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Nat Genet. 2015 Jun;47(6):582-8. doi: 10.1038/ng.3303. Epub 2015 May 11.

Excess of rare, inherited truncating mutations in autism.

Author information

1
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
2
1] Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA.
3
Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
4
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.

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.

PMID:
25961944
PMCID:
PMC4449286
DOI:
10.1038/ng.3303
[Indexed for MEDLINE]
Free PMC Article

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