PT  - JOURNAL ARTICLE
AU  - Jack A. Kosmicki
AU  - Kaitlin E. Samocha
AU  - Daniel P. Howrigan
AU  - Stephan J. Sanders
AU  - Kamil Slowikowski
AU  - Monkol Lek
AU  - Konrad J. Karczewski
AU  - David J. Cutler
AU  - Bernie Devlin
AU  - Kathryn Roeder
AU  - Joseph D. Buxbaum
AU  - Benjamin M. Neale
AU  - Daniel G. MacArthur
AU  - Dennis P. Wall
AU  - Elise B. Robinson
AU  - Mark J. Daly
TI  - Refining the role of <em>de novo</em> protein truncating variants in neurodevelopmental disorders using population reference samples
AID  - 10.1101/052886
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 052886
4099  - http://biorxiv.org/content/early/2017/02/08/052886.short
4100  - http://biorxiv.org/content/early/2017/02/08/052886.full
AB  - 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.