Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

Overview

Journal Science

Specialty Science

Date 2012 Nov 20

PMID 23160955

Citations 692

Authors

Brian J ORoak

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 ODay

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

Affiliations

Soon will be listed here.

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-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 β-catenin-chromatin-remodeling network to ASD etiology.

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