Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Tianyun Wang(University of Washington), Kendra Hoekzema(University of Washington), Davide Vecchio(Bambino Gesù Children's Hospital), Huidan Wu(Central South University), Arvis Sulovari(University of Washington), Bradley P. Coe(University of Washington), Madelyn A. Gillentine(University of Washington), Amy B. Wilfert(University of Washington), Luis A. Pérez‐Jurado(Universitat Pompeu Fabra), Malin Kvarnung(Karolinska University Hospital), Yoeri Sleyp(KU Leuven), Rachel K. Earl(University of Washington), Jill A. Rosenfeld(Baylor College of Medicine), Madeleine R. Geisheker(University of Washington), Lin Han(Central South University), Bing Du(Central South University), Chris Barnett(Women's and Children's Hospital), E. A. Thompson(Women's and Children's Hospital), Marie Shaw(The University of Adelaide), Renée Carroll(The University of Adelaide), Kathryn Friend(South Australia Pathology), Rachael Catford(South Australia Pathology), Elizabeth E. Palmer(UNSW Sydney), Xiaobing Zou(Sun Yat-sen University), Jianjun Ou(Central South University), Honghui Li(Liuzhou Maternal and Child Health Hospital), Hui Guo(Central South University), Jennifer Gerdts(University of Washington), Emanuela Avola(Oasi Maria SS), Giuseppe Calabrese(Oasi Maria SS), Maurizio Elia(Oasi Maria SS), Donatella Greco(Oasi Maria SS), Anna Lindstrand(Karolinska University Hospital), Ann Nordgren(Karolinska University Hospital), Britt‐Marie Anderlid(Karolinska University Hospital), Geert Vandeweyer(University of Antwerp), Anke Van Dijck(University of Antwerp), Nathalie Van der Aa(University of Antwerp), Brooke G. McKenna(Emory University), Miroslava Hančárová(Charles University), Šárka Bendová(Charles University), Markéta Havlovicová(Charles University), Giovanni Malerba(University of Verona), Bernardo Dalla Bernardina, Pierandrea Muglia(UCB Pharma (Belgium)), Arie van Haeringen(Leiden University Medical Center), Mariëtte J.V. Hoffer(Leiden University Medical Center), Barbara Franke(Radboud University Nijmegen), Gerarda Cappuccio(Federico II University Hospital), Martin B. Delatycki(Murdoch Children's Research Institute), Paul J. Lockhart(The University of Melbourne), Melanie A. Manning(Stanford University), Pengfei Liu(Baylor College of Medicine), Ingrid E. Scheffer(Royal Children's Hospital), Nicola Brunetti‐Pierri(Federico II University Hospital), Nanda Rommelse(Radboud University Nijmegen), David G. Amaral(University of California, Davis), Gijs W.E. Santen(Leiden University Medical Center), Elisabetta Trabetti(University of Verona), Zdeněk Sedláček(Charles University), Jacob J. Michaelson(University of Iowa), Karen Pierce(University of California San Diego), Eric Courchesne(University of California San Diego), R. Frank Kooy(University of Antwerp), John Acampado(Simons Foundation), Andrea J. Ace(Simons Foundation), Alpha Amatya(Simons Foundation), Irina Astrovskaya(Simons Foundation), Asif Bashar(Simons Foundation), Elizabeth Brooks(Simons Foundation), Martin E. Butler(Simons Foundation), Lindsey A. Cartner(Simons Foundation), Wubin Chin(Simons Foundation), Wendy K. Chung(Simons Foundation), Amy M. Daniels(Simons Foundation), Pamela Feliciano(Simons Foundation), Chris Fleisch(Simons Foundation), Swami Ganesan(Simons Foundation), William B. Jensen(Simons Foundation), Alex Lash(Simons Foundation), Richard P. Marini(Simons Foundation), Vincent J. Myers(Simons Foundation), Eirene O’Connor(Simons Foundation), Chris Rigby(Simons Foundation), B. E. Robertson(Simons Foundation), Neelay Shah(Simons Foundation), Swapnil Shah(Simons Foundation), Emily Singer(Simons Foundation), LeeAnne Green Snyder(Simons Foundation), Alexandra N. Stephens(Simons Foundation), Jennifer Tjernagel(Simons Foundation), Brianna M. Vernoia(Simons Foundation), Natalia Volfovsky(Simons Foundation), L. Casey White(Simons Foundation), Alexander Hsieh(Columbia University), Yufeng Shen(Columbia University), Xueya Zhou(Columbia University), Tychele N. Turner(Washington University in St. Louis), Ethan Bahl(University of Iowa), Taylor Thomas(University of Iowa), Leo Brueggeman(University of Iowa), Tanner Koomar(University of Iowa), Jacob J. Michaelson(University of Iowa), Brian J. O’Roak(Oregon Health & Science University), Rebecca Barnard(Oregon Health & Science University), Richard A. Gibbs(Baylor College of Medicine), Donna M. Muzny(Baylor College of Medicine), Aniko Sabo(Baylor College of Medicine), Kelli L. Baalman Ahmed(Baylor College of Medicine), Evan E. Eichler(Howard Hughes Medical Institute), Matthew Siegel(Maine Medical Center), Leonard Abbeduto(University of California, Davis), David G. Amaral(University of California, Davis), Brittani A. Hilscher(University of California, Davis), Deana Li(University of California, Davis), Kaitlin Smith(University of California, Davis), Samantha Thompson(University of California, Davis), Charles F. Albright(Nationwide Children's Hospital), Eric Butter(Nationwide Children's Hospital), Sara Eldred(Nationwide Children's Hospital), Nathan Hanna(Nationwide Children's Hospital), Mark Jones(Nationwide Children's Hospital), Daniel L. Coury(Nationwide Children's Hospital), Jessica Scherr(Nationwide Children's Hospital), Taylor Pifher(Nationwide Children's Hospital), Erin Roby(Nationwide Children's Hospital), Brandy Dennis(Nationwide Children's Hospital), Lorrin Higgins(Nationwide Children's Hospital), Melissa A. Brown(Nationwide Children's Hospital), Michael Alessandri(University of Miami), Anibal Gutierrez(University of Miami), Melissa N. Hale(University of Miami), Lynette M. Herbert(University of Miami), Hoa Lam Schneider(University of Miami), Giancarla David(University of Miami), Robert D. Annett(Jackson Memorial Hospital), Dustin E. Sarver(Jackson Memorial Hospital), Ivette Arriaga(University of California, Los Angeles), Alexies Camba(University of California, Los Angeles), Amanda C. Gulsrud(University of California, Los Angeles), Monica Haley(University of California, Los Angeles), James T. McCracken(University of California, Los Angeles), Sophia Sandhu(University of California, Los Angeles), Maira Tafolla(University of California, Los Angeles), Wha S. Yang(University of California, Los Angeles), Laura A. Carpenter(University of Southern Maine), Catherine C. Bradley(University of Southern Maine), Frampton Gwynette(University of Southern Maine), Patricia Manning(Cincinnati Children's Hospital Medical Center), Rebecca C. Shaffer(Cincinnati Children's Hospital Medical Center), Carrie A. Thomas(Cincinnati Children's Hospital Medical Center), Raphael Bernier(University of Washington), Emily A. Fox(Center for Autism and Related Disorders), Jennifer A. Gerdts(University of Washington), Micah Pepper(Center for Autism and Related Disorders), Theodore Ho(Center for Autism and Related Disorders), Daniel Cho(Center for Autism and Related Disorders), Joseph Piven(University of North Carolina at Chapel Hill), Holly Lechniak(Rush University Medical Center), Latha Soorya(Rush University Medical Center), Rachel Gordon(Rush University Medical Center), Allison Wainer(Rush University Medical Center), Lisa C. Yeh(Rush University Medical Center), Cesar Ochoa-Lubinoff(Rush University Medical Center), Nicole M. Russo‐Ponsaran(Rush University Medical Center), Elizabeth Berry‐Kravis(Rush University Medical Center), Stephanie Booker(Cincinnati Children's Hospital Medical Center), Craig A. Erickson(Cincinnati Children's Hospital Medical Center), Lisa M. Prock(Boston Children's Hospital), Katherine G. Pawlowski(Boston Children's Hospital), Emily T. Matthews(Boston Children's Hospital), Stephanie Brewster(Boston Children's Hospital), Margaret A. Hojlo(Boston Children's Hospital), Evi Abada(Boston Children's Hospital), Elena Lamarche(University of North Carolina at Chapel Hill), Tianyun Wang(University of Washington), Shwetha C. Murali(University of Washington), William T. Harvey(University of Washington), Hannah E. Kaplan(University of California San Diego), Karen Pierce(University of California San Diego), Lindsey DeMarco(Children's Hospital of Philadelphia), Susannah Horner(Children's Hospital of Philadelphia), Juhi Pandey(Children's Hospital of Philadelphia), Samantha Plate(Children's Hospital of Philadelphia), Mustafa Şahin(Boston Children's Hospital), Katherine D. Riley(Boston Children's Hospital), Erin Carmody(Boston Children's Hospital), Julia Constantini(Howard Hughes Medical Institute), Amy Esler(University of Minnesota), Ali Fatemi(Kennedy Krieger Institute), Hanna Hutter(Kennedy Krieger Institute), Rebecca Landa(Kennedy Krieger Institute), Alexander P. McKenzie(Kennedy Krieger Institute), Jason Neely(Kennedy Krieger Institute), Vini Singh(Kennedy Krieger Institute), Bonnie Van Metre(Kennedy Krieger Institute), Ericka L. Wodka(Kennedy Krieger Institute), Éric Fombonne(Oregon Health & Science University), Lark Y. Huang-Storms(Oregon Health & Science University), Lillian D. Pacheco(Oregon Health & Science University), Sarah Mastel(Oregon Health & Science University), Leigh A. Coppola(Oregon Health & Science University), Sunday M. Francis(University of Minnesota), Andrea Jarrett(University of Minnesota), Suma Jacob(University of Minnesota), Natasha Lillie(University of Minnesota), Jaclyn Gunderson(University of Minnesota), Dalia Istephanous(University of Minnesota), Laura Simon(University of Minnesota), Ori Wasserberg(University of Minnesota), Angela L. Rachubinski(University of Colorado Denver), Cordelia Robinson Rosenberg(University of Colorado Denver), Stephen M. Kanne(University of Missouri Health System), Amanda D. Shocklee(University of Missouri), Nicole Takahashi(University of Missouri), Shelby L. Bridwell(University of Missouri), Rebecca L. Klimczac(University of Missouri), Melissa A. Mahurin(University of Missouri), Hannah E. Cotrell(University of Missouri), Cortaiga A. Grant(University of Missouri), Samantha G. Hunter(University of Missouri), Christa Lese Martin(Autism & Developmental Medicine Institute), Cora Taylor(Autism & Developmental Medicine Institute), Lauren K. Walsh(Autism & Developmental Medicine Institute), Katherine A. Dent(Autism & Developmental Medicine Institute), Andrew L. Mason(Southwest Autism Research & Resource Center), Anthony Sziklay(Southwest Autism Research & Resource Center), Christopher J. Smith(Southwest Autism Research & Resource Center), Magnus Nordenskjöld(Karolinska University Hospital), Corrado Romano(Oasi Maria SS), Hilde Peeters(KU Leuven), Raphael Bernier(University of Washington), Jozef Gécz(South Australia Pathology), Kun Xia(Central South University), Evan E. Eichler(Howard Hughes Medical Institute)
Cited by 214Open Access
Abstract
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.
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