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Nature DOI:10.1038/nature11011

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

Publication TypeJournal Article
Year of Publication2012
AuthorsNeale, BM, Kou, Y, Liu, L, Ma'ayan, A, Samocha, KE, Sabo, A, Lin, C-F, Stevens, C, San Wang, L-, Makarov, V, Polak, P, Yoon, S, Maguire, J, Crawford, EL, Campbell, NG, Geller, ET, Valladares, O, Schafer, C, Liu, H, Zhao, T, Cai, G, Lihm, J, Dannenfelser, R, Jabado, O, Peralta, Z, Nagaswamy, U, Muzny, D, Reid, JG, Newsham, I, Wu, Y, Lewis, L, Han, Y, Voight, BF, Lim, E, Rossin, E, Kirby, A, Flannick, J, Fromer, M, Shakir, K, Fennell, T, Garimella, K, Banks, E, Poplin, R, Gabriel, S, DePristo, M, Wimbish, JR, Boone, BE, Levy, SE, Betancur, C, Sunyaev, S, Boerwinkle, E, Buxbaum, JD, Cook, EH, Devlin, B, Gibbs, RA, Roeder, K, Schellenberg, GD, Sutcliffe, JS, Daly, MJ
JournalNature
Volume485
Issue7397
Pages242-5
Date Published2012 Apr 04
ISSN1476-4687
KeywordsAutistic 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
Abstract

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.

URLhttp://dx.doi.org/10.1038/nature11011
DOI10.1038/nature11011
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/22495311?dopt=Abstract

Alternate JournalNature
PubMed ID22495311
PubMed Central IDPMC3613847
Grant ListR01 MH089208 / MH / NIMH NIH HHS / United States
P50 GM071558 / GM / NIGMS NIH HHS / United States
R01 MH089004 / MH / NIMH NIH HHS / United States
R01 MH061009 / MH / NIMH NIH HHS / United States
R01MH084676 / MH / NIMH NIH HHS / United States
TL1 RR024978 / RR / NCRR NIH HHS / United States
P30 HD015052 / HD / NICHD NIH HHS / United States
KL2 RR024977 / RR / NCRR NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
R01MH089175 / MH / NIMH NIH HHS / United States
R01 MH057881 / MH / NIMH NIH HHS / United States
P50 HD055751 / HD / NICHD NIH HHS / United States
R01 MH089025 / MH / NIMH NIH HHS / United States
R01MH089208 / MH / NIMH NIH HHS / United States
R01 MH089175 / MH / NIMH NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States
R01 MH089482 / MH / NIMH NIH HHS / United States