Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes
Authors: Zhou Xueya , Feliciano Pamela , Shu Chang , Wang Tianyun , Astrovskaya Irina , Hall Jacob B. , Obiajulu Joseph U. , Wright Jessica R. , Murali Shwetha C. , Xu Simon Xuming , Brueggeman Leo , Thomas Taylor R. , Marchenko Olena , Fleisch Christopher , Barns Sarah D. , Snyder LeeAnne Green , Han Bing , Chang Timothy S. , Turner Tychele N. , Harvey William T. , Nishida Andrew , O’Roak Brian J. , Geschwind Daniel H. ,   The SPARK Consortium, Adams Adrienne , Amatya Alpha , Andrus Alicia , Bashar Asif , Berman Anna , Brown Alison , Camba Alexies , Gulsrud Amanda C. , Krentz Anthony D. , Shocklee Amanda D. , Esler Amy , Lash Alex E. , Fanta Anne , Fatemi Ali , Fish Angela , Goler Alexandra , Gonzalez Antonio , Gutierrez Anibal , Hardan Antonio , Hess Amy , Hirshman Anna , Holbrook Alison , Ace Andrea J. , Griswold Anthony J. , Gruber Angela J. , Jarratt Andrea , Jelinek Anna , Jorgenson Alissa , Juarez A. Pablo , Kim Annes , Kitaygorodsky Alex , Luo Addie , Rachubinski Angela L. , Wainer Allison L. , Daniels Amy M. , Mankar Anup , Mason Andrew , Miceli Alexandra , Milliken Anna , Morales-Lara Amy , Stephens Alexandra N. , Nguyen Ai Nhu , Nicholson Amy , Paolicelli Anna Marie , McKenzie Alexander P. , Gupta Abha R. , Raven Ashley , Rhea Anna , Simon Andrea , Soucy Aubrie , Swanson Amy , Sziklay Anthony , Tallbull Amber , Tesng Angela , Ward Audrey , Zick Allyson , Hilscher Brittani A. , Bell Brandi , Enright Barbara , Robertson Beverly E. , Hauf Brenda , Jensen Bill , Lobisi Brandon , Vernoia Brianna M. , Schwind Brady , VanMetre Bonnie , Erickson Craig A. , Sullivan Catherine A. W. , Albright Charles , Anglo Claudine , Buescher Cate , Bradley Catherine C. , Campo-Soria Claudia , Cohen Cheryl , Colombi Costanza , Diggins Chris , Edmonson Catherine , Rice Catherine E. , Fassler Carrie , Gray Catherine , Gunter Chris , Walston Corrie H. , Klaiman Cheryl , Leonczyk Caroline , Martin Christa Lese , Lord Catherine , Taylor Cora M. , McCarthy Caitlin , Ochoa-Lubinoff Cesar , Ortiz Crissy , Pierre Cynthia , Rosenberg Cordelia R. , Rigby Chris , Roche Casey , Shrier Clara , Smith Chris , Van Wade Candace , White-Lehman Casey , Zaro Christopher , Zha Cindy , Bentley Dawn , Correa Dahriana , Sarver Dustin E. , Giancarla David , Amaral David G. , Howes Dain , Istephanous Dalia , Coury Daniel Lee , Li Deana , Limon Danica , Limpoco Desi , Phillips Diamond , Rambeck Desiree , Rojas Daniela , Srishyla Diksha , Stamps Danielle , Montes Dennis Vasquez , Cho Daniel , Cho Dave , Fox Emily A. , Bahl Ethan , Berry-Kravis Elizabeth , Blank Elizabeth , Bower Erin , Brooks Elizabeth , Courchesne Eric , Dillon Emily , Doyle Erin , Given Erin , Grimes Ellen , Jones Erica , Fombonne Eric J. , Kryszak Elizabeth , Wodka Ericka L. , Lamarche Elena , Lampert Erica , Butter Eric M. , O’Connor Eirene , Ocampo Edith , Orrick Elizabeth , Perez Esmeralda , Ruzzo Elizabeth , Singer Emily , Matthews Emily T. , Pedapati Ernest V. , Fazal Faris , Miller Fiona K. , Aberbach Gabriella , Baraghoshi Gabriele , Duhon Gabrielle , Hooks Gregory , Fischer Gregory J. , Marzano Gabriela , Schoonover Gregory , Dichter Gabriel S. , Tiede Gabrielle , Cottrell Hannah , Kaplan Hannah E. , Ghina Haidar , Hutter Hanna , Koene Hope , Schneider Hoa Lam , Lechniak Holly , Li Hai , Morotti Hadley , Qi Hongjian , Richardson Harper , Zaydens Hana , Zhang Haicang , Zhao Haoquan , Arriaga Ivette , Tso Ivy F. , Acampado John , Gerdts Jennifer A. , Beeson Josh , Brown Jennylyn , Comitre Joaquin , Cordova Jeanette , Delaporte Jennifer , Cubells Joseph F. , Harris Jill F. , Gong Jared , Gunderson Jaclyn , Hernandez Jessica , Judge Jessyca , Jurayj Jane , Law J. Kiely , Manoharan Julie , Montezuma Jessie , Neely Jason , Orobio Jessica , Pandey Juhi , Piven Joseph , Polanco Jose , Polite Jibrielle , Rosewater Jacob , Scherr Jessica , Sutcliffe James S. , McCracken James T. , Tjernagel Jennifer , Toroney Jaimie , Veenstra-Vanderweele Jeremy , Wang Jiayao , Ahlers Katie , Schweers Kathryn A. , Baalman Kelli , Beard Katie , Callahan Kristen , Coleman Kendra , Fitzgerald Kate D. , Dent Kate , Diehl Katharine , Gonring Kelsey , Pawlowski Katherine G. , Hirst Kathy , Pierce Karen L. , Murillo Karla , Murray Kailey , Nowell Kerri , O’Brien Kaela , Pama Katrina , Real Kelli , Singer Kaitlyn , Smith Kaitlin , Stephenson Kevin , Tsai Katherine , Abbeduto Leonard , Cartner Lindsey A. , Beeson Landon , Carpenter Laura , Casten Lucas , Coppola Leigh , Cordiero Lisa , DeMarco Lindsey , Pacheco Lillian D. , Corzo Lorena Ferreira , Shulman Lisa H. , Walsh Lauren Kasperson , Lesher Laurie , Herbert Lynette M. , Prock Lisa M. , Malloch Lacy , Mann Lori , Grosvenor Luke P. , Simon Laura , Soorya Latha V. , Wasserburg Lucy , Yeh Lisa , Huang-Storms Lark Y. , Alessandri Michael , Popp Marc A. , Baer Melissa , Beckwith Malia , Casseus Myriam , Coughlin Michelle , Currin Mary , Cutri Michele , Mallardi Malcolm D. , DuBois Megan , Dunlevy Megan , Butler Martin E. , Frayne Margot , Gwynette McLeod F. , Ghaziuddin Mohammad , Haley Monica , Heyman Michelle , Hojlo Margaret , Jordy Michelle , Morrier Michael J. , Kowanda Misia , Koza Melinda , Lopez Marilyn , McTaggart Megan , Norris Megan , Hale Melissa N. , O’Neil Molly , Printen Madison , Rayos Madelyn , Sabiha Mahfuza , Sahin Mustafa , Sarris Marina , Shir Mojeeb , Siegel Matthew , Steele Morgan , Sweeney Megan , Tafolla Maira , Valicenti-McDermott Maria , Verdi Mary , Dennis Megan Y. , Alvarez Nicolas , Bardett Nicole , Berger Natalie , Calderon Norma , Decius Nickelle , Gonzalez Natalia , Harris Nina , Lawson Noah , Lillie Natasha , Lo Nathan , Long Nancy , Russo-Ponsaran Nicole M. , Madi Natalie , Mccoy Nicole , Nagpal Natalie , Rodriguez Nicki , Russell Nicholas , Shah Neelay , Takahashi Nicole , Targalia Nicole , Newman Olivia , Ousley Opal Y. , Heydemann Peter , Manning Patricia , Carbone Paul S. , Bernier Raphael A. , Gordon Rachel A. , Shaffer Rebecca C. , Annett Robert D. , Clark Renee D. , Jou Roger , Landa Rebecca J. , Earl Rachel K. , Libove Robin , Marini Richard , Doan Ryan N. , Goin-Kochel Robin P. , Rana Rishiraj , Remington Richard , Shikov Roman , Schultz Robert T. , Aberle Shelley , Birdwell Shelby , Boland Sarah , Booker Stephanie , Carpenter S. , Chintalapalli Sharmista , Conyers Sarah , D’Ambrosi Sophia , Eldred Sara , Francis Sunday , Ganesan Swami , Hepburn Susan , Horner Susannah , Hunter Samantha , Brewster Stephanie J. , Lee Soo J. , Jacob Suma , Jean Stanley , Hyun So , Kramer Sydney , Friedman Sandra L. , Licona Sarely , Littlefield Sandy , Kanne Stephen M. , Mastel Sarah , Mathai Sheena , Melnyk Sophia , Michaels Sarah , Mohiuddin Sarah , Palmer Samiza , Plate Samantha , Qiu Shanping , Randall Shelley , Sandhu Sophia , Santangelo Susan , Shah Swapnil , Skinner Steve , Thompson Samantha , White Sabrina , White Stormi , Xiao Sabrina , Xu Sidi , Xu Simon , Chen Tia , Greene Tunisia , Ho Theodore , Ibanez Teresa , Koomar Tanner , Pramparo Tiziano , Rutter Tara , Shaikh Tamim , Tran Thao , Yu Timothy W. , Galbraith Virginia , Gazestani Vahid , Myers Vincent J. , Ranganathan Vaikunt , Singh Vini , Weaver William Curtis , CaI Wenteng , Chin Wubin , Yang Wha S. , Choi Y. B. , Warren Zachary E. , Michaelson Jacob J. , Volfovsky Natalia , Eichler Evan E. , Shen Yufeng , Chung Wendy K. 
Published: August 2022

To capture the full spectrum of genetic risk for autism, we performed a two-stage analysis of rare de novo and inherited coding variants in 42,607 autism cases, including 35,130 new cases recruited online by SPARK. We identified 60 genes with exome-wide significance (P < 2.5 × 10−6), including five new risk genes (NAV3,ITSN1,MARK2,SCAF1andHNRNPUL2). The association ofNAV3with autism risk is primarily driven by rare inherited loss-of-function (LoF) variants, with an estimated relative risk of 4, consistent with moderate effect. Autistic individuals with LoF variants in the four moderate-risk genes (NAV3,ITSN1,SCAF1andHNRNPUL2;n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes (CHD8, SCN2A, ADNP, FOXP1andSHANK3) (59% vs 88%,P = 1.9 × 10−6). Power calculations suggest that much larger numbers of autism cases are needed to identify additional moderate-risk genes.