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Genes, cognition, and communication: insights from neurodevelopmental disorders.

ABSTRACT: Twin and family studies have demonstrated that most cognitive traits are moderately to highly heritable. Neurodevelopmental disorders such as dyslexia, autism, and specific language impairment (SLI) also show strong genetic influence. Nevertheless, it has proved difficult for researchers to identify genes that would explain substantial amounts of variance in cognitive traits or disorders. Although this observation may seem paradoxical, it fits with a multifactorial model of how complex human traits are influenced by numerous genes that interact with one another, and with the environment, to produce a specific phenotype. Such a model can also explain why genetic influences on cognition have not vanished in the course of human evolution. Recent linkage and association studies of SLI and dyslexia are reviewed to illustrate these points. The role of nonheritable genetic mutations (sporadic copy number variants) in causing autism is also discussed. Finally, research on phenotypic correlates of allelic variation in the genes ASPM and microcephalin is considered; initial interest in these as genes for brain size or intelligence has been dampened by a failure to find phenotypic differences in people with different versions of these genes. There is a current vogue for investigators to include measures of allelic variants in studies of cognition and cognitive disorders. It is important to be aware that the effect sizes associated with these variants are typically small and hard to detect without extremely large sample sizes.

SUBMITTER: Bishop DV

PROVIDER: S-EPMC2805335 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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Genes, cognition, and communication: insights from neurodevelopmental disorders.

Bishop D V M DV

Annals of the New York Academy of Sciences 20090301

Twin and family studies have demonstrated that most cognitive traits are moderately to highly heritable. Neurodevelopmental disorders such as dyslexia, autism, and specific language impairment (SLI) also show strong genetic influence. Nevertheless, it has proved difficult for researchers to identify genes that would explain substantial amounts of variance in cognitive traits or disorders. Although this observation may seem paradoxical, it fits with a multifactorial model of how complex human tra ...[more]

PMID: 19338500

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Project description:BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

Dataset Information

Genes, cognition, and communication: insights from neurodevelopmental disorders.

Publications

Genes, cognition, and communication: insights from neurodevelopmental disorders.

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