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

By Jack A. Kosmicki, Kaitlin E Samocha, Daniel P Howrigan, Stephan J. Sanders, Kamil Slowikowski, Monkol Lek, Konrad Karczewski, David J. Cutler, Bernie Devlin, Kathryn Roeder, Joseph D. Buxbaum, Benjamin M Neale, Daniel G MacArthur, Dennis P. Wall, Elise B Robinson, Mark J Daly

Posted 12 May 2016
bioRxiv DOI: 10.1101/052886 (published DOI: 10.1038/ng.3789)

Recent research has uncovered an important 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.

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