Excess of rare, inherited truncating mutations in autism.

Publication Type:

Journal Article

Authors:

Krumm, Niklas; Turner, Tychele N; Baker, Carl; Vives, Laura; Mohajeri, Kiana; Witherspoon, Kali; Raja, Archana; Coe, Bradley P; Stessman, Holly A; He, Zong-Xiao; Leal, Suzanne M; Bernier, Raphael; Eichler, Evan E

Source:

Nature genetics (2015)

Abstract:

To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14, P = 0.0002) in comparison to unaffected siblings, an effect involving significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kb), maternally inherited events (P = 0.01) that are enriched in CHD8 target genes (P = 7.4 × 10(-3)). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent risk factors for autism, with odds ratios of 1.11 (P = 0.0002) and 1.23 (P = 0.01), respectively. This analysis identifies a second class of candidate genes (for example, RIMS1, CUL7 and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.