title: Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.
abstract: Recent research has uncovered an important role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9,246 families with autism spectrum disorder, intellectual disability, or developmental delay, we found that ∼1/3 of de novo variants are independently present as standing variation in the Exome Aggregation Consortium's cohort of 60,706 adults, and these de novo variants do not contribute to neurodevelopmental risk. We further used a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes containing the observed signal of associated de novo protein-truncating variants (PTVs) in neurodevelopmental disorders. LoF-intolerant genes also carry a modest excess of inherited PTVs, although the strongest de novo-affected genes contribute little to this excess, thus suggesting that the excess of inherited risk resides in lower-penetrant genes. These findings illustrate the importance of population-based reference cohorts for the interpretation of candidate pathogenic variants, even for analyses of complex diseases and de novo variation.
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA.|Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Kosmicki
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Howrigan
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Stephan J
authors.identifier: http://orcid.org/0000-0001-9112-5148
authors.initials: SJ
authors.lastname: Sanders
authors.affiliation: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA.|Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
authors.forename: Kamil
authors.initials: K
authors.lastname: Slowikowski
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Konrad J
authors.initials: KJ
authors.lastname: Karczewski
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Cutler
authors.affiliation: Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Bernie
authors.initials: B
authors.lastname: Devlin
authors.affiliation: Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Roeder
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Benjamin M
authors.identifier: http://orcid.org/0000-0003-1513-6077
authors.initials: BM
authors.lastname: Neale
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Departments of Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry (by courtesy), Stanford University, Stanford, California, USA.
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Wall
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Elise B
authors.initials: EB
authors.lastname: Robinson
authors.affiliation: Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.|Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
authors.forename: Mark J
authors.identifier: http://orcid.org/0000-0002-0949-8752
authors.initials: MJ
authors.lastname: Daly
mesh_terms: D000067877:Autism Spectrum Disorder / Q000235:genetics; D059472:Exome / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D010641:Phenotype