title: Excess of rare, inherited truncating mutations in autism.
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.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Krumm
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Tychele N
authors.initials: TN
authors.lastname: Turner
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Vives
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Kiana
authors.initials: K
authors.lastname: Mohajeri
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Kali
authors.initials: K
authors.lastname: Witherspoon
authors.affiliation: 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.
authors.forename: Archana
authors.initials: A
authors.lastname: Raja
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Coe
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Stessman
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Zong-Xiao
authors.initials: ZX
authors.lastname: He
authors.affiliation: Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Bernier
authors.affiliation: 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.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D018389:Codon, Nonsense; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012306:Risk
chemical_list: D018389:Codon, Nonsense