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.

For many neurodevelopmental disorder (NDD) risk genes, the significance for mutational burden is unestablished. Here, the authors sequence 125 candidate NDD genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations.

Details

Title
Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders
Author
Wang Tianyun 1   VIAFID ORCID Logo  ; Hoekzema Kendra 1 ; Vecchio Davide 2   VIAFID ORCID Logo  ; Wu Huidan 3 ; Arvis, Sulovari 1   VIAFID ORCID Logo  ; Coe, Bradley P 1 ; Gillentine, Madelyn A 1   VIAFID ORCID Logo  ; Wilfert, Amy B 1 ; Perez-Jurado, Luis A 4 ; Kvarnung Malin 5 ; Yoeri, Sleyp 6 ; Earl, Rachel K 7 ; Rosenfeld, Jill A 8   VIAFID ORCID Logo  ; Geisheker Madeleine R 1   VIAFID ORCID Logo  ; Lin, Han 3 ; Du, Bing 3 ; Barnett, Chris 9 ; Thompson, Elizabeth 10 ; Shaw, Marie 11 ; Carroll, Renee 11 ; Friend, Kathryn 12 ; Catford Rachael 12 ; Palmer, Elizabeth E 13 ; Zou Xiaobing 14 ; Ou Jianjun 15 ; Li, Honghui 16 ; Guo, Hui 3   VIAFID ORCID Logo  ; Gerdts, Jennifer 7 ; Avola Emanuela 17 ; Calabrese Giuseppe 17 ; Elia Maurizio 17 ; Greco Donatella 17 ; Lindstrand, Anna 5   VIAFID ORCID Logo  ; Nordgren, Ann 5   VIAFID ORCID Logo  ; Britt-Marie, Anderlid 5 ; Vandeweyer Geert 18 ; Anke, Van Dijck 18   VIAFID ORCID Logo  ; Van der Aa Nathalie 18 ; McKenna, Brooke 19 ; Hancarova Miroslava 20 ; Bendova Sarka 20 ; Havlovicova Marketa 20 ; Malerba Giovanni 21 ; Bernardina, Bernardo Dalla 22 ; Muglia Pierandrea 23 ; van Haeringen Arie 24 ; Hoffer, Mariette J, V 24   VIAFID ORCID Logo  ; Franke, Barbara 25   VIAFID ORCID Logo  ; Cappuccio Gerarda 26 ; Delatycki Martin 27 ; Lockhart, Paul J 28   VIAFID ORCID Logo  ; Manning, Melanie A 29 ; Liu, Pengfei 8   VIAFID ORCID Logo  ; Scheffer, Ingrid E 30 ; Brunetti-Pierri, Nicola 26   VIAFID ORCID Logo  ; Rommelse Nanda 31 ; Amaral, David G 32 ; Santen Gijs W E 24 ; Trabetti Elisabetta 21 ; Sedláček Zdeněk 20 ; Michaelson, Jacob J 33   VIAFID ORCID Logo  ; Pierce, Karen 34 ; Courchesne, Eric 34   VIAFID ORCID Logo  ; Frank, Kooy R 18   VIAFID ORCID Logo  ; Acampado, John 35 ; Ace, Andrea J 35 ; Amatya Alpha 35 ; Astrovskaya Irina 35 ; Asif, Bashar 35 ; Brooks, Elizabeth 35 ; Butler, Martin E 35 ; Cartner, Lindsey A 35 ; Chin Wubin 35 ; Chung, Wendy K 36 ; Daniels, Amy M 35 ; Feliciano, Pamela 35 ; Fleisch, Chris 35 ; Ganesan Swami 35 ; Jensen, William 35 ; Lash, Alex E 35 ; Marini, Richard 35 ; Myers, Vincent J 35 ; O’Connor Eirene 35 ; Rigby, Chris 35 ; Robertson, Beverly E 35 ; Shah Neelay 35 ; Shah Swapnil 35 ; Singer, Emily 35 ; Snyder, LeeAnne G 35 ; Stephens, Alexandra N 35 ; Tjernagel, Jennifer 35 ; Vernoia, Brianna M 35 ; Volfovsky Natalia 35 ; White, Loran Casey 35 ; Hsieh, Alexander 37 ; Shen Yufeng 37 ; Zhou Xueya 37 ; Turner, Tychele N 38 ; Bahl, Ethan 39 ; Thomas Taylor R 39 ; Brueggeman, Leo 39 ; Tanner, Koomar 39 ; O’Roak Brian J 40 ; Barnard, Rebecca A 40 ; Gibbs, Richard A 41 ; Muzny Donna 41 ; Sabo Aniko 41 ; Ahmed Kelli L Baalman 41 ; Eichler, Evan E 42 ; Siegel, Matthew 43 ; Abbeduto Leonard 44 ; Hilscher, Brittani A 44 ; Li, Deana 44 ; Smith, Kaitlin 44 ; Thompson, Samantha 44 ; Albright, Charles 45 ; Butter, Eric M 45 ; Eldred, Sara 45 ; Hanna, Nathan 45 ; Jones, Mark 45 ; Coury, Daniel Lee 45 ; Scherr, Jessica 45 ; Taylor, Pifher 45 ; Roby, Erin 45 ; Dennis, Brandy 45 ; Higgins Lorrin 45 ; Brown, Melissa 45 ; Alessandri, Michael 46 ; Gutierrez, Anibal 46 ; Hale, Melissa N 46 ; Herbert, Lynette M 46 ; Schneider, Hoa Lam 46 ; Giancarla, David 46 ; Annett, Robert D 47 ; Sarver, Dustin E 47 ; Arriaga Ivette 48 ; Camba Alexies 48 ; Gulsrud, Amanda C 48 ; Haley, Monica 48 ; McCracken, James T 48 ; Sandhu, Sophia 48 ; Maira, Tafolla 48 ; Yang, Wha S 48 ; Carpenter, Laura A 49 ; Bradley, Catherine C 49 ; Frampton, Gwynette 49 ; Manning, Patricia 50 ; Shaffer, Rebecca 50 ; Thomas, Carrie 50 ; Bernier, Raphael A 51 ; Fox, Emily A 51 ; Gerdts, Jennifer A 51 ; Pepper Micah 51 ; Ho, Theodore 51 ; Cho, Daniel 51 ; Piven, Joseph 52 ; Lechniak Holly 53 ; Soorya, Latha V 53 ; Gordon, Rachel 53 ; Wainer, Allison 53 ; Yeh, Lisa 53 ; Ochoa-Lubinoff Cesar 54 ; Russo, Nicole 54 ; Berry-Kravis, Elizabeth 55 ; Booker, Stephanie 56 ; Erickson, Craig A 56 ; Prock, Lisa M 57 ; Pawlowski, Katherine G 57 ; Matthews, Emily T 57 ; Brewster, Stephanie J 57 ; Hojlo, Margaret A 57 ; Abada Evi 57 ; Lamarche, Elena 52 ; Murali, Shwetha C 58 ; Harvey, William T 58 ; Kaplan, Hannah E 59 ; Pierce, Karen L 59 ; DeMarco, Lindsey 60 ; Horner, Susannah 60 ; Pandey Juhi 60 ; Plate, Samantha 60 ; Sahin Mustafa 57 ; Riley, Katherine D 57 ; Carmody, Erin 57 ; Constantini Julia 42 ; Esler, Amy 61 ; Fatemi, Ali 62 ; Hutter, Hanna 62 ; Landa, Rebecca J 62 ; McKenzie, Alexander P 62 ; Neely, Jason 62 ; Singh, Vini 62 ; Van Metre Bonnie 62 ; Wodka Ericka L 62 ; Fombonne, Eric J 40 ; Huang-Storms, Lark Y 40 ; Pacheco, Lillian D 40 ; Mastel, Sarah A 40 ; Coppola, Leigh A 40 ; Francis, Sunday 61 ; Jarrett, Andrea 61 ; Jacob Suma 61 ; Lillie, Natasha 61 ; Gunderson Jaclyn 61 ; Istephanous Dalia 61 ; Simon, Laura 61 ; Wasserberg Ori 61 ; Rachubinski, Angela L 63 ; Rosenberg, Cordelia R 63 ; Kanne, Stephen M 64 ; Shocklee, Amanda D 65 ; Takahashi, Nicole 65 ; Bridwell, Shelby L 65 ; Klimczac, Rebecca L 65 ; Mahurin, Melissa A 65 ; Cotrell, Hannah E 65 ; Grant, Cortaiga A 65 ; Hunter, Samantha G 65 ; Martin Christa Lese 66 ; Taylor, Cora M 66 ; Walsh, Lauren K 66 ; Dent, Katherine A 66 ; Mason, Andrew 67 ; Sziklay Anthony 67 ; Smith, Christopher J 67 ; Nordenskjöld Magnus 5 ; Romano, Corrado 68   VIAFID ORCID Logo  ; Peeters Hilde 6 ; Gecz Jozef 69   VIAFID ORCID Logo  ; Xia Kun 70   VIAFID ORCID Logo 

1  University of Washington, Department of Genome Sciences, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
2  Rare Disease and Medical Genetics, Academic Department of Pediatrics, Bambino Gesù Children’s Hospital, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809); Genetics and Rare Diseases Research Division, Bambino Gesù Children’s Hospital, Rome, Italy (GRID:grid.414125.7) (ISNI:0000 0001 0727 6809) 
3  Central South University, Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
4  Women’s and Children’s Hospital, Paediatric and Reproductive Genetics unit, Adelaide, Australia (GRID:grid.1694.a); South Australian Health and Medical Research Institute, Adelaide, Australia (GRID:grid.430453.5) (ISNI:0000 0004 0565 2606); Genetics Unit, Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM) and CIBERER, Barcelona, Spain (GRID:grid.5612.0) (ISNI:0000 0001 2172 2676) 
5  Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626); Karolinska University Hospital, Department of Clinical Genetics, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
6  Centre for Human Genetics, KU Leuven and Leuven Autism Research (LAuRes), Leuven, Belgium (GRID:grid.24381.3c) 
7  University of Washington, Department of Psychiatry and Behavioral Sciences, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
8  Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X); Baylor Genetics, Houston, USA (GRID:grid.39382.33) 
9  Women’s and Children’s Hospital, Paediatric and Reproductive Genetics unit, Adelaide, Australia (GRID:grid.1694.a); the University of Adelaide, Adelaide Medical School and the Robinson Research Institute, Adelaide, Australia (GRID:grid.1010.0) (ISNI:0000 0004 1936 7304) 
10  Women’s and Children’s Hospital, Paediatric and Reproductive Genetics unit, Adelaide, Australia (GRID:grid.1694.a) 
11  the University of Adelaide, Adelaide Medical School and the Robinson Research Institute, Adelaide, Australia (GRID:grid.1010.0) (ISNI:0000 0004 1936 7304) 
12  Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia (GRID:grid.414733.6) (ISNI:0000 0001 2294 430X) 
13  Hunter New England Health Service, Genetics of Learning Disability Service, Waratah, Australia (GRID:grid.3006.5) (ISNI:0000 0004 0438 2042); University of New South Wales, School of Women’s and Children’s Health, Randwick, Australia (GRID:grid.1005.4) (ISNI:0000 0004 4902 0432) 
14  Sun Yat-Sen University, Guangzhou, Children Development Behavior Center, The Third Affiliated Hospital, Guangdong, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X) 
15  Central South University, Mental Health Institute of the Second Xiangya Hospital, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
16  Liuzhou Maternity and Child Healthcare Hospital, Key Laboratory of Developmental Disorders in Children, Liuzhou, China (GRID:grid.477238.d) 
17  Oasi Research Institute-IRCCS, Troina, Italy (GRID:grid.34477.33) 
18  University of Antwerp, Department of Medical Genetics, Antwerp, Belgium (GRID:grid.5284.b) (ISNI:0000 0001 0790 3681) 
19  Emory University, Department of Psychology, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
20  Charles University 2nd Faculty of Medicine and University Hospital Motol, Department of Biology and Medical Genetics, Prague, Czech Republic (GRID:grid.4491.8) (ISNI:0000 0004 1937 116X) 
21  University of Verona, Department of Neurosciences, Biomedicine and Movement Sciences, Verona, Italy (GRID:grid.5611.3) (ISNI:0000 0004 1763 1124) 
22  Child Neuropsychiatry Unit, AOUI, Verona, Italy (GRID:grid.411475.2) (ISNI:0000 0004 1756 948X) 
23  UCB Pharma, Bruxelles, Belgium (GRID:grid.421932.f) (ISNI:0000 0004 0605 7243) 
24  Leiden University Medical Center (LUMC), Department of Clinical Genetics, Leiden, Netherlands (GRID:grid.10419.3d) (ISNI:0000000089452978) 
25  Radboud University Medical Center, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Radboud University Medical Center, Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
26  Federico II University, Department of Translational Medicine, Naples, Italy (GRID:grid.4691.a) (ISNI:0000 0001 0790 385X); Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy (GRID:grid.410439.b) (ISNI:0000 0004 1758 1171) 
27  Murdoch Children’s Research Institute, Melbourne, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X) 
28  Murdoch Children’s Research Institute, Melbourne, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X); University of Melbourne, Department of Paediatrics, Parkville, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X) 
29  Stanford University, Division of Medical Genetics, Department of Pediatrics, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956); Stanford University, Department of Pathology, Stanford, USA (GRID:grid.168010.e) (ISNI:0000000419368956) 
30  Murdoch Children’s Research Institute, Melbourne, Australia (GRID:grid.1058.c) (ISNI:0000 0000 9442 535X); University of Melbourne, Royal Children’s Hospital, Department of Paediatrics, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); University of Melbourne, Austin Health, Department of Medicine, Melbourne, Australia (GRID:grid.1008.9) (ISNI:0000 0001 2179 088X); The Florey Institute of Neuroscience and Mental Health, Parkville, Australia (GRID:grid.418025.a) (ISNI:0000 0004 0606 5526) 
31  Radboud University Medical Center, Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Karakter Child and Adolescent Psychiatry Center, Nijmegen, Netherlands (GRID:grid.10417.33) 
32  University of California, Davis, Department of Psychiatry and Behavioral Sciences and the MIND Institute, Sacramento, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
33  University of Iowa Carver College of Medicine, Department of Psychiatry, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
34  University of California San Diego, Department of Neurosciences, UC San Diego Autism Center, School of Medicine, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
35  Simons Foundation, New York, USA (GRID:grid.430264.7) 
36  Simons Foundation, New York, USA (GRID:grid.430264.7); Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
37  Columbia University, New York, USA (GRID:grid.21729.3f) (ISNI:0000000419368729) 
38  Washington University School of Medicine, St. Louis, USA (GRID:grid.4367.6) (ISNI:0000 0001 2355 7002) 
39  University of Iowa Carver College of Medicine, Iowa City, USA (GRID:grid.214572.7) (ISNI:0000 0004 1936 8294) 
40  Oregon Health & Science University, Portland, USA (GRID:grid.5288.7) (ISNI:0000 0000 9758 5690) 
41  Baylor College of Medicine, Houston, USA (GRID:grid.39382.33) (ISNI:0000 0001 2160 926X) 
42  University of Washington School of Medicine & Howard Hughes Medical Institute, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
43  Maine Medical Center Research Institute, Portland, USA (GRID:grid.416311.0) (ISNI:0000 0004 0433 3945) 
44  University of California, Davis, Sacramento, USA (GRID:grid.27860.3b) (ISNI:0000 0004 1936 9684) 
45  Nationwide Children’s Hospital, Columbus, USA (GRID:grid.240344.5) (ISNI:0000 0004 0392 3476) 
46  University of Miami, Coral Gables, USA (GRID:grid.26790.3a) (ISNI:0000 0004 1936 8606) 
47  University of Mississippi Medical Center, Jackson, USA (GRID:grid.410721.1) (ISNI:0000 0004 1937 0407) 
48  University of California, Los Angeles, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
49  Medical University of Southern Carolina (MUSC), Portland, USA (GRID:grid.19006.3e) 
50  Cincinnati Children’s Hospital Medical Center-Research Foundation, Cincinnati, USA (GRID:grid.239573.9) (ISNI:0000 0000 9025 8099) 
51  Seattle Children’s Autism Center/UW, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
52  University of North Carolina at Chapel Hill, Chapel Hill, USA (GRID:grid.10698.36) (ISNI:0000000122483208) 
53  Rush University Medical Center, Department of Child & Adolescent Psychiatry, Chicago, USA (GRID:grid.240684.c) (ISNI:0000 0001 0705 3621) 
54  Rush University Medical Center, Department of Developmental & Behavioral Pediatrics, Chicago, USA (GRID:grid.240684.c) (ISNI:0000 0001 0705 3621) 
55  Rush University Medical Center, Department of Neurological Sciences, Department of Pediatrics, Department of Biochemistry, Chicago, USA (GRID:grid.240684.c) (ISNI:0000 0001 0705 3621) 
56  Cincinnati Children’s Hospital Medical Center - Research Foundation, Cincinnati, USA (GRID:grid.239573.9) (ISNI:0000 0000 9025 8099) 
57  Boston Children’s Hospital (BCH), Boston, USA (GRID:grid.2515.3) (ISNI:0000 0004 0378 8438) 
58  University of Washington School of Medicine, Seattle, USA (GRID:grid.34477.33) (ISNI:0000000122986657) 
59  University of California, San Diego, School of Medicine, La Jolla, USA (GRID:grid.266100.3) (ISNI:0000 0001 2107 4242) 
60  Children’s Hospital of Philadelphia, Philadelphia, USA (GRID:grid.239552.a) (ISNI:0000 0001 0680 8770) 
61  University of Minnesota, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000000419368657) 
62  Kennedy Krieger Institute, Baltimore, USA (GRID:grid.240023.7) (ISNI:0000 0004 0427 667X) 
63  University of Colorado School of Medicine, Aurora, USA (GRID:grid.430503.1) (ISNI:0000 0001 0703 675X) 
64  University of Missouri, Department of Health Psychology, Columbia, USA (GRID:grid.134936.a) (ISNI:0000 0001 2162 3504); University of Missouri, Thompson Center for Autism and Neurodevelopmental Disorders, Columbia, USA (GRID:grid.134936.a) (ISNI:0000 0001 2162 3504) 
65  University of Missouri, Thompson Center for Autism and Neurodevelopmental Disorders, Columbia, USA (GRID:grid.134936.a) (ISNI:0000 0001 2162 3504) 
66  Geisinger Autism & Developmental Medicine Institute, Lewisburg, USA (GRID:grid.476963.9) 
67  Southwest Autism Research and Resource Center, Phoenix, USA (GRID:grid.430554.3) (ISNI:0000 0004 0567 7109) 
68  Oasi Research Institute-IRCCS, Troina, Italy (GRID:grid.24381.3c) 
69  South Australian Health and Medical Research Institute, Adelaide, Australia (GRID:grid.430453.5) (ISNI:0000 0004 0565 2606); the University of Adelaide, Adelaide Medical School and the Robinson Research Institute, Adelaide, Australia (GRID:grid.1010.0) (ISNI:0000 0004 1936 7304); Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia (GRID:grid.414733.6) (ISNI:0000 0001 2294 430X) 
70  Central South University, Center for Medical Genetics & Hunan Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Changsha, China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164); CAS Center for Excellence in Brain Science and Intelligences Technology (CEBSIT), Chinese Academy of Sciences, Shanghai, China (GRID:grid.9227.e) (ISNI:0000000119573309) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-18723-y
ProQuest document ID
2449454336
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.