotide polymorphisms spanning within KIAA0319 and ROBO1 genes, and DD as a dichotomic trait, related neuropsychological phenotypes and comorbid language and mathematical (dis)abilities in a large cohort of 493 Italian nuclear families ascertained through a proband with a diagnosis of DD. Marker-trait association was analyzed by implementing a general test of family-based association for quantitative traits (that is, the Quantitative Transmission Disequilibrium Test, version 2.5.1). By providing evidence for significant association with mathematics skills, our data add further result in support of ROBO1 contributing to the deficits in DD and its correlated phenotypes. Taken together, our findings shed further light into the etiologic basis and the phenotypic complexity of this developmental disorder. <s> BIB041 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> BackgroundPrevious studies have shown that KIAA0319 is a candidate gene for dyslexia in western populations. In view of the different languages used in Caucasian and Chinese populations, the aim of the present study was to investigate whether there is also an association of KIAA0319 in Chinese children with dyslexia and/or to the language-related cognitive skills.Method and resultsA total of twenty six single nucleotide polymorphisms (SNPs) were genotyped from three hundred and ninety three individuals from 131 Chinese families. Four of the SNPs have been reported in the literature and twenty two being tag SNPs at KIAA0319. Analysis for allelic and haplotypic associations was performed with the UNPHASED program and multiple testing was corrected using permutation. Results indicate that KIAA0319 is not associated with Chinese children with dyslexia but a haplotype consisting of rs2760157 and rs807507 SNPs were significantly associated with an onset detection test, a measure of phonological awareness (pnominal = 6.85 10-5 and pcorrected = 0.0029).ConclusionIn conclusion, our findings suggest that KIAA0319 is associated with a reading-related cognitive skill. <s> BIB042 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Reading disability (RD) and language impairment (LI) are common neurodevelopmental disorders with moderately strong genetic components and lifelong implications. RD and LI are marked by unexpected difficulty acquiring and processing written and verbal language, respectively, despite adequate opportunity and instruction. RD and LI—and their associated deficits—are complex, multifactorial, and often comorbid. Genetic studies have repeatedly implicated the DYX2 locus, specifically the genes DCDC2 and KIAA0319, in RD, with recent studies suggesting they also influence LI, verbal language, and cognition. Here, we characterize the relationship of the DYX2 locus with RD, LI, and IQ. To accomplish this, we developed a marker panel densely covering the 1.4 Mb DYX2 locus and assessed association with reading, language, and IQ measures in subjects from the Avon Longitudinal Study of Parents and Children. We then replicated associations in three independent, disorder-selected cohorts. As expected, there were associations with known RD risk genes KIAA0319 and DCDC2. In addition, we implicated markers in or near other DYX2 genes, including TDP2, ACOT13, C6orf62, FAM65B, and CMAHP. However, the LD structure of the locus suggests that associations within TDP2, ACOT13, and C6orf62 are capturing a previously reported risk variant in KIAA0319. Our results further substantiate the candidacy of KIAA0319 and DCDC2 as major effector genes in DYX2, while proposing FAM65B and CMAHP as new DYX2 candidate genes. Association of DYX2 with multiple neurobehavioral traits suggests risk variants have functional consequences affecting multiple neurological processes. Future studies should dissect these functional, possibly interactive relationships of DYX2 candidate genes. <s> BIB043 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> ObjectiveDYX1C1 has been identified as a susceptible candidate gene for developmental dyslexia (DD); studies in various populations have yielded inconclusive results and the causal allele is unknown in the Indian population. On the basis of the initial association studies and the role of DYX1C1 in neuronal migration, we investigated the role of DYX1C1 in causing DD in an Indian population.Materials and methodsTen single-nucleotide polymorphisms (SNPs) of DYX1C1 were genotyped in 210 cases with DD and 256 age-matched nondyslexic controls. Genotyping of these SNPs was carried with the MassARRAY technique using SpectroCHIP and analysed with MALDI-TOF MS. Single-marker and two-marker haplotype analyses were carried out and the (2)-test, odds ratios, 95% confidence intervals and Yates correction were applied to identify the significance of the genotyped SNPs.ResultsA significant association was observed for the homozygous genotype (GG) of the SNP rs12899331 (3.12%) and individual allele frequency (P=0.039). Psycholinguistic tests showed an association between rs12899331 with dyslexic phenotypes such as word and nonword reading, syllable reversal task, spoonerism task and spelling. Two-marker haplotype analysis also showed a significant association for the markers G/C at rs12899331/rs1075938 (P=0.039) with the phenotypes rapid naming ability and phonological awareness, as well as with word reading, spelling and sentence repetition.ConclusionThe promoter SNP rs12899331 of DYX1C1 may contribute towards the manifestation of DD. This study supports the association of DYX1C1 with DD in an Indian population. <s> BIB044 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Linkage studies have identified a locus on chromosome 3 as reading disabilities (RD) and speech and sound disorder (SSD) susceptibility region, with both RD and SSD sharing similar phonological processing and phonological memory difficulties. One gene in this region, roundabout homolog 1 (ROBO1), has been indicated as a RD candidate and has shown significant association with measures of phonological memory in a population-based sample. In this study, we conducted a family-based association analysis using two independent samples collected in Toronto and Calgary, Canada. Using the two samples, we tested for association between ROBO1 single nucleotide polymorphisms (SNPs) and RD, along with quantitative measures for reading, spelling and phonological memory. One SNP, rs331142, which was selected based on its correlation withROBO1 expression in brain tissue, was found to be significantly associated with RD in the Toronto sample with over transmission of the minor C allele (P = 0.001), correlated with low expression. This SNP is located ∼200 bp from a putative enhancer and results for a marker within the enhancer, rs12495133, showed evidence for association with the same allele in both the Toronto and Calgary samples (P = 0.005 and P = 0.007). These results support previous associations between ROBO1 and RD, as well as correlation with low gene expression, suggesting a possible mechanism of risk conferred by this gene. <s> BIB045 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Dyslexia is a specific impairment in reading that affects 1 in 10 people. Previous studies have failed to isolate a single cause of the disorder, but several candidate genes have been reported. We measured motion perception in two groups of dyslexics, with and without a deletion within the DCDC2 gene, a risk gene for dyslexia. We found impairment for motion particularly strong at high spatial frequencies in the population carrying the deletion. The data suggest that deficits in motion processing occur in a specific genotype, rather than the entire dyslexia population, contributing to the large variability in impairment of motion thresholds in dyslexia reported in the literature. <s> BIB046 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia (DD) is a heritable neurodevelopmental reading disorder that could arise from auditory, visual, and cross-modal integration deficits. A deletion in intron 2 of the DCDC2 gene (hereafter DCDC2d) increases the risk for DD and related phenotypes. In this study, first we report that illusory visual motion perception - specifically processed by the magnocellular-dorsal (M-D) stream - is impaired in children with DD compared with age-matched and reading-level controls. Second, we test for the specificity of the DCDC2d effects on the M-D stream. Children with DD and DCDC2d need significantly more contrast to process illusory motion relative to their counterpart without DCDC2d and to age-matched and reading-level controls. Irrespective of the genetic variant, children with DD perform normally in the parvocellular-ventral task. Finally, we find that DCDC2d is associated with the illusory motion perception also in adult normal readers, showing that the M-D deficit is a potential neurobiological risk factor of DD rather than a simple effect of reading disorder. Our findings demonstrate, for the first time, that a specific neurocognitive dysfunction tapping the M-D stream is linked with a well-defined genetic susceptibility. <s> BIB047 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Dyslexia and language impairment (LI) are complex traits with substantial genetic components. We recently completed an association scan of the DYX2 locus, where we observed associations of markers in DCDC2, KIAA0319, ACOT13, and FAM65B with reading-, language-, and IQ-related traits. Additionally, the effects of reading-associated DYX3 markers were recently characterized using structural neuroimaging techniques. Here, we assessed the neuroimaging implications of associated DYX2 and DYX3 markers, using cortical volume, cortical thickness, and fractional anisotropy. To accomplish this, we examined eight DYX2 and three DYX3 markers in 332 subjects in the Pediatrics Imaging Neurocognition Genetics study. Imaging-genetic associations were examined by multiple linear regression, testing for influence of genotype on neuroimaging. Markers in DYX2 genes KIAA0319 and FAM65B were associated with cortical thickness in the left orbitofrontal region and global fractional anisotropy, respectively. KIAA0319 and ACOT13 were suggestively associated with overall fractional anisotropy and left pars opercularis cortical thickness, respectively. DYX3 markers showed suggestive associations with cortical thickness and volume measures in temporal regions. Notably, we did not replicate association of DYX3 markers with hippocampal measures. In summary, we performed a neuroimaging follow-up of reading-, language-, and IQ-associated DYX2 and DYX3 markers. DYX2 associations with cortical thickness may reflect variations in their role in neuronal migration. Furthermore, our findings complement gene expression and imaging studies implicating DYX3 markers in temporal regions. These studies offer insight into where and how DYX2 and DYX3 risk variants may influence neuroimaging traits. Future studies should further connect the pathways to risk variants associated with neuroimaging/neurocognitive outcomes. <s> BIB048 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> The doublecortin domain-containing 2 (DCDC2) gene, which is located on chromosome 6p22.1, has been widely suggested to be a candidate gene for dyslexia, but its role in typical reading development over time remains to be clarified. In the present study, we explored the role of DCDC2 in contributing to the individual differences in reading development from ages 6 to 11 years by analysing data from 284 unrelated children who were participating in the Chinese Longitudinal Study of Reading Development (CLSRD). The associations of eight single nucleotide polymorphisms (SNPs) in DCDC2 with the latent intercept and slope of children’s reading scores were examined in the first step. There was significant support for an association of rs807724 with the intercept for the reading comprehension measure of reading fluency, and the minor “G” allele was associated with poor reading performance. Next, we further tested the rs807724 SNP in association with the reading ability at each tested time and revealed that, in addition to significant associations with the two main reading measures (reading fluency and Chinese character reading) over multiple testing occasions, this SNP also showed associations with reading-related cognitive skills, including morphological production, orthographic judgment and phonological processing skills (rapid number naming, phoneme deletion, and tone detection). This study provides support for DCDC2 as a risk gene for reading disability and suggests that this gene is also operative for typical reading development in the Han population. <s> BIB049 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Literacy learning depends on the flexibility of the human brain to reconfigure itself in response to environmental influences. At the same time, literacy and disorders of literacy acquisition are heritable and thus to some degree genetically predetermined. Here we used a multivariate non-parametric genetic model to relate literacy-associated genetic variants to grey and white matter volumes derived by voxel-based morphometry in a cohort of 141 children. Subsequently, a sample of 34 children attending grades 4 to 8, and another sample of 20 children, longitudinally followed from kindergarten to first grade, were classified as dyslexics and controls using linear binary support vector machines. The NRSN1 -associated grey matter volume of the ‘visual word form area’ achieved a classification accuracy of ~ 73% in literacy-experienced students and distinguished between later dyslexic individuals and controls with an accuracy of 75% at kindergarten age. These findings suggest that the cortical plasticity of a region vital for literacy might be genetically modulated, thereby potentially preconstraining literacy outcome. Accordingly, these results could pave the way for identifying and treating the most common learning disorder before it manifests itself in school. ::: ::: * Abbreviations ::: : SNP = ::: : single nucleotide polymorphism ::: VWFA = ::: : visual word form area <s> BIB050 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> DYX1C1, DCDC2, and KIAA0319 are three of the most replicated dyslexia candidate genes (DCGs). Recently, these DCGs were implicated in functions at the cilium. Here, we investigate the regulation of... <s> BIB051 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Background ::: The DYX5 locus for developmental dyslexia was mapped to chromosome 3 by linkage study of a large Finnish family, and later, roundabout guidance receptor 1 (ROBO1) was implicated as a candidate gene at DYX5 with suppressed expression from the segregating rare haplotype. A functional magnetoencephalographic study of several family members revealed abnormal auditory processing of interaural interaction, supporting a defect in midline crossing of auditory pathways. In the current study, we have characterized genetic variation in the broad ROBO1 gene region in the DYX5-linked family, aiming to identify variants that would increase our understanding of the altered expression of ROBO1. <s> BIB052 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | <s> Developmental dyslexia is a complex reading and writing disorder with strong genetic components. In previous genetic studies about dyslexia, a number of candidate genes have been identified. These include DCDC2, which has repeatedly been associated with developmental dyslexia in various European and American populations. However, data regarding this relationship are varied according to population. The Uyghur people of China represent a Eurasian population with an interesting genetic profile. Thus, this group may provide useful information about the association between DCDC2 gene polymorphisms and dyslexia. In the current study, we examined genetic data from 392 Uyghur children aged 8–12 years old from the Xinjiang Uyghur Autonomous Region of China. Participants included 196 children with dyslexia and 196 grade-, age-, and gender-matched controls. DNA was isolated from oral mucosal cell samples and fourteen single nucleotide polymorphisms (rs6456593, rs1419228, rs34647318, rs9467075, rs793862, rs9295619, rs807701, rs807724, rs2274305, rs7765678, rs4599626, rs6922023, rs3765502, and rs1087266) in DCDC2 were screened via the SNPscan method. We compared SNP frequencies in five models (Codominant, Dominant, Recessive, Heterozygote advantage, and Allele) between the two groups by means of the chi-squared test. A single-locus analysis indicated that, with regard to the allele frequency of these polymorphisms, three SNPs (rs807724, rs2274305, and rs4599626) were associated with dyslexia. rs9467075 and rs2274305 displayed significant associations with developmental dyslexia under the dominant model. rs6456593 and rs6922023 were significantly associated with developmental dyslexia under the dominant model and in the heterozygous genotype. Additionally, we discovered that the T-G-C-T of the four-marker haplotype (rs9295619-rs807701-rs807724-rs2274305) and the T-A of the two-marker haplotype (rs3765502-1087266) were significantly different between cases and controls. Thus, we conclude that DCDC2 gene polymorphisms are associated with developmental dyslexia in Chinese Uyghur children. <s> BIB053
Variation on DCDC2 has been associated with performance on several measures of reading and reading-related skills including phonological skills, word/pseudoword reading, and spelling in samples with SRD BIB053 BIB016 BIB028   BIB017 ) and without SRD BIB018 BIB034 Scerri et al., 2011; BIB038 BIB035 BIB049 . Extant research suggests that variation in this gene is associated with subtle cortical malformations in brain areas important for reading  . For example, in a study of typically developing Swedish-speaking children and young adults, one SNP in DCDC2 (rs793842 3 ) was related to white matter volume in left temporo-parietal cortex, with the highest white matter volume indices in CC homozygotes and lowest in TT homozygotes, and heterozygotes falling in between BIB029 . In addition, the authors found a significant positive correlation between white matter volume and reading fluency; however, no direct associations between SNPs and behavioral performance were significant . The association between rs793842 and left temporo-parietal white matter volume was replicated in a follow-up analysis that examined the same sample with the inclusion of a third longitudinal time point, and a significant association between this SNP and cortical thickness in the left temporo-parietal and occipital cortices emerged in this follow-up analysis, such that T-allele carriers had thicker cortex in these regions BIB039 . Additionally, rs793842 was associated with reading comprehension scores. A second polymorphism in DCDC2, a deletion in intron 2 (hereafter, DCDC2d), which encompasses BV677278, has been associated with SRD, and with interindividual variation reading performance and motion perception in children with SRD and typical development (TD; BIB011 BIB046 BIB047 BIB008 BIB028  BIB017 . 4 One imaging genetics study of the DCDC2d reports significantly increased gray matter volume in a number of regions related to language and reading, including bilateral temporo-parietal regions, in typically developing individuals heterozygous for DCDC2d BIB012 . Moreover, a study of white matter microstructure in individuals with and without SRD found the DCDC2d to be associated with reduced white matter integrity in the left arcuate fasciculus and the posterior corpus callosum, regardless of reading impairment status. Within the reading impaired group, white matter integrity was reduced bilaterally in the inferior longitudinal fasciculus and anterior corpus callosum in those with the deletion relative to those without . BIB040 also reported positive correlations between white matter integrity and average reading scores in several left-hemisphere tracts related to reading and language. In addition to structural findings, recent fMRI and event-related potential (ERP) studies that engage the neural circuitry for reading and language provide evidence for links between DCDC2 and brain function. One ERP of particular interest in reading and language research is the mismatch negativity (MMN) response, a commonly used index of auditory discrimination (typically of tones or phonemes) that is characteristically reduced in individuals with reading and language impairment (Schulte-Körne, Deimel, BIB001 . BIB023 reported an attenuated late MMN response to phonemic stimuli in minor allele carriers of one SNP in DCDC2 (chr6:24459391/rs1052724905) and three locations between DCDC2 and KIAA0319 (chr6:24564881, chr6:24571041, and chr6:24581378/rs1033367480) in a sample of children with SRD. Further, using fMRI, BIB030 identified patterns of activation associated with alleles of BV677278 during a set of language and reading tasks and replicated previous findings of gene/reading behavioral associations. Specifically, BV677278 alleles were significantly associated with activation in the left temporo-parietal cortex (positive correlation) and the right occipitotemporal gyrus (negative correlation) during processing of printed words and negatively associated with activation in the right occipito-temporal gyrus during processing of spoken words, indicating relevance of this gene for both written and spoken language. The functional association in the temporo-parietal cortex is consistent with the localization of structural associations with DCDC2d discussed above BIB012 , and together, these results link DCDC2 and temporo-parietal anomalies that are characteristic of SRD. A close neighbor of DCDC2 within the same locus on chromosome 6p22.3, KIAA0319, is another well-studied candidate gene for SRD that has been associated with reading ability within SRD BIB006 BIB019  BIB016 BIB041 and the general population BIB042 BIB013  Scerri et al., 2011; BIB035 BIB038 . Animal research shows that the expression pattern of KIAA0319 in the developing brain is consistent with its hypothesized role in neuronal migration, and recent bioinformatics analysis has suggested its involvement in additional neurodevelopmental and signaling functions BIB020 BIB021 BIB036 BIB031 BIB022 . Consistent with KIAA0319's hypothesized role from animal findings, structural associations with KIAA0319 have been reported in human MRI research. An association between white matter volume in the left temporo-parietal region and KIAA0319 SNP rs6935076 has been identified and replicated with an additional right hemisphere effect when data from a third longitudinal time point were added to the analysis BIB039 . Furthermore, BIB048 reported decreased cortical thickness in a left orbitofrontal region in carriers of the minor allele of the SNP rs9461045 (associated with single-word reading and spelling ability;  relative to those homozygous for the major allele within a sample of individuals ages 3-20 years from the Pediatrics Imaging Neurocognition Genetics study (PING) database. 5 With regard to structural connectivity, the minor allele of the same SNP was associated with reduced white matter integrity in the corpus callosum. These findings point toward an effect of KIAA0319 on language-related brain structures that may underlie individual differences in language and reading abilities. In addition to DCDC2 and KIAA0319, two additional genes within 6p22-21.3 (THEM2 and NRSN1) have been linked with reading-associated neural structure and/or function across multiple studies. Presence of the minor allele at rs3777663 in THEM2 (also known as ACOT13 and previously identified as a protective allele BIB043 ) has been linked to increased cortical thickness in the left inferior frontal region BIB048 . In a separate study,  found that THEM2 SNP rs17243157 was associated with functional asymmetry in a posterior temporal region during reading and speech listening tasks, with a stronger effect for reading. NRSN1 has recently been implicated in reading-related cortical structure. Specifically, recent work has identified associations between variation on NRSN1 and gray matter volume in right parieto-occipital, left lateral occipital, and left occipito-temporal regions, as well as white matter volume in a left postcentral region BIB050 . In a follow-up classification analysis, left occipito-temporal volume performed significantly above chance in classifying subjects into SRD and control groups, and variation on NRSN1 was further associated with reading comprehension BIB050 . These structural and functional associations may be attributed to variation in NRSN1 expression, which has been linked to axon and dendrite growth BIB003 . Together, these findings support THEM2 and NRSN1 as loci for further investigation of links between genes, neural structure/function, and reading. The remaining candidate genes for SRD have received relatively little attention in human neuroimaging studies. Like those of other SRD candidate genes, the protein encoded by DYX1C1 has been linked to neurodevelopmental processes BIB024  BIB025 BIB051 BIB037 BIB014 BIB009 , and variation on this gene has been associated with reading and spelling abilities in both general population BIB018 BIB032 and clinical samples BIB026 BIB015 BIB044 . With respect to neuroimaging, BIB029 found a relationship between SNP rs3743204 in DYX1C1 and white matter volume in bilateral temporo-parietal regions and correlations between white matter volume in these regions and reading scores. As with the KIAA0319 findings described above, these findings were replicated when a third longitudinal time point was added for the same sample BIB039 . ROBO1 appears to serve an axon guidance function that regulates the connections between brain hemispheres and between cortical and subcortical structures BIB010 BIB007 BIB052 BIB004 . Linkage studies suggest that this gene is related to SRD BIB005 BIB041 BIB002 BIB045 and speech-sound disorder  , and research in the general population indicates an association with phonological skills BIB027 . In the context of neuroimaging, ROBO1 has been investigated in one study that employed magnetoencephalography (MEG) to examine auditory processing in individuals with reading impairment from a family carrying a rare, weakly expressing haplotype of the ROBO1 gene relative to typical controls BIB033 . Ipsilateral auditory suppression in both hemispheres was related to ROBO1 expression levels in the haplotype carrier group, and these subjects showed significantly weaker ipsilateral suppression compared to the control group. These imaging findings point toward a possible auditory processing deficit as the source of previously observed associations between ROBO1, phonological skills, and speech-sound disorders.