Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Authors: Wang Tianyun , Hoekzema Kendra , Vecchio Davide , Wu Huidan , Sulovari Arvis , Coe Bradley P. , Gillentine Madelyn A. , Wilfert Amy B. , Perez-Jurado Luis A. , Kvarnung Malin , Sleyp Yoeri , Earl Rachel K. , Rosenfeld Jill A. , Geisheker Madeleine R. , Han Lin , Du Bing , Barnett Chris , Thompson Elizabeth , Shaw Marie , Carroll Renee , Friend Kathryn , Catford Rachael , Palmer Elizabeth E. , Zou Xiaobing , Ou Jianjun , Li Honghui , Guo Hui , Gerdts Jennifer , Avola Emanuela , Calabrese Giuseppe , Elia Maurizio , Greco Donatella , Lindstrand Anna , Nordgren Ann , Anderlid Britt-Marie , Vandeweyer Geert , Van Dijck Anke , Van der Aa Nathalie , McKenna Brooke , Hancarova Miroslava , Bendova Sarka , Havlovicova Marketa , Malerba Giovanni , Bernardina Bernardo Dalla , Muglia Pierandrea , van Haeringen Arie , Hoffer Mariette J. V. , Franke Barbara , Cappuccio Gerarda , Delatycki Martin , Lockhart Paul J. , Manning Melanie A. , Liu Pengfei , Scheffer Ingrid E. , Brunetti-Pierri Nicola , Rommelse Nanda , Amaral David G. , Santen Gijs W. E. , Trabetti Elisabetta , Sedláček Zdeněk , Michaelson Jacob J. , Pierce Karen , Courchesne Eric , Kooy R. Frank ,   The SPARK Consortium, Acampado John , Ace Andrea J. , Amatya Alpha , Astrovskaya Irina , Bashar Asif , Brooks Elizabeth , Butler Martin E. , Cartner Lindsey A. , Chin Wubin , Chung Wendy K. , Daniels Amy M. , Feliciano Pamela , Fleisch Chris , Ganesan Swami , Jensen William , Lash Alex E. , Marini Richard , Myers Vincent J. , O’Connor Eirene , Rigby Chris , Robertson Beverly E. , Shah Neelay , Shah Swapnil , Singer Emily , Snyder LeeAnne G. , Stephens Alexandra N. , Tjernagel Jennifer , Vernoia Brianna M. , Volfovsky Natalia , White Loran Casey , Hsieh Alexander , Shen Yufeng , Zhou Xueya , Turner Tychele N. , Bahl Ethan , Thomas Taylor R. , Brueggeman Leo , Koomar Tanner , Michaelson Jacob J. , O’Roak Brian J. , Barnard Rebecca A. , Gibbs Richard A. , Muzny Donna , Sabo Aniko , Ahmed Kelli L. Baalman , Eichler Evan E. , Siegel Matthew , Abbeduto Leonard , Amaral David G. , Hilscher Brittani A. , Li Deana , Smith Kaitlin , Thompson Samantha , Albright Charles , Butter Eric M. , Eldred Sara , Hanna Nathan , Jones Mark , Coury Daniel Lee , Scherr Jessica , Pifher Taylor , Roby Erin , Dennis Brandy , Higgins Lorrin , Brown Melissa , Alessandri Michael , Gutierrez Anibal , Hale Melissa N. , Herbert Lynette M. , Schneider Hoa Lam , David Giancarla , Annett Robert D. , Sarver Dustin E. , Arriaga Ivette , Camba Alexies , Gulsrud Amanda C. , Haley Monica , McCracken James T. , Sandhu Sophia , Tafolla Maira , Yang Wha S. , Carpenter Laura A. , Bradley Catherine C. , Gwynette Frampton , Manning Patricia , Shaffer Rebecca , Thomas Carrie , Bernier Raphael A. , Fox Emily A. , Gerdts Jennifer A. , Pepper Micah , Ho Theodore , Cho Daniel , Piven Joseph , Lechniak Holly , Soorya Latha V. , Gordon Rachel , Wainer Allison , Yeh Lisa , Ochoa-Lubinoff Cesar , Russo Nicole , Berry-Kravis Elizabeth , Booker Stephanie , Erickson Craig A. , Prock Lisa M. , Pawlowski Katherine G. , Matthews Emily T. , Brewster Stephanie J. , Hojlo Margaret A. , Abada Evi , Lamarche Elena , Wang Tianyun , Murali Shwetha C. , Harvey William T. , Kaplan Hannah E. , Pierce Karen L. , DeMarco Lindsey , Horner Susannah , Pandey Juhi , Plate Samantha , Sahin Mustafa , Riley Katherine D. , Carmody Erin , Constantini Julia , Esler Amy , Fatemi Ali , Hutter Hanna , Landa Rebecca J. , McKenzie Alexander P. , Neely Jason , Singh Vini , Van Metre Bonnie , Wodka Ericka L. , Fombonne Eric J. , Huang-Storms Lark Y. , Pacheco Lillian D. , Mastel Sarah A. , Coppola Leigh A. , Francis Sunday , Jarrett Andrea , Jacob Suma , Lillie Natasha , Gunderson Jaclyn , Istephanous Dalia , Simon Laura , Wasserberg Ori , Rachubinski Angela L. , Rosenberg Cordelia R. , Kanne Stephen M. , Shocklee Amanda D. , Takahashi Nicole , Bridwell Shelby L. , Klimczac Rebecca L. , Mahurin Melissa A. , Cotrell Hannah E. , Grant Cortaiga A. , Hunter Samantha G. , Martin Christa Lese , Taylor Cora M. , Walsh Lauren K. , Dent Katherine A. , Mason Andrew , Sziklay Anthony , Smith Christopher J. , Nordenskjöld Magnus , Romano Corrado , Peeters Hilde , Bernier Raphael A. , Gecz Jozef , Xia Kun , Eichler Evan E. 
Published: October 2020

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E−07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.