Patterns and rates of exonic de novo mutations in autism spectrum disorders

Abstract

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

Figure 1. Protein-Protein interaction for genes with an observed functional de novo event

Direct protein connections from InWeb, restricting to genes harboring de novo mutations for DAPPLE analysis. Two extensive networks are identified, the first centered on SMARCC2 with 12 connections across 11 genes and the second centered on FN1 with 7 connections across 6 genes. The P-value for each gene having as many connections as those observed color the nodes of the network.

Figure 2. Direct and indirect Protein-Protein interaction for genes with a functional de novo event and existing ASD/ID genes

PPI network analysis for de novo variants and prior ASD genes (ASD112). Nodes are sized based on connectivity. Genes harboring de novo variants (left) and prior ASD genes (right) are colored blue with dark blue nodes represent genes that belong to one of these lists and are also intermediate proteins. Intermediate proteins (center) are colored in shades of orange based on a p-value computed using a proportion test where darker color represents a lower p-value. Green edges represent direct connections between genes harboring de novo variants (left) and prior ASD genes. All other edges, connecting to intermediate proteins are shown in grey.