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Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

ABSTRACT: To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (? 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.

SUBMITTER: Lim ET

PROVIDER: S-EPMC3613849 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

Lim Elaine T ET Raychaudhuri Soumya S Sanders Stephan J SJ Stevens Christine C Sabo Aniko A MacArthur Daniel G DG Neale Benjamin M BM Kirby Andrew A Ruderfer Douglas M DM Fromer Menachem M Lek Monkol M Liu Li L Flannick Jason J Ripke Stephan S Nagaswamy Uma U Muzny Donna D Reid Jeffrey G JG Hawes Alicia A Newsham Irene I Wu Yuanqing Y Lewis Lora L Dinh Huyen H Gross Shannon S Wang Li-San LS Lin Chiao-Feng CF Valladares Otto O Gabriel Stacey B SB dePristo Mark M Altshuler David M DM Purcell Shaun M SM State Matthew W MW Boerwinkle Eric E Buxbaum Joseph D JD Cook Edwin H EH Gibbs Richard A RA Schellenberg Gerard D GD Sutcliffe James S JS Devlin Bernie B Roeder Kathryn K Daly Mark J MJ

Neuron 20130101 2

To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (≤ 5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observa ...[more]

PMID: 23352160

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Project description:BackgroundRare genetic variants contribute to the etiology of both autism spectrum disorder (ASD) and schizophrenia (SCZ). Most genetic studies limit their focus to likely gene-disrupting mutations because they are relatively easier to interpret their effects on the gene product. Interpretation of missense variants is also informative to some pathophysiological mechanisms of these neurodevelopmental disorders; however, their contribution has not been elucidated because of relatively small effects. Therefore, we characterized missense variants detected in NRXN1, a well-known neurodevelopmental disease-causing gene, from individuals with ASD and SCZ.MethodsTo discover rare variants with large effect size and to evaluate their role in the shared etiopathophysiology of ASD and SCZ, we sequenced NRXN1 coding exons with a sample comprising 562 Japanese ASD and SCZ patients, followed by a genetic association analysis in 4273 unrelated individuals. Impact of each missense variant detected here on cell surface expression, interaction with NLGN1, and synaptogenic activity was analyzed using an in vitro functional assay and in silico three-dimensional (3D) structural modeling.ResultsThrough mutation screening, we regarded three ultra-rare missense variants (T737M, D772G, and R856W), all of which affected the LNS4 domain of NRXN1α isoform, as disease-associated variants. Diagnosis of individuals with T737M, D772G, and R856W was 1ASD and 1SCZ, 1ASD, and 1SCZ, respectively. We observed the following phenotypic and functional burden caused by each variant. (i) D772G and R856W carriers had more serious social disabilities than T737M carriers. (ii) In vitro assay showed reduced cell surface expression of NRXN1α by D772G and R856W mutations. In vitro functional analysis showed decreased NRXN1α-NLGN1 interaction of T737M and D772G mutants. (iii) In silico 3D structural modeling indicated that T737M and D772G mutations could destabilize the rod-shaped structure of LNS2-LNS5 domains, and D772G and R856W could disturb N-glycan conformations for the transport signal.ConclusionsThe combined data suggest that missense variants in NRXN1 could be associated with phenotypes of neurodevelopmental disorders beyond the diagnosis of ASD and/or SCZ.

Dataset Information

Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

Publications

Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.

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