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Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

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21 Dec 2012: Vol. 338, Issue 6114, pp. 1619-1622 DOI: 10.1126/science.1227764
Brian J. O’Roak
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Laura Vives
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Wenqing Fu
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Jarrett D. Egertson
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Ian B. Stanaway
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Ian G. Phelps
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Seattle Children’s Hospital, Seattle, WA 98105, USA.
Gemma Carvill
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Seattle Children’s Hospital, Seattle, WA 98105, USA.
Akash Kumar
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Choli Lee
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Katy Ankenman
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Jeff Munson
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Joseph B. Hiatt
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Emily H. Turner
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Roie Levy
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Diana R. O’Day
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Niklas Krumm
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Bradley P. Coe
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Beth K. Martin
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Elhanan Borenstein
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. Department of Computer Science and Engineering, University of Washington, Seattle, WA 98195, USA. Santa Fe Institute, Santa Fe, NM 87501, USA.
Deborah A. Nickerson
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Heather C. Mefford
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Seattle Children’s Hospital, Seattle, WA 98105, USA.
Dan Doherty
Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98195, USA. Seattle Children’s Hospital, Seattle, WA 98105, USA.
Joshua M. Akey
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Raphael Bernier
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
Evan E. Eichler
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA. Howard Hughes Medical Institute, Seattle, WA 98195, USA.
Jay Shendure
Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.

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Abstract

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—, , , , , and —may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (-macrocephaly and -microcephaly) and replicate the importance of a β-catenin–chromatin-remodeling network to ASD etiology.

Science

Vol 338, Issue 611421 December 2012

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Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

By Brian J. O’Roak , Laura Vives , Wenqing Fu , Jarrett D. Egertson , Ian B. Stanaway , Ian G. Phelps , Gemma Carvill , Akash Kumar , Choli Lee , Katy Ankenman , Jeff Munson , Joseph B. Hiatt , Emily H. Turner , Roie Levy , Diana R. O’Day , Niklas Krumm , Bradley P. Coe , Beth K. Martin , Elhanan Borenstein , Deborah A. Nickerson , Heather C. Mefford , Dan Doherty , Joshua M. Akey , Raphael Bernier , Evan E. Eichler , Jay Shendure

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Translations of “concurrence”

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