Recessive gene disruptions in autism spectrum disorder

Nat Genet. 2019 Jul;51(7):1092-1098. doi: 10.1038/s41588-019-0433-8.

Ryan N Doan ¹ ², Elaine T Lim ¹ ², Silvia De Rubeis ³ ⁴ ⁵, Catalina Betancur ⁶, David J Cutler ⁷, Andreas G Chiocchetti ⁸, Lynne M Overman ⁹, Aubrie Soucy ¹, Susanne Goetze ¹, Autism Sequencing Consortium, Christine M Freitag ⁸, Mark J Daly ² ¹⁰ ¹¹, Christopher A Walsh ¹ ² ¹⁰ ¹², Joseph D Buxbaum ³ ⁴ ⁵ ¹³ ¹⁴ ¹⁵, Timothy W Yu ¹⁶ ¹⁷ ¹⁸

Affiliations

1 Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
2 Harvard Medical School, Boston, MA, USA.
3 Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4 Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
5 Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6 Neuroscience Paris Seine, Institut de Biologie Paris Seine, Sorbonne Université, INSERM, CNRS, Paris, France.
7 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA.
8 Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Autism Research and Intervention Center of Excellence, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
9 Human Developmental Biology Resource, Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle-upon-Tyne, UK.
10 The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
11 Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
12 Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA.
13 Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
14 Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
15 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
16 Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA. [email protected].
17 Harvard Medical School, Boston, MA, USA. [email protected].
18 The Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].

PMID: 31209396 DOI: 10.1038/s41588-019-0433-8

Abstract

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals¹. Genome-wide association and large-scale sequencing studies strongly implicate both common variants^2-4 and rare de novo variants^5-10 in ASD. Recessive mutations have also been implicated^11-14 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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