Using Whole-Exome Sequencing to Identify Inherited Causes of Autism

• DOI: 10.1016/j.neuron.2012.11.002
• Publication Date: 2013-01-23T16:48:48Z
• Authors: Timothy W. Yu; Maria H. Chahrour; Michael E. Coulter; Sarn Jiralerspong; Kazuko Okamura-Ikeda; Bulent Ataman; Klaus Schmitz-Abe; David A. Harmin; Mazhar Adli; Athar N. Malik; Alissa M. D’Gama; Elaine T. Lim; Stephan J. Sanders; Ganesh H. Mochida; Jennifer N. Partlow; Christine M. Sunu; Jillian M. Felie; Jacqueline Rodriguez; Ramzi H. Nasir; Janice Ware; Robert M. Joseph; R. Sean Hill; Benjamin Y. Kwan; Muna Al-Saffar; Nahit M. Mukaddes; Asif Hashmi; Soher Balkhy; Generoso G. Gascon; Fuki M. Hisama; Elaine LeClair; Annapurna Poduri; Ozgur Oner; Samira Al-Saad; Sadika A. Al-Awadi; Laila Bastaki; Tawfeg Ben-Omran; Ahmad S. Teebi; Lihadh Al-Gazali; Valsamma Eapen; Christine R. Stevens; Leonard Rappaport; Stacey B. Gabriel; Kyriacos Markianos; Matthew W. State; Michael E. Greenberg; Hisaaki Taniguchi; Nancy E. Braverman; Eric M. Morrow; Christopher A. Walsh
• Keywords: Mendelian inheritance; Exome; Allelic heterogeneity; Missing heritability problem

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.