Peer-Reviewed Publication
Am J Hum Genet2026September 4, 2026Journal Article
Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features.
Susan M Hiatt1, Wenjing Zhao2, Zhongqing Wang2, Yingjie Wan3, Kewen Chen3, Ke Wang4, Senwei Tan3, Magalie Barth5, Gaber Bergant6, Thomas Besnard7, Emily Boothe8, Theresa Brunet9, Caleb Bupp10, Benjamin Cogne7, Julie S Cohen11, Christine Coubes12, Bert B A de Vries13, Madison Donald10, Colin A Ellis14, Stephanie Riley Eriksson15, Benjamin Ganne16, David Genevieve17, Benedicte Gerard18, Aixa Gonzalez Garcia19, Laura G Hendon20, Noa Henig21, Kristina Huss22, Bertrand Isidor7, Taylor Laut23, Benjamin R Leadem24, Elysa J Marco25, Daphna Marom26, Saadet Mercimek-Andrews23, Alison M Muir24, Benjamin Navet27, Slavica Ostojić28, Borut Peterlin6, Rolph Pfundt13, Anna Prentice29, Clement Prouteau27, Bethany Robinette8, Dmitrijs Rots30, Gita Taurina31, Marjon van Slegtenhorst32, Ludmila Volozonoka31, Marja Wessels32, Brayden West33, Ayelet Zerem34, Yinhong Zhang2, Baosheng Zhu2, Alban Ziegler35, Cécile Courdier36, Patricia Fergelot36, Julien Van Gils36, Shannon Terek37, Grace E VanNoy37, Brianna Berlin38, Alexandra G Buonomo38, Jillian L McKee29, Gregory M Cooper39, Hui Guo40
1HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address: shiatt@hudsonalpha.org.
2Department of Medical Genetics, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, Yunnan Provincial Key Laboratory for Birth Defects and Genetic Diseases, The First People's Hospital of Yunnan Province, Kunming, Yunnan, China; School of Medicine, Kunming University of Science and Technology, Kunming, Yunnan, China.
3Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China; MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China.
4MOE Key Lab of Rare Pediatric Diseases, School of Basic Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
5Angers University Hospital, Angers, France.
6Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
7Service de Génétique Médicale, CHU de Nantes, Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
8University of Mississippi Medical Center, Department of Pediatrics, Division of Medical Genetics, Jackson, MS, USA.
9Institute of Human Genetics, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany.
10Corewell Health Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
11Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA; Departments of Neurology and Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
12Reference Center for Rare Disease Developmental Anomaly and Malformative Syndrome, Genetic Département, CHU Montpellier, Montpellier, France.
13Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
14The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
15Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA.
16Chromosomal Genetics Unit, ChromoStem Research Platform, CHU Montpellier, Montpellier University, Montpellier, France; PFMG2025 Genome Sequencing Platform, Auragen Laboratory, Lyon, France.
17PFMG2025 Genome Sequencing Platform, Auragen Laboratory, Lyon, France; Montpellier University, INSERM U1183, Reference Center for Developmental Anomaly and Malformative Syndrome, CHU Montpellier, Montpellier, France.
18Clinical Genetic Laboratory, Genetic Department, Strasbourg University Hospital, Strasbourg, France.
19Department of Pediatrics, Genetics Section, Arkansas Children's Hospital and University of Arkansas for Medical Sciences, Little Rock, AR, USA.
20University of Mississippi Medical Center, Departments of Pediatrics and Obstetrics and Gynecology, Jackson, MS, USA.
21The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
22Division of Pediatric Neurology, Department of Pediatrics, Developmental Medicine and Social Pediatrics, Ludwig Maximilian University Munich, Dr. von Hauner Children's Hospital, University Hospital, Munich, Germany.
23Department of Medical Genetics, University of Alberta, Faculty of Medicine and Dentistry, Edmonton, AB, Canada.
24GeneDx, LLC, Gaithersburg, MD 20877, USA.
25Cortica Healthcare, San Rafael, CA, USA; Lifetime Neurodevelopmental Care, Corte Madera, CA, USA.
26The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel.
27Department of Genetics, Angers University Hospital, Angers, France.
28Neurology Department, The Institute for Health Care of Mother and Child of Serbia "Dr. Vukan Čupić," 11070 Belgrade, Serbia.
29The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics (DBHi), Children's Hospital of Philadelphia, Philadelphia, PA 19146, USA.
30Children's Clinical University Hospital, Riga, Latvia; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
31Children's Clinical University Hospital, Riga, Latvia.
32Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
33Department of Pathology, Arkansas Children's Hospital, Little Rock, AR, USA.
34Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel; Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel.
35Department of Genetics, University Hospital of Toulouse, Toulouse, France.
36Department of Clinical Genetics, Bordeaux University Hospital, Bordeaux, France; GCS AURAGEN, 69003 Lyon, France.
37Ambry Genetics, 1 Enterprise Drive, Aliso Viejo, CA 92656, USA.
38The Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
39HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
40Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China; MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, Hunan, China. Electronic address: guohui2@csu.edu.cn.
Abstract
ZNF536 encodes a C2H2 zinc-finger transcription factor that functions as a transcriptional repressor. While common noncoding variants at the ZNF536 locus have been reported to be associated with schizophrenia in a genome-wide association study (GWAS), the contribution of rare, protein-altering variants to human disease has not been systematically investigated. Through an international collaboratio…
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