Whole genome sequencing in multiplex families reveals novel inherited and de novo genetic risk in autism

Abstract

Genetic studies of autism spectrum disorder (ASD) have revealed a complex, heterogeneous architecture, in which the contribution of rare inherited variation remains relatively un-explored. We performed whole-genome sequencing (WGS) in 2,308 individuals from families containing multiple affected children, including analysis of single nucleotide variants (SNV) and structural variants (SV). We identified 16 new ASD-risk genes, including many supported by inherited variation, and provide statistical support for 69 genes in total, including previously implicated genes. These risk genes are enriched in pathways involving negative regulation of synaptic transmission and organelle organization. We identify a significant protein-protein interaction (PPI) network seeded by inherited, predicted damaging variants disrupting highly constrained genes, including members of the BAF complex and established ASD risk genes. Analysis of WGS also identified SVs effecting non-coding regulatory regions in developing human brain, implicating NR3C2 and a recurrent 2.5Kb deletion within the promoter of DLG2. These data lend support to studying multiplex families for identifying inherited risk for ASD. We provide these data through the Hartwell Autism Research and Technology Initiative (iHART), an open access cloud-computing repository for ASD genetics research.