Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes

Authors: Xueya Zhou, Pamela Feliciano, Chang Shu, Tianyun Wang, Irina Astrovskaya, Jacob B. Hall, Joseph Obiajulu, Jessica Wright, Shwetha C. Murali, Simon Xu, Leo Brueggeman, Taylor Thomas, Olena Marchenko, Christopher Fleisch, Sarah D. Barns, LeeAnne Green Snyder, Bing Han, Timothy S. Chang, Tychele N. Turner, William T. Harvey, Andrew Nishida, Brian J. O’Roak, Daniel H. Geschwind, Adrienne Adams, Alpha Amatya, Alicia Andrus, Asif Bashar, Anna Berman, Alison Brown, Alexies Camba, Amanda C. Gulsrud, Anthony D. Krentz, Amanda D. Shocklee, Amy Esler, Alex Lash, Anne Fanta, Ali Fatemi, Angela Fish, Alexandra Goler, Antonio González, Anibal Gutierrez, Antonio Y. Hardan, Amy Hess, Anna Hirshman, Alison Holbrook, Andrea J. Ace, Anthony J. Griswold, Angela Gruber, A Jarratt, Anna Jelinek, Alissa Jorgenson, Aline Juárez, Annes Kim, Alex Kitaygorodsky, Addie Luo, Angela L. Rachubinski, Allison Wainer, Amy M. Daniels, Anup Mankar, Andrew L. Mason, Alexandra Miceli, Anna Milliken, Amy Morales-Lara, Alexandra N. Stephens, Ai Nhu Nguyen, Amy Nicholson, Anna Marie Paolicelli, Alexander P. McKenzie, Abha R. Gupta, A Raven, Anna Rhea, Andrea Simon, Aubrie Soucy, Amy Swanson, Anthony Sziklay, Amber Tallbull, Angela Tesng, Audrey W. M. Ward, Allyson Zick, Brittani A. Hilscher, Brandi Bell, Barbara Enright, B. E. Robertson, Brenda Hauf, Bill Jensen, Brandon Lobisi, Brianna M. Vernoia, Brady Schwind, Bonnie VanMetre, Craig A. Erickson, Catherine Sullivan, Charles F. Albright, Claudine Anglo, Cate Buescher, Catherine C. Bradley, Claudia Campo-Soria, Cheryl Cohen, Costanza Colombi, Chris Diggins, Catherine Edmonson, Catherine E. Rice, Carrie Fassler, Catherine Gray, Chris Gunter, Corrie H. Walston, Cheryl Klaiman, Caroline Leonczyk, Christa Lese Martin, Catherine Lord, Cora Taylor, Caitlin McCarthy, Cesar Ochoa-Lubinoff, Crissy Ortiz, Cynthia L. Pierre, Cordelia Robinson Rosenberg, Chris Rigby, Casey Roche, Clara Shrier, Christopher R. Smith, Candace Van Wade, Casey White‐Lehman, Christopher Zaro, Cindy Zha, Dawn Bentley, Dahriana Correa, Dustin E. Sarver, David Giancarla, David G. Amaral, D.R. Howes, Dalia Istephanous, Daniel L. Coury, Deana Li, Danica L. Limon, Desi Limpoco, Diamond Phillips, Desiree Rambeck, Daniela Rojas, Diksha Srishyla, Danielle Stamps, Dennis Vasquez Montes, Daniel Cho, Dave Cho, Emily Fox, Ethan Bahl, Elizabeth Berry‐Kravis, Elizabeth Blank, Erin Bower, Elizabeth Brooks, Eric Courchesne, Emily Dillon, Erin Doyle, Erin Given, Ellen Grimes, Erica Jones, Éric Fombonne, Elizabeth Kryszak, Ericka L. Wodka, Elena Lamarche, Erica Lampert, Eric Butter, Eirene O’Connor, Edith V. Ocampo, Elizabeth Orrick, Esmeralda Perez, Elizabeth K. Ruzzo, Emily Singer, Emily T. Matthews, Ernest V. Pedapati, Faris Z. Fazal, Fiona K. Miller, Gabriella Aberbach, Gabriele K. Baraghoshi, Gabrielle F. Duhon, Gregory Hooks, Gregory J. Fischer, Gabriela Marzano, Gregory Schoonover, Gabriel S. Dichter, Gabrielle Tiede, Hannah Cottrell, Hannah E. Kaplan, Haidar Ghina, Hanna Hutter, Hope Koene, Hoa Lam Schneider, Holly Lechniak, Hai Li, Hadley Morotti, Hongjian Qi, Harper Richardson, Hana Zaydens, Haicang Zhang, Haoquan Zhao, Ivette Arriaga, Ivy F. Tso, John Acampado, Jennifer Gerdts, Josh Beeson, Jennylyn Brown, Joaquin Comitre, Jeanette M Cordova, Jennifer Delaporte, Joseph F. Cubells, Jill Harris, Xinyi Gong, Jaclyn Gunderson, Jessica Hernández, Jessyca Judge, Jane Jurayj, Kiely Law, Julie Manoharan, Jessie Montezuma, Jason Neely, Jéssica Orobio, Juhi Pandey, Joseph Piven, José Polanco, Jibrielle Polite, Jacob Rosewater, Jessica Scherr, James S. Sutcliffe, James T. McCracken, Jennifer Tjernagel, Jaimie Toroney, Jeremy Veenstra‐VanderWeele, Jiayao Wang, Katie Ahlers, Kathryn A. Schweers, Kelli Baalman, Katie Beard, Kristen Callahan, Kendra Coleman, Kate D. Fitzgerald, Kate Dent, Katharine Diehl, Kelsey Gonring, Katherine G. Pawlowski, Kathy Hirst, Karen Pierce, Karla Murillo, K. Daniel Murray, Kerri P. Nowell, Kaela O’Brien, Katrina Pama, Kelli Real, Kaitlyn Singer, Kaitlin N. Smith, Kevin G. Stephenson, Katherine Tsai, Leonard Abbeduto, Lindsey A. Cartner, Landon Beeson, Laura A. Carpenter, Lucas G. Casten, Leigh A. Coppola, Lisa Cordiero, Lindsey DeMarco, Lillian D. Pacheco, Lorena Ferreira Corzo, Lisa H. Shulman, Lauren Kasperson Walsh, Laurie Lesher, Lynette M. Herbert, Lisa M. Prock, Lacy Malloch, Lori Mann, Luke P. Grosvenor, Laura Simon, Latha Soorya, Lucy Wasserburg, Lisa C. Yeh, Lark Y. Huang-Storms, Michael Alessandri, Marc A. Popp, Melissa Baer, Malia Beckwith, Myriam Casseus, Michelle Coughlin, Mary Hannah Currin, Michele Cutri, Malcolm D. Mallardi, Megan DuBois, Megan Dunlevy, Martin E. Butler, Margot Frayne, McLeod F. Gwynette, Mohammad Ghaziuddin, Monica Haley, Michelle Heyman, Margaret A. Hojlo, Michelle Jordy, Michael J. Morrier, Misia Kowanda, Melinda Koza, Marilyn Lopez, Megan McTaggart, Megan Norris, Melissa N. Hale, Molly O’Neil, Madison Printen, Madelyn Rayos, Mahfuza Sabiha, Mustafa Şahin, Marina Sarris, Mojeeb Shir, Matthew Siegel, Morgan Steele, Megan Sweeney, Maira Tafolla, Maria Valicenti-McDermott, Mary Verdi, Megan Y. Dennis, Nicolas Alvarez, Nicole Bardett, Natalie Berger, Norma Eugenia García Calderón, Nickelle Decius, Natalia González, Nina Harris, Noah Lawson, Natasha Lillie, Nathan Lo, Nancy Long, Nicole M. Russo‐Ponsaran, Natalie Madi, Nicole Amber McCoy, Natalie Nagpal, Nicki Rodriguez, Nicholas Russell, Neelay Shah, Nicole Takahashi, Nicole Targalia, O Newman, Opal Ousley, Peter Heydemann, Patricia Manning, Paul S. Carbone, Raphael Bernier, Rachel Gordon, Rebecca C. Shaffer, Robert D. Annett, Renee D. Clark, Roger J. Jou, Rebecca Landa, Rachel K. Earl, Robin A. Libove, Richard P. Marini, Ryan N. Doan, Robin P. Goin‐Kochel, Rishiraj Rana, Richard Remington, Roman Shikov, Robert T. Schultz, S. B. D. Aberle, Shelby Birdwell, Sarah Boland, Stephanie Booker, Simon Carpenter, Sharmista Chintalapalli, Sarah Conyers, Sophia D’Ambrosi, Sara Eldred, Sunday M. Francis, Swami Ganesan, Susan Hepburn, Susannah Horner, Samantha Hunter, Stephanie Brewster, Soo J. Lee, Suma Jacob, Stanley Jean, So Hyun, Sydney Kramer, Sandra Friedman, Sarely Licona, Sandy Littlefield, Stephen M. Kanne, Sarah Mastel, Sheena Mathai, Sophia Melnyk, Sarah Michaels, Sarah Mohiuddin, Samiza Palmer, Samantha Plate, Shanping Qiu, Shelley Randall, Sophia Sandhu, Susan L. Santangelo, Swapnil Shah, Steve A. Skinner, Samantha Thompson, Sabrina White, Stormi P. White, Sabrina Xiao, Sidi Xu, Simon Xu, Tia Chen, Tunisia Greene, Theodore Ho, Teresa Ibáñez, Tanner Koomar, Tiziano Pramparo, Tara M. Rutter, Tamim H. Shaikh, Thao Tran, Timothy W. Yu, V. H. Galbraith, Vahid Gazestani, Vincent J. Myers, Vaikunt Ranganathan, Vini Singh, W Curtis Weaver, Wenteng CaI, Wubin Chin, Wha S. Yang, Y. B. Choi, Zachary Warren, Jacob J. Michaelson, Natalia Volfovsky, Evan E. Eichler, Yufeng Shen, Wendy K. Chung - Nature Genetics 2022 cited by 461

Abstract 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 , SCAF1 and HNRNPUL2 ). The association of NAV3 with 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 , SCAF1 and HNRNPUL2 ; n = 95) have less cognitive impairment than 129 autistic individuals with LoF variants in highly penetrant genes ( CHD8, SCN2A, ADNP, FOXP1 and SHANK3 ) (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.