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

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

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Title: Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples
Author: Kosmicki, Jack A.; Samocha, Kaitlin E.; Howrigan, Daniel P.; Sanders, Stephan J.; Slowikowski, Kamil; Lek, Monkol; Karczewski, Konrad J.; Cutler, David J.; Devlin, Bernie; Roeder, Kathryn; Buxbaum, Joseph D.; Neale, Benjamin M.; MacArthur, Daniel G.; Wall, Dennis P.; Robinson, Elise B.; Daly, Mark J.

Note: Order does not necessarily reflect citation order of authors.

Citation: Kosmicki, J. A., K. E. Samocha, D. P. Howrigan, S. J. Sanders, K. Slowikowski, M. Lek, K. J. Karczewski, et al. 2017. “Refining the role of de novo protein truncating variants in neurodevelopmental disorders using population reference samples.” Nature genetics 49 (4): 504-510. doi:10.1038/ng.3789. http://dx.doi.org/10.1038/ng.3789.
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Abstract: Recent research has uncovered a significant role for de novo variation in neurodevelopmental disorders. Using aggregated data from 9246 families with autism spectrum disorder, intellectual disability, or developmental delay, we show ~1/3 of de novo variants are independently observed 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 use a loss-of-function (LoF)-intolerance metric, pLI, to identify a subset of LoF-intolerant genes that contain 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; though the strongest de novo impacted genes contribute little to this, suggesting the excess of inherited risk resides 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.
Published Version: doi:10.1038/ng.3789
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5496244/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375306
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