Patterns and rates of exonic de novo mutations in autism spectrum disorders

被引：1261

作者：

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

Kou, Yan ^{[4
,5
]}

Liu, Li ^{[6
]}

Ma'ayan, Avi ^{[4
]}

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

Sabo, Aniko ^{[7
]}

Lin, Chiao-Feng

Stevens, Christine ^{[3
]}

Wang, Li-San

Makarov, Vladimir ^{[5
,8
]}

Polak, Paz ^{[3
,9
,10
]}

Yoon, Seungtai ^{[5
,8
]}

Maguire, Jared ^{[3
]}

Crawford, Emily L. ^{[11
,12
]}

Campbell, Nicholas G. ^{[11
,12
]}

Geller, Evan T.

Valladares, Otto

Schafer, Chad ^{[6
]}

Liu, Han ^{[13
,14
]}

Zhao, Tuo ^{[13
,14
]}

Cai, Guiqing ^{[5
,8
]}

Lihm, Jayon ^{[5
,8
]}

Dannenfelser, Ruth ^{[4
]}

Jabado, Omar ^{[15
]}

Peralta, Zuleyma ^{[15
]}

Nagaswamy, Uma ^{[7
]}

Muzny, Donna ^{[7
]}

Reid, Jeffrey G. ^{[7
]}

Newsham, Irene ^{[7
]}

Wu, Yuanqing ^{[7
]}

Lewis, Lora ^{[7
]}

Han, Yi ^{[7
]}

Voight, Benjamin F. ^{[3
,16
]}

Lim, Elaine ^{[1
,2
,3
]}

Rossin, Elizabeth ^{[1
,2
,3
]}

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

Flannick, Jason ^{[3
]}

Fromer, Menachem ^{[1
,2
,3
]}

Shakir, Khalid ^{[3
]}

Fennell, Tim ^{[3
]}

Garimella, Kiran ^{[3
]}

Banks, Eric ^{[3
]}

Poplin, Ryan ^{[3
]}

Gabriel, Stacey ^{[3
]}

DePristo, Mark ^{[3
]}

Wimbish, Jack R. ^{[17
]}

Boone, Braden E. ^{[17
]}

Levy, Shawn E. ^{[17
]}

Betancur, Catalina ^{[18
,19
,20
]}

Sunyaev, Shamil ^{[3
,9
,10
]}

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 02142 USA

[4] Mt Sinai Sch Med, Dept Pharmacol & Syst Therapeut, New York, NY 10029 USA

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

[6] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15232 USA

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

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

[9] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[10] Harvard Univ, Sch Med, Boston, MA 02115 USA

[11] Vanderbilt Univ, Vanderbilt Brain Inst, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[12] Vanderbilt Univ, Vanderbilt Brain Inst, Dept Psychiat, Nashville, TN 37232 USA

[13] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA

[14] Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21205 USA

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

[16] Univ Penn, Perelman Sch Med, Dept Pharmacol, Philadelphia, PA 19104 USA

[17] HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USA

[18] INSERM, U952, F-75005 Paris, France

[19] CNRS, UMR 7224, F-75005 Paris, France

[20] Univ Paris 06, F-75005 Paris, France

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

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

[23] Univ Illinois, Dept Psychiat, Chicago, IL 60608 USA

[24] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA

来源：

NATURE | 2012年 / 485卷 / 7397期

基金：

美国国家科学基金会;

关键词：

DNA-SEQUENCING DATA; ASSOCIATION; FRAMEWORK; DISEASE;

D O I：

10.1038/nature11011

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified(1,2). To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivityamong themselves and to previous ASD genes(3) as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

引用

页码：242 / U129

页数：5

共 18 条

[1] A method and server for predicting damaging missense mutations [J].