Brian J. O’Roak 1 , Laura Vives 1 , Santhosh Girirajan 1 , Emre Karakoc 1 , Nik Krumm 1 , Bradley P. Coe 1 , Roie Levy 1 , Arthur Ko 1 , Choli Lee 1 , Joshua D. Smith 1 , Emily H. Turner 1 , Ian B. Stanaway 1 , Benjamin Vernot 1 , Maika Malig 1 , Carl Baker 1 , Beau Reilly 4 , Joshua M. Akey 1 , Elhanan Borenstein 1 , 2 , 3 , Mark J. Rieder 1 , Deborah A. Nickerson 1 , Raphael Bernier 4 , Jay Shendure 1 , Evan E. Eichler 1 , 5
04 April 2012
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 1 . 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 2, 3 , we sequenced all coding regions of the genome, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 previously reported 4 . Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19) 4 , for a total of 677 individual exomes from 209 families. Here we show 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 5 . Moreover, 39% (49/126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodeling 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 suggest extreme locus heterogeneity but also provide a target for future discovery, diagnostics, and therapeutics.