Title |
Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples
|
---|---|
Published in |
Nature Genetics, February 2017
|
DOI | 10.1038/ng.3789 |
Pubmed ID | |
Authors |
Jack A Kosmicki, Kaitlin E Samocha, Daniel P Howrigan, Stephan J Sanders, Kamil Slowikowski, Monkol Lek, Konrad J 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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 41 | 36% |
United Kingdom | 13 | 11% |
Spain | 2 | 2% |
Argentina | 2 | 2% |
Israel | 2 | 2% |
Ireland | 2 | 2% |
France | 2 | 2% |
Switzerland | 1 | <1% |
Sweden | 1 | <1% |
Other | 7 | 6% |
Unknown | 42 | 37% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 58 | 50% |
Scientists | 50 | 43% |
Science communicators (journalists, bloggers, editors) | 3 | 3% |
Practitioners (doctors, other healthcare professionals) | 3 | 3% |
Unknown | 1 | <1% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | <1% |
Germany | 1 | <1% |
Netherlands | 1 | <1% |
Italy | 1 | <1% |
France | 1 | <1% |
Argentina | 1 | <1% |
United States | 1 | <1% |
Unknown | 337 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 76 | 22% |
Student > Ph. D. Student | 68 | 20% |
Student > Master | 38 | 11% |
Student > Bachelor | 29 | 8% |
Other | 19 | 6% |
Other | 53 | 15% |
Unknown | 62 | 18% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 90 | 26% |
Agricultural and Biological Sciences | 76 | 22% |
Medicine and Dentistry | 38 | 11% |
Neuroscience | 34 | 10% |
Computer Science | 11 | 3% |
Other | 24 | 7% |
Unknown | 72 | 21% |