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 unknown1. 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 families2, 3—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 reported4. 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 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 ASD5. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-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.
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- Supplementary Information (2.1M)
This file contains Supplementary Discussion; Supplementary Figures 1–13; Supplementary Tables 2, 4, 6-13; and Supplementary References.
- Supplementary Tables (203K)
This file contains Supplementary Tables 1, 3 and 5 which give detailed information on exome capture, sequence coverage, paternal age, de novo mutation sites, and functional annotations.