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Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples
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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.
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“Autistic females are more likely to have high-impact de novo variants than autistic males17,26,46,47”
From Genetic correlates of phenotypic heterogeneity in autism (2022) · cites this paper as [26]
In the citing paper
“These results provide further evidence that rare, inherited LGD variants in constrained genes confer increased risk for ASD.14,15”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [15]
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“Existing methods to detect gene-specific enrichments of damaging DNMs ignore much prior information about which variants are more likely to be disease-associated; missense variants and protein-truncating variants (PTVs) vary in their impact on protein function3–6.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [5]
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“missense variants and protein-truncating variants (PTVs) vary in their impact on protein function3–6.”
From Evidence for 28 genetic disorders discovered by combining healthcare and research data (2020) · cites this paper as [5]
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“Samocha et al. (2017) recently introduced the MPC score, a missense deleteriousness metric composed of ‘‘Missense badness,’’ PolyPhen-2 (Adzhubei et al., 2010), and Constraint.”
BackgroundMethodResultInfluentialSelf-citationThe mutational constraint spectrum quantified from variation in 141,456 humans
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Evidence for 28 genetic disorders discovered by combining healthcare and research data
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Metadata
- Authors
- Kosmicki, J. A., Samocha, K. E., Howrigan, D. P., Sanders, S. J., Slowikowski, K., Lek, M., Karczewski, K. J., Cutler, D. J., Devlin, B., Roeder, K., Buxbaum, J. D., Neale, B. M., MacArthur, D. G., Wall, D. P., Robinson, E. B., & Daly, M. J.
- Affiliations
- Broad Institute (US)
- University of California, San Francisco (US)
- Emory University (US)
- University of Pittsburgh (US)
- Carnegie Mellon University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Stanford Medicine (US)
- Corresponding author
- Daly, Mark J
- ORCID
- Venue
- Nature Genetics
- Published
- 2017-02-13
- Volume
- 49
- Issue
- 4
- Pages
- 504-510
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC5496244
- OpenAlex
- W2949181286
- Cited by
- 340
- References
- 48
- Citations by year
- 2026: 12 · 2025: 20 · 2024: 35 · 2023: 22 · 2022: 34 · 2021: 38 · 2020: 46 · 2019: 54 · 2018: 45 · 2017: 34
- FWCI
- 32.49
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nd
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Simons Foundation (SFARI 342292)
- National Alliance for Research on Schizophrenia and Depression
- Simons Foundation Autism Research Initiative
- National Institutes of Health (5k01mh099286-02, T32 HG002295/HG/NHGRI)
- Simons Center for the Social Brain, Massachusetts Institute of Technology
- National Institute of Mental Health (U01MH100209, U01MH111661, U01MH100229, R01MH097849, U01MH111658, U01MH100239, R56MH097849, K01 MH099286, U01MH111660, U01MH100233)
- National Human Genome Research Institute (T32 HG002295/HG/NHGRI, HG002295, T32HG002295)
- National Institute of General Medical Sciences (R01GM104371)
- National Institute of Diabetes and Digestive and Kidney Diseases (U54DK105566)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- neurodevelopmental disorders, autism spectrum disorder, intellectual disability, developmental delay, loss-of-function intolerance, ExAC, inherited mutations, genetic risk
- MeSH terms
- Autism Spectrum Disorder, Humans, Intellectual Disability, Phenotype, Genetic Variation, Genetic Predisposition to Disease, Exome, Neurodevelopmental Disorders
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