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Title | A framework for the interpretation of de novo mutation in human disease. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Samocha KE, Robinson EB, Sanders SJ, Stevens C, Sabo A, McGrath LM, Kosmicki JA, Rehnström K, Mallick S, Kirby A, Wall DP, MacArthur DG, Gabriel SB, DePristo M, Purcell SM, Palotie A, Boerwinkle E, Buxbaum JD, Cook EH, Gibbs RA, Schellenberg GD, Sutcliffe JS, Devlin B, Roeder K, Neale BM, Daly MJ |
Journal | Nat Genet |
Volume | 46 |
Issue | 9 |
Pagination | 944-50 |
Date Published | 2014 Sep |
ISSN | 1546-1718 |
Keywords | Child Development Disorders, Pervasive, Exome, Female, Genetic Code, Genetic Predisposition to Disease, Genetics, Medical, Humans, Male, Mutation |
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. |
DOI | 10.1038/ng.3050 |
Alternate Journal | Nat. Genet. |
PubMed ID | 25086666 |
PubMed Central ID | PMC4222185 |
Grant List | U24 MH081810 / MH / NIMH NIH HHS / United States R01 MH089208 / MH / NIMH NIH HHS / United States HL-103010 / HL / NHLBI NIH HHS / United States R37 MH057881 / MH / NIMH NIH HHS / United States U54HG003273 / HG / NHGRI NIH HHS / United States U01 MH100229 / MH / NIMH NIH HHS / United States P50HD055751 / HD / NICHD NIH HHS / United States R01 MH089004 / MH / NIMH NIH HHS / United States R01 MH061009 / MH / NIMH NIH HHS / United States U24MH068457 / MH / NIMH NIH HHS / United States 1U24MH081810 / MH / NIMH NIH HHS / United States R01MH061009 / MH / NIMH NIH HHS / United States U54HG003067 / HG / NHGRI NIH HHS / United States T32 HG002295 / HG / NHGRI NIH HHS / United States U54 HG003273 / HG / NHGRI NIH HHS / United States R01MH089175 / MH / NIMH NIH HHS / United States R01 MH057881 / MH / NIMH NIH HHS / United States HL-102924 / HL / NHLBI NIH HHS / United States HL-102926 / HL / NHLBI NIH HHS / United States R01 MH089025 / MH / NIMH NIH HHS / United States R01MH089004 / MH / NIMH NIH HHS / United States R01MH089208 / MH / NIMH NIH HHS / United States R01 MH089175 / MH / NIMH NIH HHS / United States U24 MH068457 / MH / NIMH NIH HHS / United States R01MH057881 / MH / NIMH NIH HHS / United States HL-102925 / HL / NHLBI NIH HHS / United States RC2 HL103010 / HL / NHLBI NIH HHS / United States HL-102923 / HL / NHLBI NIH HHS / United States R01MH089025 / MH / NIMH NIH HHS / United States R01MH089482 / MH / NIMH NIH HHS / United States R01 MH089482 / MH / NIMH NIH HHS / United States |