Recessive gene disruptions in autism spectrum disorder

• Type of Material: Article
• Authors: Ryan N. Doan, Boston Childrens Hospital; Elaine T. Lim, Boston Childrens Hospital; Silvia De Rubeis, Icahn School of Medicine at Mount Sinai; Catalina Betancur, Sorbonne Universite; David Cutler, Emory University; Andreas G. Chiocchetti, Goethe University; Lynne M. Overman, Newcastle University; Aubrie Soucy, Boston Childrens Hospital; Susanne Goetze, Boston Childrens Hospital; Christine M. Freitag, Goethe University; Mark J. Daly, Harvard Medical School; Christopher A. Walsh, Boston Childrens Hospital; Joseph D. Buxbaum, Icahn School of Medicine at Mount Sinai; Timothy W. Yu, Boston Childrens Hospital
• Language: English
• Date: 2019-07-01
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-019-0433-8
• Title of Journal or Parent Work: Nature Genetics
• Volume: 51
• Issue: 7
• Start Page: 1092
• End Page: +
• Grant/Funding Information: Collection of the PAGES cohort is supported by the National Institute of Mental Health (grant MH097849); This work was supported in part through the computational resources provided by the Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai, and the Research Information Technology Group at Harvard Medical School, which is partially supported by NIH grant NCRR 1S10RR028832–01.; C.A.W. is an Investigator of the Howard Hughes Medical Institute. C.A.W. and T.W.Y. were supported by the National Institute of Mental Health (NIMH) (grants RC2MH089952 and RO1MH083565).; We thank A. Hossain and N. Hatem for their help with sample preparation, and Janet Kerwin for her help with analysis of in situ hybridization results. R.N.D. was supported by an NIH T32 fellowship from the Fundamental Neurobiology Training Grant (5 T32 NS007484–14) and the Nancy Lurie Marks Clinical and Research Fellowship Program in Autism.; T.W.Y. was supported by NIH/NIMH R01MH113761, NICHD/NHGRI/NIH U19HD077671, NIH/NICHD U24HD0938487 and a SFARI Pilot Research Award.; The ASC is supported by the National Institute of Mental Health (grants MH100233, MH100229, MH100209, MH100239, MH111661, MH111660, MH111662, and MH111658).; S.D.R. and J.D.B. are supported by the Beatrice and Samuel A. Seaver Foundation.; Human embryonic and fetal material was provided by the joint MRC/Wellcome Trust (grant # MR/R006237/1) Human Developmental Biology Resource (www.hdbr.org).
• Keywords: PET-1; ASSOCIATION; DE-NOVO MUTATIONS; DICARBOXYLIC AMINOACIDURIA; Genetics & Heredity; LOCALIZATION; TRANSCRIPTION FACTOR; Science & Technology; GABA SYNTHESIS; GLUTAMATE; RARE; RISK; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2–4 and rare de novo variants5–10 in ASD. Recessive mutations have also been implicated11–14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to approximately 5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2,DDHD1,NSUN2,PAH,RARB,ROGDI,SLC1A1,USH2A) as well as other genes not previously implicated in ASD including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition.