Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.


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.

DOI: 10.1126/science.1227764

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@article{ORoak2012MultiplexTS, title={Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.}, author={Brian J. O'Roak and Laura Vives and Wenqing Fu and Jarrett D. Egertson and Ian Byrell Stanaway and Ian G. Phelps and G. Carvill and Akash Kumar and Choli Lee and Katy Ankenman and Jeff Munson and Joseph B. Hiatt and Emily H Turner and Roie Levy and Diana R O'Day and Niklas Krumm and Bradley P. Coe and Beth K. Martin and Elhanan Borenstein and Deborah A. Nickerson and Heather C. Mefford and Daniel A Doherty and Joshua M. Akey and Raphael A. Bernier and Evan E. Eichler and Jay Shendure}, journal={Science}, year={2012}, volume={338 6114}, pages={1619-22} }