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Nat Genet. 2017 Apr;49(4):504-510. doi: 10.1038/ng.3789. Epub 2017 Feb 13.

Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples.

Kosmicki JA1,2,3,4,5, Samocha KE1,2,3,5, Howrigan DP1,2,3, Sanders SJ6, Slowikowski K2,4,7,8, Lek M1,2, Karczewski KJ1,2, Cutler DJ9, Devlin B10, Roeder K11, Buxbaum JD12,13,14,15,16,17, Neale BM1,2,3, MacArthur DG1,2, Wall DP18, Robinson EB1,2,3, Daly MJ1,2,3.

Author information

1
Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
3
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
4
Program in Bioinformatics and Integrative Genomics, Harvard University, Cambridge, Massachusetts, USA.
5
Program in Genetics and Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
6
Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA.
7
Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
8
Partners Center for Personalized Genetic Medicine, Boston, Massachusetts, USA.
9
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
10
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
11
Department of Statistics, Carnegie Mellon University, Pittsburgh, Pennsylvania, USA.
12
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
13
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
14
Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
15
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
16
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
17
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
18
Departments of Pediatrics (Systems Medicine), Biomedical Data Science, and Psychiatry (by courtesy), Stanford University, Stanford, California, USA.

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.

PMID:
28191890
PMCID:
PMC5496244
DOI:
10.1038/ng.3789
[Indexed for MEDLINE]
Free PMC Article

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