Recessive gene disruptions in autism spectrum disorder


Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2,3,4 and rare de novo variants5,6,7,8,9,10 in ASD. Recessive mutations have also been implicated11,12,13,14 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.

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Fig. 1: An excess of rare, damaging, biallelic mutation in ASD.
Fig. 2: Biallelic mutations in ASD: the effects of sex.
Fig. 3: Biallelic mutations in ASD: ExAC filtration.

Data availability

Data included in this manuscript have been deposited at the database of Genotypes and Phenotypes, merged with published data under accession number phs000298.v4.p3. Correspondence and requests for materials should be addressed to


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We thank A. Hossain and N. Hatem for their help with sample preparation, and J. 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 (no. 5 T32 NS007484-14) and the Nancy Lurie Marks Clinical and Research Fellowship Program in Autism. The ASC is supported by the National Institute of Mental Health (NIMH; grant nos. MH100233, MH100229, MH100209, MH100239, MH111661, MH111660, MH111662 and MH111658). Collection of the PAGES cohort is supported by the NIMH (grant no. 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 National Institutes of Health grant no. NCRR 1S10RR028832-01. Human embryonic and fetal material was provided jointly by the MRC/Wellcome Trust (grant no. MR/R006237/1) Human Developmental Biology Resource ( C.A.W. is an Investigator of the Howard Hughes Medical Institute. C.A.W. and T.W.Y. were supported by NIMH grant nos. RC2MH089952 and RO1MH083565. T.W.Y. was supported by grant nos. NIH/NIMH R01MH113761, NICHD/NHGRI/NIH U19HD077671 and NIH/NICHD U24HD0938487, and by a SFARI Pilot Research Award. S.D.R. and J.D.B. are supported by the Beatrice and Samuel A. Seaver Foundation.

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T.W.Y., R.N.D., E.T.L. and M.J.D. designed the study, with important additional contributions from C.B., D.J.C, C.A.W. and J.D.B. R.N.D., E.T.L. and A.S. performed the data analyses. S.D.R. and S.G. performed the Sanger validation. A.G.C. and C.M.F. characterized the FEV family. L.O., S.G. and T.W.Y. designed and performed the in situ expression analyses. R.N.D. and T.W.Y. wrote the manuscript. All authors reviewed and approved the manuscript.

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Correspondence to Timothy W. Yu.

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Doan, R.N., Lim, E.T., De Rubeis, S. et al. Recessive gene disruptions in autism spectrum disorder. Nat Genet 51, 1092–1098 (2019).

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