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, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 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 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% (49/126) 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.

To understand the genetic heterogeneity underlying developmental delay, we compare copy-number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects to 8,329 adult controls. We estimate that ~14.2% of disease in these individuals is due to large CNVs > 400 kbp. We find greater CNV enrichment in patients with craniofacial anomalies and cardiovascular defects than epilepsy or autism. We identify 59 pathogenic CNVs including 14 novel or previously weakly supported candidates. We refine the critical interval for several genomic disorders such as the 17q21.31 microdeletion syndrome and identify 940 candidate dosage-sensitive genes. We also develop methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map combined with exome/genome sequencing will be critical for deciphering the genetic basis of developmental delay, intellectual disability, and autism spectrum disorders.

Evidence for the etiology of autism spectrum disorders (ASD) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity1,2. We sequenced the exomes of 20 sporadic cases of ASD and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, of which 11 were protein-altering. Protein-altering mutations were significantly enriched for changes at highly conserved residues. We identified potentially causative de novo events in 4/20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A, and LAMC3. In the FOXP1 mutation carrier, we also observed a rare inherited CNTNAP2 mutation and provide functional support for a multihit model for disease risk3. Our results demonstrate that trio-based exome sequencing is a powerful approach for identifying novel candidate genes for ASD and suggest that de novo mutations may contribute substantially to the genetic risk for ASD.