Excess of rare, inherited truncating mutations in autism

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

Research output: Contribution to journalArticlepeer-review

405 Scopus citations


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 â'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.

Original languageEnglish
Pages (from-to)582-588
Number of pages7
JournalNature Genetics
Issue number6
StatePublished - May 27 2015


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