Excess of rare inherited truncating mutations in autism

In order to quantify the effect of private, inherited mutations on autism risk, we generated a callset of both inherited and de novo single nucleotide variants (SNVs) and copy number variants (CNVs) across 2,377 Simons Simplex Collection families. The publically deposited dataset includes 1,786 parents-child-unaffected sibling "quads" allowing us to compare burden of inherited and de novo mutations between affected and unaffected siblings in simplex autism families. We find that private, inherited truncating SNV mutations in conserved genes are significantly enriched in probands (odds ratio = 1.14, p = 0.0002) and more likely to be transmitted to children with autism when compared to their unaffected siblings (p < 0.0001). We find that this effect becomes more pronounced with increasing gene conservation (Residual Variation Intolerance Score, RVIS). Likewise, we observe a similar bias for inherited CNVs specifically for small (<100 kbp), maternally inherited events (p = 9.6x10^-3) that are enriched in CHD8 target genes (OR = 3.6, p = 2.0x10^-3). We quantified autism spectrum disorder (ASD) risk for de novo and inherited CNVs and SNVs by using a conditional logistic regression model. Independent from de novo mutations, private truncating SNVs and rare, inherited CNVs contribute an increase in risk with an odds ratio 1.11 (p = 0.0002) and 1.23 (p = 0.01), respectively. Our results indicate a statistically independent role for inherited mutations in ASD risk and identify additional high-impact risk candidate genes (e.g., RIMS1, CUL7, LZTR1 and CC2D2A) where transmitted mutations may create a sensitized background for autism but are unlikely to be necessary and sufficient for the disorder.