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Nat Genet DOI:10.1038/ng.3050

A framework for the interpretation of de novo mutation in human disease.

Publication TypeJournal Article
Year of Publication2014
AuthorsSamocha, 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
JournalNat Genet
Volume46
Issue9
Pages944-50
Date Published2014 Sep
ISSN1546-1718
KeywordsChild 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.

URLhttp://dx.doi.org/10.1038/ng.3050
DOI10.1038/ng.3050
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25086666?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID25086666
PubMed Central IDPMC4222185
Grant ListU24 MH081810 / MH / NIMH NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102926 / HL / NHLBI NIH HHS / United States
R01 MH089208 / MH / NIMH NIH HHS / United States
UC2 HL103010 / HL / NHLBI NIH HHS / United States
HL-103010 / HL / NHLBI NIH HHS / United States
R37 MH057881 / MH / NIMH NIH HHS / United States
U54 HG003067 / HG / NHGRI 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
RC2 HL102926 / HL / NHLBI 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
RC2 HL102924 / HL / NHLBI NIH HHS / United States
P50 HD055751 / HD / NICHD 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
UC2 HL102923 / HL / NHLBI NIH HHS / United States
UC2 HL102924 / HL / NHLBI 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
RC2 HL102925 / HL / NHLBI NIH HHS / United States
UC2 HL102925 / HL / NHLBI NIH HHS / United States
R01 MH089482 / MH / NIMH NIH HHS / United States