Abstract
The genetic architecture of autism spectrum disorder (ASD) is known to consist of contributions from gene-disrupting de novo mutations and common variants of modest effect. We hypothesize that the unexplained heritability of ASD also includes rare inherited variants with intermediate effects. We investigated the genome-wide distribution and functional impact of structural variants (SVs) through whole genome analysis (>30X coverage) of 3,169 subjects from 829 families affected by ASD. Genes that are intolerant to inactivating variants in the exome aggregation consortium (ExAC) were depleted for SVs in parents, specifically within fetal-brain promoters, UTRs and exons. Rare paternally-inherited SVs that disrupt promoters or UTRs were over-transmitted to cases (P = 0.0013) and not to their typically-developing siblings. Protein-coding SVs were also associated with ASD (P = 0.0025). Recurrent functional noncoding deletions implicate the gene LEO1 in ASD. Our results establish that rare inherited SVs predispose children to ASD, with differing contributions from each parent.
