Rare variants and the oligogenic architecture of autism

Most large-scale genetic studies of autism have focused on the discovery of genes by proving an enrichment of de novo mutations (DNMs) in autism probands or characterizing polygenic risk based on the association of common variants. We present evidence in support of an oligogenic model where two or more ultrarare mutations of more modest effect are preferentially transmitted to children with autism. Such private gene-disruptive mutations are enriched in families where there are multiple affected individuals, emerged two or three generations ago, and map to genes not previously associated with autism. Although no single gene has reached statistical significance, this class of variation should be considered along with genetic and nongenetic factors to better explain the etiology of this complex trait.