Klaus Schmitz-Abe, Nahit Motavalli Mukaddes, Ahmad S. Teebi, Ganesh H. Mochida, Stephen Sanders, R. Sean Hill, Maria H. Chahrour, Bulent Ataman, Annapurna Poduri, Athar N. Malik, Hisaaki Taniguchi, Sarn Jiralerspong, Samira Al-Saad, Mazhar Adli, Muna Al-Saffar, Lihadh Al-Gazali, Timothy W. Yu, Stacey Gabriel, Laila Bastaki, Soher Balkhy, Janice Ware, Robert M. Joseph, Alissa M. D'Gama, Fuki M. Hisama, Ramzi Nasir, David A. Harmin, Matthew W. State, Jillian M. Felie, Nancy Braverman, Ozgur Oner, S. A. Al-Awadi, Christine Stevens, Valsamma Eapen, Jacqueline Rodriguez, Michael E. Greenberg, Generoso G. Gascon, Benjamin Y. Kwan, Jennifer N. Partlow, Kazuko Okamura-Ikeda, Michael E. Coulter, Christopher A. Walsh, Leonard Rappaport, Elaine T. Lim, Christine M. Sunu, Asif Hashmi, Kyriacos Markianos, Eric M. Morrow, Tawfeg Ben-Omran, and Elaine LeClair
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, POMGNT1), some implicated for the first time in ASD. 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.