Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders

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. NickersonHeather C. Mefford, Dan Doherty, Joshua M. Akey, Raphael Bernier, Evan E. Eichler, Jay Shendure

Research output: Contribution to journalArticlepeer-review

970 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1619-1622
Number of pages4
Issue number6114
StatePublished - Dec 21 2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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