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- Title
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
- Authors
O'Roak, Brian J.; Vives, Laura; Girirajan, Santhosh; Karakoc, Emre; Krumm, Niklas; Coe, Bradley P.; Levy, Roie; Ko, Arthur; Lee, Choli; Smith, Joshua D.; Turner, Emily H.; Stanaway, Ian B.; Vernot, Benjamin; Malig, Maika; Baker, Carl; Reilly, Beau; Akey, Joshua M.; Borenstein, Elhanan; Rieder, Mark J.; Nickerson, Deborah A.
- Abstract
It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected ?-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.
- Subjects
AUTISM; DEVELOPMENTAL disabilities; GENES; LOCUS (Genetics); GENETICS; GENETIC mutation
- Publication
Nature, 2012, Vol 485, Issue 7397, p246
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature10989