Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <s> In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily. Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location. Furthermore, we show that the localization of Caspr2 and clustering of K+ channels at the juxtaparanodal region depends on the presence of TAG-1, an immunoglobulin-like cell adhesion molecule that binds Caspr2. These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon–glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <s> Contactin-associated protein-like 2 (CASPR2) is encoded by CNTNAP2 and clusters voltage-gated potassium channels (K(v)1.1) at the nodes of Ranvier. We report a homozygous mutation of CNTNAP2 in Old Order Amish children with cortical dysplasia, focal epilepsy, relative macrocephaly, and diminished deep-tendon reflexes. Intractable focal seizures began in early childhood, after which language regression, hyperactivity, impulsive and aggressive behavior, and mental retardation developed in all children. Resective surgery did not prevent the recurrence of seizures. Temporal-lobe specimens showed evidence of abnormalities of neuronal migration and structure, widespread astrogliosis, and reduced expression of CASPR2. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <s> BACKGROUND ::: Rare mutations affecting the FOXP2 transcription factor cause a monogenic speech and language disorder. We hypothesized that neural pathways downstream of FOXP2 influence more common phenotypes, such as specific language impairment. ::: ::: ::: METHODS ::: We performed genomic screening for regions bound by FOXP2 using chromatin immunoprecipitation, which led us to focus on one particular gene that was a strong candidate for involvement in language impairments. We then tested for associations between single-nucleotide polymorphisms (SNPs) in this gene and language deficits in a well-characterized set of 184 families affected with specific language impairment. ::: ::: ::: RESULTS ::: We found that FOXP2 binds to and dramatically down-regulates CNTNAP2, a gene that encodes a neurexin and is expressed in the developing human cortex. On analyzing CNTNAP2 polymorphisms in children with typical specific language impairment, we detected significant quantitative associations with nonsense-word repetition, a heritable behavioral marker of this disorder (peak association, P=5.0x10(-5) at SNP rs17236239). Intriguingly, this region coincides with one associated with language delays in children with autism. ::: ::: ::: CONCLUSIONS ::: The FOXP2-CNTNAP2 pathway provides a mechanistic link between clinically distinct syndromes involving disrupted language. <s> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <s> Recent genetic studies have implicated a number of candidate genes in the pathogenesis of Autism Spectrum Disorder (ASD). Polymorphisms of CNTNAP2 (contactin-associated like protein-2), a member of the neurexin family, have already been implicated as a susceptibility gene for autism by at least 3 separate studies. We investigated variation in white and grey matter morphology using structural MRI and diffusion tensor imaging. We compared volumetric differences in white and grey matter and fractional anisotropy values in control subjects characterised by genotype at rs7794745, a single nucleotide polymorphism in CNTNAP2. Homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation. Thus a risk allele for autism results in significant cerebral morphological variation, despite the absence of overt symptoms or behavioural abnormalities. The results are consistent with accumulating evidence of CNTNAP2's function in neuronal development. The finding suggests the possibility that the heterogeneous manifestations of ASD can be aetiologically characterised into distinct subtypes through genetic-morphological analysis. <s> BIB004 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <s> Recent neuroimaging studies have demonstrated that Contactin-associated protein-like2 (CNTNAP2) polymorphisms affect left-hemispheric function of language processing in healthy individuals, but no study has investigated the influence of these polymorphisms on right-hemispheric function involved in human voice perception. Further, although recent reports suggest that determination of handedness is influenced by genetic effect, the interaction effect between handedness and CNTNAP2 polymorphisms for brain activity in human voice perception and language processing has not been revealed. We aimed to investigate the interaction effect of handedness and CNTNAP2 polymorphisms in respect to brain function for human voice perception and language processing in healthy individuals. Brain function of 108 healthy volunteers (74 right-handed and 34 non-right-handed) was examined while they were passively listening to reverse sentences (rSEN), identifiable non-vocal sounds (SND), and sentences (SEN). Full factorial design analysis was calculated by using three factors: 1) rs7794745 (A/A or A/T), 2) rs2710102 (G/G or A carrier (A/G and A/A)), and 3) voice-specific response (rSEN or SND). The main effect of rs7794745 (A/A or A/T) was significantly revealed at the right middle frontal gyrus (MFG) and bilateral superior temporal gyrus (STG). This result suggests that rs7794745 genotype affects voice-specific brain function. Furthermore, interaction effect was significantly observed among MFG-STG activations by human voice perception, rs7794745 (A/A or A/T), and handedness. These results suggest that CNTNAP2 polymorphisms could be one of the important factors in the neural development related to vocal communication and language processing in both right-handed and non-right-handed healthy individuals. <s> BIB005 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <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> BIB006 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <s> The CNTNAP2 gene encodes a cell-adhesion molecule that influences the properties of neural networks and the morphology and density of neurons and glial cells. Previous studies have shown association of CNTNAP2 variants with language-related phenotypes in health and disease. Here, we report associations of a common CNTNAP2 polymorphism (rs7794745) with variation in grey matter in a region in the dorsal visual stream. We tried to replicate an earlier study on 314 subjects by Tan et al. (2010), but now in a substantially larger group of more than 1700 subjects. Carriers of the T allele showed reduced grey matter volume in left superior occipital gyrus, while we did not replicate associations with grey matter volume in other regions identified by Tan et al. (2010). Our work illustrates the importance of independent replication in neuroimaging genetic studies of language-related candidate genes. <s> BIB007 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | CNTNAP2 <s> Although it is clear that early language acquisition can be a target of CNTNAP2, the pathway between gene and language is still largely unknown. This research focused on the mediation role of rapid auditory processing (RAP). We tested RAP at 6 months of age by the use of event-related potentials, as a mediator between common variants of the CNTNAP2 gene (rs7794745 and rs2710102) and 20-month-old language outcome in a prospective longitudinal study of 96 Italian infants. The mediation model examines the hypothesis that language outcome is explained by a sequence of effects involving RAP and CNTNAP2. The ability to discriminate spectrotemporally complex auditory frequency changes at 6 months of age mediates the contribution of rs2710102 to expressive vocabulary at 20 months. The indirect effect revealed that rs2710102 C/C was associated with lower P3 amplitude in the right hemisphere, which, in turn, predicted poorer expressive vocabulary at 20 months of age. These findings add to a growing body of literature implicating RAP as a viable marker in genetic studies of language development. The results demonstrate a potential developmental cascade of effects, whereby CNTNAP2 drives RAP functioning that, in turn, contributes to early expressive outcome. <s> BIB008
CNTNAP2 has been identified as a risk-gene for DLD and autism (Alarcón et al., 2008; BIB002 , and variation in CNTNAP2 has been associated with performance on nonsense word repetition BIB003 and with rapid auditory processing BIB008 . CNTNAP2 (also known as CASPR2), a gene proximal to and regulated by FOXP2, is involved in regulation of neuron-glia interaction related to myelination and localization of ion channels BIB001  BIB003 . These functions have been taken as support for a role of this gene in structural connectivity and neural activity. Functional neuroimaging studies implicate a relationship between CNTNAP2 polymorphisms and atypical lateralization of language processing. For example,  found associations between lateralization for language and two CNTNAP2 polymorphisms in typically developing adults during a sentence completion task. Specifically, increased activation in the right inferior frontal cortex combined with decreased activation in the left superior parietal lobule was observed in individuals homozygous for the risk allele at rs2710102 compared to all other subjects; and increased activation in the right middle temporal gyrus was observed in those homozygous for risk allele at rs7794745 compared to all other subjects. Further evidence for atypical lateralization for language associated with CNTNAP2 polymorphisms comes from a study of language, voice, and general auditory processing. BIB005 reported increased activation in the right middle frontal gyrus during native language listening in Japanese carriers of the nondominant allele for rs7794745. This pattern of increased right hemisphere activation also held for human voice perception (reversed sentences) the right middle frontal gyrus. Further, these authors observed an interaction between lateralization of function during voice processing (forward and reversed speech), rs7794745 genotype, and handedness, suggesting a complex influence of this SNP on voice processing networks in relation to handedness and lateralization. 6 With respect to brain structure, two studies have identified regional reductions in gray matter volume associated with the risk allele on rs7794745 primarily affecting occipital, fusiform, and cerebellar regions BIB004 BIB007 . Additionally, altered white matter structure associated with CNTNAP2 has been reported in fronto-occipital and thalamic tracts BIB004 as well as midbrain tracts that facilitate communication among the cortex, cerebellum, and other central nervous system structures BIB006 . Using diffusion MRI,  identified a pattern of white matter structure characterized by local rather than long-range connections in individuals homozygous for the risk allele on CNTNAP2 SNP rs2710102. These reductions in long-range connectivity may indicate a weakened link between frontal and temporal cortical regions important for language processing and production. These white matter findings are consistent with CNTNAP2's role in myelination and suggest that CNTNAP2 may contribute to variation in language skills via modulation of connectivity among regions that are needed for effective language function.