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Patterns and rates of exonic de novo mutations in autism spectrum disorders.

Nature | Apr 4, 2012

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

Pubmed ID: 22495311 RIS Download

Mesh terms: Autistic Disorder | Case-Control Studies | DNA-Binding Proteins | Exome | Exons | Family Health | Genetic Predisposition to Disease | Humans | Models, Genetic | Multifactorial Inheritance | Mutation | Phenotype | Poisson Distribution | Protein Interaction Maps | Transcription Factors

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Associated grants

  • Agency: NIMH NIH HHS, Id: R01 MH089208
  • Agency: NHGRI NIH HHS, Id: U54 HG003067
  • Agency: NIGMS NIH HHS, Id: P50 GM071558
  • Agency: NIMH NIH HHS, Id: R01 MH089004
  • Agency: NIMH NIH HHS, Id: R01 MH061009
  • Agency: NIMH NIH HHS, Id: R01MH084676
  • Agency: NCRR NIH HHS, Id: TL1 RR024978
  • Agency: NICHD NIH HHS, Id: P30 HD015052
  • Agency: NCRR NIH HHS, Id: KL2 RR024977
  • Agency: NIGMS NIH HHS, Id: T32 GM007753
  • Agency: NHGRI NIH HHS, Id: U54 HG003273
  • Agency: NIMH NIH HHS, Id: R01MH089175
  • Agency: NIMH NIH HHS, Id: R01 MH057881
  • Agency: NICHD NIH HHS, Id: P50 HD055751
  • Agency: NIMH NIH HHS, Id: R01 MH089025
  • Agency: NIMH NIH HHS, Id: R01MH089208
  • Agency: NIMH NIH HHS, Id: R01 MH089175
  • Agency: NCRR NIH HHS, Id: UL1 RR024975
  • Agency: NIMH NIH HHS, Id: R01 MH089482

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