Article

Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
Science (Impact Factor: 31.48). 11/2012; 338(6114). DOI: 10.1126/science.1227764
Source: PubMed

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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