Title |
A framework for the interpretation of de novo mutation in human disease
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Published in |
Nature Genetics, September 2014
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DOI | 10.1038/ng.3050 |
Pubmed ID | |
Authors |
Kaitlin E Samocha, Elise B Robinson, Stephan J Sanders, Christine Stevens, Aniko Sabo, Lauren M McGrath, Jack A Kosmicki, Karola Rehnström, Swapan Mallick, Andrew Kirby, Dennis P Wall, Daniel G MacArthur, Stacey B Gabriel, Mark DePristo, Shaun M Purcell, Aarno Palotie, Eric Boerwinkle, Joseph D Buxbaum, Edwin H Cook, Richard A Gibbs, Gerard D Schellenberg, James S Sutcliffe, Bernie Devlin, Kathryn Roeder, Benjamin M Neale, Mark J Daly |
Abstract |
Spontaneously arising (de novo) mutations have an important role in medical genetics. For diseases with extensive locus heterogeneity, such as autism spectrum disorders (ASDs), the signal from de novo mutations is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. Here we provide a statistical framework for the analysis of excesses in de novo mutation per gene and gene set by calibrating a model of de novo mutation. We applied this framework to de novo mutations collected from 1,078 ASD family trios, and, whereas we affirmed a significant role for loss-of-function mutations, we found no excess of de novo loss-of-function mutations in cases with IQ above 100, suggesting that the role of de novo mutations in ASDs might reside in fundamental neurodevelopmental processes. We also used our model to identify ∼1,000 genes that are significantly lacking in functional coding variation in non-ASD samples and are enriched for de novo loss-of-function mutations identified in ASD cases. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 13 | 27% |
United Kingdom | 5 | 10% |
India | 3 | 6% |
Australia | 3 | 6% |
France | 3 | 6% |
Netherlands | 2 | 4% |
Italy | 1 | 2% |
Montenegro | 1 | 2% |
Canada | 1 | 2% |
Other | 2 | 4% |
Unknown | 14 | 29% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 27 | 56% |
Members of the public | 19 | 40% |
Science communicators (journalists, bloggers, editors) | 1 | 2% |
Practitioners (doctors, other healthcare professionals) | 1 | 2% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 13 | 1% |
United Kingdom | 7 | <1% |
Spain | 4 | <1% |
Italy | 3 | <1% |
Brazil | 3 | <1% |
Hong Kong | 2 | <1% |
Germany | 2 | <1% |
Denmark | 2 | <1% |
Netherlands | 2 | <1% |
Other | 16 | 2% |
Unknown | 926 | 94% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 242 | 25% |
Researcher | 226 | 23% |
Student > Master | 80 | 8% |
Student > Bachelor | 64 | 7% |
Student > Doctoral Student | 52 | 5% |
Other | 188 | 19% |
Unknown | 128 | 13% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 322 | 33% |
Biochemistry, Genetics and Molecular Biology | 249 | 25% |
Medicine and Dentistry | 114 | 12% |
Neuroscience | 44 | 4% |
Computer Science | 39 | 4% |
Other | 66 | 7% |
Unknown | 146 | 15% |