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

被引：685

作者：

Samocha, Kaitlin E. ^{[1
,2
,3
,4
,5
]}

Robinson, Elise B. ^{[1
,2
,3
,4
]}

Sanders, Stephan J. ^{[6
,7
]}

Stevens, Christine ^{[3
,4
]}

Sabo, Aniko ^{[8
]}

McGrath, Lauren M. ^{[9
,10
]}

Kosmicki, Jack A. ^{[1
,2
,11
,12
]}

Rehnstrom, Karola ^{[13
,14
]}

Mallick, Swapan ^{[15
]}

Kirby, Andrew ^{[1
,2
,3
]}

Wall, Dennis P. ^{[11
,12
]}

MacArthur, Daniel G. ^{[1
,2
,3
]}

Gabriel, Stacey B. ^{[3
]}

DePristo, Mark ^{[16
]}

Purcell, Shaun M. ^{[1
,2
,3
,9
,10
,17
,18
,19
]}

Palotie, Aarno ^{[9
,10
,13
,14
]}

Boerwinkle, Eric ^{[8
,20
]}

Buxbaum, Joseph D. ^{[17
,18
,19
,21
,22
,23
]}

Cook, Edwin H., Jr. ^{[24
]}

Gibbs, Richard A. ^{[8
]}

Schellenberg, Gerard D. ^{[25
]}

Sutcliffe, James S. ^{[26
]}

Devlin, Bernie ^{[27
]}

Roeder, Kathryn ^{[28
,29
]}

Neale, Benjamin M. ^{[1
,2
,3
,4
]}

Daly, Mark J. ^{[1
,2
,3
,4
]}

机构：

[1] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Boston, MA 02114 USA

[3] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA

[4] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA USA

[5] Harvard Univ, Sch Med, Program Genet & Gen Biol & Biomed Sci, Boston, MA USA

[6] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA

[7] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA

[8] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[9] Massachusetts Gen Hosp, Dept Psychiat, Psychiatr & Neurodev Genet Unit, Boston, MA 02114 USA

[10] Harvard Univ, Sch Med, Boston, MA USA

[11] Harvard Univ, Sch Med, Ctr Biomed Informat, Boston, MA USA

[12] Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA

[13] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[14] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England

[15] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA

[16] Synapdx, Lexington, MA USA

[17] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA

[18] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY 10029 USA

[19] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[20] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[21] Icahn Sch Med Mt Sinai, Seaver Autism Ctr Res & Treatment, New York, NY 10029 USA

[22] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA

[23] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA

[24] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA

[25] Univ Penn, Perelman Sch Med, Pathol & Lab Med, Philadelphia, PA USA

[26] Vanderbilt Univ, Ctr Mol Neurosci, Nashville, TN 37235 USA

[27] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA USA

[28] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA

[29] Carnegie Mellon Univ, Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 09期

基金：

美国国家卫生研究院;

关键词：

AUTISM SPECTRUM DISORDERS; DNA-SEQUENCING DATA; INTELLECTUAL DISABILITY; GENOME; PATTERNS; GENES; RATES;

D O I：

10.1038/ng.3050

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 similar to 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.

引用

页码：944 / +

页数：8

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