Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | Summary: Neuroimaging genetics studies of DLD <s> Half the members of the KE family suffer from a speech and language disorder caused by a mutation in the FOXP2 gene. We examined functional brain abnormalities associated with this mutation using two fMRI language experiments, one involving covert (silent) verb generation and the other overt (spoken) verb generation and word repetition. The unaffected family members showed a typical left-dominant distribution of activation involving Broca's area in the generation tasks and a more bilateral distribution in the repetition task, whereas the affected members showed a more posterior and more extensively bilateral pattern of activation in all tasks. Consistent with previously reported bilateral morphological abnormalities, the affected members showed significant underactivation relative to the unaffected members in Broca's area and its right homolog, as well as in other cortical language-related regions and in the putamen. Our findings suggest that the FOXP2 gene is critically involved in the development of the neural systems that mediate speech and language. <s> BIB001 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | Summary: Neuroimaging genetics studies of DLD <s> That speech and language are innate capacities of the human brain has long been widely accepted, but only recently has an entry point into the genetic basis of these remarkable faculties been found. The discovery of a mutation in FOXP2 in a family with a speech and language disorder has enabled neuroscientists to trace the neural expression of this gene during embryological development, track the effects of this gene mutation on brain structure and function, and so begin to decipher that part of our neural inheritance that culminates in articulate speech. <s> BIB002 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | Summary: Neuroimaging genetics studies of DLD <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> BIB003 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | Summary: Neuroimaging genetics studies of DLD <s> Correction to: European Journal of Human Genetics (2012) 20, 224–229; doi:10.1038/ejhg.2011.160; published online 7 September 2011 The authors would like to make the following amendments: The following sentence in the Materials and Methods section: ‘Furthermore, we genotyped the mutation R553H, previously found in a large Pakistani family with severe speech and language disorder’ should read: ‘Furthermore, we genotyped the mutation R553H, previously found in a large English Caucasian family with severe speech and language disorder. <s> BIB004 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | Summary: Neuroimaging genetics studies of DLD <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> BIB005 </s> Neuroimaging genetics studies of specific reading disability and developmental language disorder: A review <s> | Summary: Neuroimaging genetics studies of DLD <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> BIB006
Neuroimaging genetic investigations of these two primary DLD candidate genes suggest specific roles of each gene in language-related neural function. Imaging genetics studies of FOXP2 indicate that this gene affects brain regions associated with language production and speech motor planning BIB001  BIB002 , with preliminary links to activity in posterior language regions BIB004 . CNTNAP2 has also been found to have effects on functional activation in languagerelated regions, including inferior frontal and middle temporal gyri  and on gray matter morphology in occipital, fusiform, and cerebellar regions BIB003 BIB006 ; in addition, this gene has effects on structural and functional connectivity among language-associated regions and more domain general regions  BIB005 . The compelling neuroimaging genetic findings related to both of these genes may direct future research to further characterize their roles in DLD. Further examination of FOXP2 in the general population will be particularly useful to disentangle the specific effects of the KE Family mutation from more common polymorphisms that may contribute to individual differences in language abilities. Additional functional neuroimaging research is needed to clarify the associations of these genes with specific aspects of language processing. Furthermore, several additional DLD candidate genes (e.g., ATP2C2 and CMIP) have yet to be studied using neuroimaging genetics, and this approach may provide insight into the mechanisms by which they impact language function.