Exome sequencing of 457 autism families recruited online provides evidence for novel ASD genes
Authors: Feliciano Pamela , Zhou Xueya , Astrovskaya Irina , Turner Tychele N. , Wang Tianyun , Brueggeman Leo , Barnard Rebecca , Hsieh Alexander , Snyder LeeAnne Green , Muzny Donna M. , Sabo Aniko ,   The SPARK Consortium, Gibbs Richard A. , Eichler Evan E. , O’Roak Brian J. , Michaelson Jacob J. , Volfovsky Natalia , Shen Yufeng , Chung Wendy K. , Abbeduto Leonard , Acampado John , Ace Andrea J. , Albright Charles , Alessandri Michael , Amaral David G. , Amatya Alpha , Annett Robert D. , Arriaga Ivette , Astrovskaya Irina , Bahl Ethan , Balasubramanian Adithya , Bardett Nicole , Barnard Rebecca A. , Bashar Asif , Beaudet Arthur , Beeson Landon , Bernier Raphael A. , Berry-Kravis Elizabeth , Booker Stephanie , Brewster Stephanie J. , Brooks Elizabeth , Brueggeman Leo , Butler Martin E. , Butter Eric M. , Callahan Kristen , Camba Alexies , Carpenter Sarah , Carriero Nicholas , Cartner Lindsey A. , Chatha Ahmad S. , Chin Wubin , Chung Wendy K. , Clark Renee D. , Cohen Cheryl , Courchesne Eric , Cubells Joseph F. , Currin Mary Hannah , Daniels Amy M. , DeMarco Lindsey , Dennis Megan Y. , Dichter Gabriel S. , Ding Yan , Dinh Huyen , Doan Ryan , Doddapaneni HarshaVardhan , Eichler Evan E. , Eldred Sara , Eng Christine , Erickson Craig A. , Esler Amy , Fatemi Ali , Feliciano Pamela , Fischer Gregory , Fisk Ian , Fombonne Eric J. , Fox Emily A. , Francis Sunday , Friedman Sandra L. , Ganesan Swami , Garrett Michael , Gazestani Vahid , Geisheker Madeleine R. , Gerdts Jennifer A. , Geschwind Daniel H. , Gibbs Richard A. , Goin-Kochel Robin P. , J.Griswold Anthony , Grosvenor Luke P. , Gruber Angela J. , Gulsrud Amanda C. , Gunderson Jaclyn , Gutierrez Anibal , Hale Melissa N. , Haley Monica , Hall Jacob B. , Hamer Kira E. , Han Bing , Hanna Nathan , Harkins Christina , Harris Nina , Hauf Brenda , Hayes Caitlin , Hepburn Susan L. , Herbert Lynette M. , Heyman Michelle , Hilscher Brittani A. , Horner Susannah , Hsieh Alexander , Hu Jianhong , Huang-Storms Lark Y. , Hutter Hanna , Istephanous Dalia , Jacob Suma , Jensen William , Jones Mark , Jordy Michelle , Juarez A. Pablo , Kanne Stephen , Kaplan Hannah E. , Kent Matt , Kitaygorodsky Alex , Koomar Tanner , Korchina Viktoriya , Krentz Anthony D. , Schneider Hoa Lam , Lamarche Elena , Landa Rebecca J. , Lash Alex E. , Law J. Kiely , Lawson Noah , Layman Kevin , Lechniak Holly , Lee Sandra , Lee Soo J. , Coury Daniel Lee , Martin Christa Lese , Li Hai , Li Deana , Lillie Natasha , Liu Xiuping , Lord Catherine , Mallardi Malcolm D. , Manning Patricia , Manoharan Julie , Marini Richard , Marzano Gabriela , Mason Andrew , Matthews Emily T. , McCracken James T. , McKenzie Alexander P. , Michaelson Jacob J. , Momin Zeineen , Morrier Michael J. , Murali Shwetha , Muzny Donna , Myers Vincent J. , Neely Jason , Nessner Caitlin , Nicholson Amy , O’Brien Kaela , O’Connor Eirene , O’Roak Brian J. , Ochoa-Lubinoff Cesar , Orobio Jessica , Ousley Opal Y. , Pacheco Lillian D. , Pandey Juhi , Paolicelli Anna Marie , Pawlowski Katherine G. , Pierce Karen L. , Piven Joseph , Plate Samantha , Popp Marc , Pramparo Tiziano , Prock Lisa M. , Qi Hongjian , Qiu Shanping , Rachubinski Angela L. , Rajbhandari Kshitij , Rana Rishiraj , Remington Rick , Rice Catherine E. , Rigby Chris , Robertson Beverly E. , Roeder Katherine , Rosenberg Cordelia R. , Russo-Ponsaran Nicole , Ruzzo Elizabeth , Sabo Aniko , Sahin Mustafa , Salomatov Andrei , Sandhu Sophia , Santangelo Susan , Sarver Dustin E. , Scherr Jessica , Schultz Robert T. , Schweers Kathryn A. , Shah Swapnil , Shaikh Tamim , Shen Yufeng , Shocklee Amanda D. , Simon Andrea R. , Simon Laura , Singh Vini , Skinner Steve , Smith Christopher J. , Smith Kaitlin , Snyder LeeAnne G. , Soorya Latha V. , Soucy Aubrie , Stephens Alexandra N. , Stock Colleen M. , Sutcliffe James S. , Sutcliffe James S. , Swanson Amy , Tafolla Maira , Takahashi Nicole , Thomas Carrie , Thomas Taylor , Thompson Samantha , Tjernagel Jennifer , Turner Tychele N. , Metre Bonnie Van , Veenstra-Vanderweele Jeremy , Vernoia Brianna M. , Volfovsky Natalia , Wallace Jermel , Walston Corrie H. , Wang Jiayao , Wang Tianyun , Warren Zachary , Wasserburg Lucy , White Loran Casey , White Sabrina , Wodka Ericka L. , Xu Simon , Yang Wha S. , Yinger Meredith , Yu Timothy , Zang Lan , Zaydens Hana , Zhang Haicang , Zhao Haoquan , Zhou Xueya 
Published: January 2019

Autism spectrum disorder (ASD) is a genetically heterogeneous condition, caused by a combination of rare de novo and inherited variants as well as common variants in at least several hundred genes. However, significantly larger sample sizes are needed to identify the complete set of genetic risk factors. We conducted a pilot study for SPARK (SPARKForAutism.org) of 457 families with ASD, all consented online. Whole exome sequencing (WES) and genotyping data were generated for each family using DNA from saliva. We identified variants in genes and loci that are clinically recognized causes or significant contributors to ASD in 10.4% of families without previous genetic findings. Additionally, we identified variants that are possibly associated with autism in an additional 3.4% of families. A meta-analysis using the TADA framework at a false discovery rate (FDR) of 0.2 provides statistical support for 34 ASD risk genes with at least one damaging variant identified in SPARK. Nine of these genes (BRSK2, DPP6, EGR3, FEZF2, ITSN1, KDM1B, NR4A2, PAX5 and RALGAPB) are newly emerging genes in autism, of which BRSK2 has the strongest statistical support as a risk gene for autism (TADA q-value = 0.0015). Future studies leveraging the thousands of individuals with ASD that have enrolled in SPARK are likely to further clarify the genetic risk factors associated with ASD as well as allow accelerate autism research that incorporates genetic etiology.