Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

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 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.

Figure 1. De novo mutation events in autism spectrum disorder

a Haplotype phasing using informative markers shows a strong parent-of-origin bias with 41/51 de novo events occurring on the paternally inherited haplotype. b and c, Box and whisker plots for 189 SSC probands. b, The paternal estimated age at conception versus the number of observed de novo point mutations (0, n = 53; 1, n = 65; 2, n = 44; 3+, n = 27). c, Decreased nonverbal IQ is significantly associated with an increasing number of “extreme” mutation events (0, n = 138; 1, n = 41; 2+, n = 10), both with and without CNVs (Supplementary Discussion). d, Browser images showing CNVs identified in del(18)(q12.2q21.1) syndrome region. Truncating point mutation in SETBP1 occurs within the critical region, identifying the likely causative locus. Each red (deletion) and green (duplication) line represents an identified CNV in cases (solid lines) versus controls (dashed lines), with arrowheads showing point mutation.

Figure 2. Mutations identified in protein-protein interaction (PPI) networks

a The 49-gene connected component of the PPI network formed from 126 genes with severe de novo mutations among the 209 probands. b, Proband 13844 inherits three rare gene-disruptive CNVs and carries two de novo truncating mutations. c, GeneMANIA view of three of the affected genes (b) (red labels) which encode proteins that are part of a beta-catenin linked network. This proband is macrocephalic, impaired cognitively, and has deficits in social behavior and language development (Supplementary Discussion).