Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders

作者：Brian J. O’Roak, Laura Vives, Wenqing Fu, Jarrett D. Egertson, Ian B. Stanaway, Ian G. Phelps, Gemma L. 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 Martin, Elhanan Borenstein, Deborah A. Nickerson, Heather C. Mefford, Dan Doherty, Joshua M. Akey, Raphael Bernier, Evan E. Eichler, Jay Shendure · 发表于：Science · 年份：2012 · DOI：10.1126/science.1227764 · 被引用次数：1303 · 研究领域：Genetics and Neurodevelopmental Disorders、Congenital heart defects research、Autism Spectrum Disorder Research

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.