Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

被引：948

作者：

O'Roak, Brian J. ^{[1
]}

Vives, Laura ^{[1
]}

Fu, Wenqing ^{[1
]}

Egertson, Jarrett D. ^{[1
]}

Stanaway, Ian B. ^{[1
]}

Phelps, Ian G. ^{[2
,3
]}

Carvill, Gemma ^{[2
,3
]}

Kumar, Akash ^{[1
]}

Lee, Choli ^{[1
]}

Ankenman, Katy ^{[4
]}

Munson, Jeff ^{[4
]}

Hiatt, Joseph B. ^{[1
]}

Turner, Emily H. ^{[1
]}

Levy, Roie ^{[1
]}

O'Day, Diana R. ^{[2
]}

Krumm, Niklas ^{[1
]}

Coe, Bradley P. ^{[1
]}

Martin, Beth K. ^{[1
]}

Borenstein, Elhanan ^{[1
,5
,6
]}

Nickerson, Deborah A. ^{[1
]}

Mefford, Heather C. ^{[2
,3
]}

Doherty, Dan ^{[2
,3
]}

Akey, Joshua M. ^{[1
]}

Bernier, Raphael ^{[4
]}

Eichler, Evan E. ^{[1
,7
]}

Shendure, Jay ^{[1
]}

机构：

[1] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA

[2] Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA

[3] Seattle Childrens Hosp, Seattle, WA 98105 USA

[4] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[5] Univ Washington, Dept Comp Sci & Engn, Seattle, WA 98195 USA

[6] Santa Fe Inst, Santa Fe, NM 87501 USA

[7] Howard Hughes Med Inst, Seattle, WA 98195 USA

来源：

SCIENCE | 2012年 / 338卷 / 6114期

关键词：

DE-NOVO MUTATIONS; DYRK1A; AMPLIFICATION; RISK;

D O I：

10.1126/science.1227764

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：

Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a beta-catenin-chromatin-remodeling network to ASD etiology.

引用

页码：1619 / 1622

页数：4

共 21 条

[1] Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting [J].

Betancur, Catalina .

BRAIN RESEARCH, 2011, 1380 :42-77

[2] A copy number variation morbidity map of developmental delay [J].

Cooper, Gregory M. ;

Coe, Bradley P. ;

Girirajan, Santhosh ;

Rosenfeld, Jill A. ;

Vu, Tiffany H. ;

Baker, Carl ;

Williams, Charles ;

Stalker, Heather ;

Hamid, Rizwan ;

Hannig, Vickie ;

Abdel-Hamid, Hoda ;

Bader, Patricia ;

McCracken, Elizabeth ;

Niyazov, Dmitriy ;

Leppig, Kathleen ;

Thiese, Heidi ;

Hummel, Marybeth ;

Alexander, Nora ;

Gorski, Jerome ;

Kussmann, Jennifer ;

Shashi, Vandana ;

Johnson, Krys ;

Rehder, Catherine ;

Ballif, Blake C. ;

Shaffer, Lisa G. ;

Eichler, Evan E. .

NATURE GENETICS, 2011, 43 (09) :838-U44

[3] The Simons Simplex Collection: A Resource for Identification of Autism Genetic Risk Factors [J].

Fischbach, Gerald D. ;

Lord, Catherine .

NEURON, 2010, 68 (02) :192-195

[4] DYRK1A: A master regulatory protein controlling brain growth [J].

Guedj, Faycal ;

Pereira, Patricia Lopes ;

Najas, Sonia ;

Barallobre, Maria-Jose ;

Chabert, Caroline ;

Souchet, Benoit ;

Sebrie, Catherine ;

Verney, Catherine ;

Herault, Yann ;

Arbones, Mariona ;

Delabar, Jean M. .

NEUROBIOLOGY OF DISEASE, 2012, 46 (01) :190-203

[5] De Novo Gene Disruptions in Children on the Autistic Spectrum [J].

Iossifov, Ivan ;

Ronemus, Michael ;

Levy, Dan ;

Wang, Zihua ;

Hakker, Inessa ;

Rosenbaum, Julie ;

Yamrom, Boris ;

Lee, Yoon-ha ;

Narzisi, Giuseppe ;

Leotta, Anthony ;

Kendall, Jude ;

Grabowska, Ewa ;

Ma, Beicong ;

Marks, Steven ;

Rodgers, Linda ;

Stepansky, Asya ;

Troge, Jennifer ;

Andrews, Peter ;

Bekritsky, Mitchell ;

Pradhan, Kith ;

Ghiban, Elena ;

Kramer, Melissa ;

Parla, Jennifer ;

Demeter, Ryan ;

Fulton, Lucinda L. ;

Fulton, Robert S. ;

Magrini, Vincent J. ;

Ye, Kenny ;

Darnell, Jennifer C. ;

Darnell, Robert B. ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

Schatz, Michael C. ;

McCombie, W. Richard ;

Wigler, Michael .

NEURON, 2012, 74 (02) :285-299

[6] Rate of de novo mutations and the importance of father's age to disease risk [J].

Kong, Augustine ;

Frigge, Michael L. ;

Masson, Gisli ;

Besenbacher, Soren ;

Sulem, Patrick ;

Magnusson, Gisli ;

Gudjonsson, Sigurjon A. ;

Sigurdsson, Asgeir ;

Jonasdottir, Aslaug ;

Jonasdottir, Adalbjorg ;

Wong, Wendy S. W. ;

Sigurdsson, Gunnar ;

Walters, G. Bragi ;

Steinberg, Stacy ;

Helgason, Hannes ;

Thorleifsson, Gudmar ;

Gudbjartsson, Daniel F. ;

Helgason, Agnar ;

Magnusson, Olafur Th. ;

Thorsteinsdottir, Unnur ;

Stefansson, Kari .

NATURE, 2012, 488 (7412) :471-475

[7] A comprehensive assay for targeted multiplex amplification of human DNA sequences [J].

Krishnakumar, Sujatha ;

Zheng, Jianbiao ;

Wilhelmy, Julie ;

Faham, Malek ;

Mindrinos, Michael ;

Davis, Ronald .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (27) :9296-9301

[8] Power of deep, all-exon resequencing for discovery of human trait genes [J].

Kryukov, Gregory V. ;

Shpunt, Alexander ;

Stamatoyannopoulos, John A. ;

Sunyaev, Shamil R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2009, 106 (10) :3871-3876

[9] SMART 7: recent updates to the protein domain annotation resource [J].

Letunic, Ivica ;

Doerks, Tobias ;

Bork, Peer .

NUCLEIC ACIDS RESEARCH, 2012, 40 (D1) :D302-D305

[10] Rate, molecular spectrum, and consequences of human mutation [J].

Lynch, Michael .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (03) :961-968

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