ArticleAmerican journal of human genetics2026
Monoallelic loss-of-function variants in ZNF536 are associated with a neurodevelopmental disorder with prominent behavioral features.
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Article in American journal of human genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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61 authors.
Susan M HiattHudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address: shiatt@hudsonalpha.org.
Wenjing ZhaoDepartment 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.
Zhongqing WangDepartment 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.
Yingjie WanCenter 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.
Kewen ChenCenter 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.
Ke WangMOE Key Lab of Rare Pediatric Diseases, School of Basic Medicine, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China.
Senwei TanCenter 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.
Magalie BarthAngers University Hospital, Angers, France.
Gaber BergantClinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Thomas BesnardService de Génétique Médicale, CHU de Nantes, Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Emily BootheUniversity of Mississippi Medical Center, Department of Pediatrics, Division of Medical Genetics, Jackson, MS, USA.
Theresa BrunetInstitute of Human Genetics, Klinikum Rechts der Isar, School of Medicine and Health, Technical University of Munich, Munich, Germany.
Caleb BuppCorewell Health Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Benjamin CogneService de Génétique Médicale, CHU de Nantes, Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Julie S CohenDepartment 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.
Christine CoubesReference Center for Rare Disease Developmental Anomaly and Malformative Syndrome, Genetic Département, CHU Montpellier, Montpellier, France.
Bert B A de VriesDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
Madison DonaldCorewell Health Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Colin A EllisThe 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.
Stephanie Riley ErikssonDepartment of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, USA.
Benjamin GanneChromosomal Genetics Unit, ChromoStem Research Platform, CHU Montpellier, Montpellier University, Montpellier, France; PFMG2025 Genome Sequencing Platform, Auragen Laboratory, Lyon, France.
David GenevievePFMG2025 Genome Sequencing Platform, Auragen Laboratory, Lyon, France; Montpellier University, INSERM U1183, Reference Center for Developmental Anomaly and Malformative Syndrome, CHU Montpellier, Montpellier, France.
Benedicte GerardClinical Genetic Laboratory, Genetic Department, Strasbourg University Hospital, Strasbourg, France.
Aixa Gonzalez GarciaDepartment of Pediatrics, Genetics Section, Arkansas Children's Hospital and University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Laura G HendonUniversity of Mississippi Medical Center, Departments of Pediatrics and Obstetrics and Gynecology, Jackson, MS, USA.
Noa HenigThe Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Kristina HussDivision 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.
Bertrand IsidorService de Génétique Médicale, CHU de Nantes, Nantes, France; Université de Nantes, CNRS, INSERM, l'institut du thorax, Nantes, France.
Taylor LautDepartment of Medical Genetics, University of Alberta, Faculty of Medicine and Dentistry, Edmonton, AB, Canada.
Benjamin R LeademGeneDx, LLC, Gaithersburg, MD 20877, USA.
Elysa J MarcoCortica Healthcare, San Rafael, CA, USA; Lifetime Neurodevelopmental Care, Corte Madera, CA, USA.
Daphna MaromThe 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.
Saadet Mercimek-AndrewsDepartment of Medical Genetics, University of Alberta, Faculty of Medicine and Dentistry, Edmonton, AB, Canada.
Alison M MuirGeneDx, LLC, Gaithersburg, MD 20877, USA.
Benjamin NavetDepartment of Genetics, Angers University Hospital, Angers, France.
Slavica OstojićNeurology Department, The Institute for Health Care of Mother and Child of Serbia "Dr. Vukan Čupić," 11070 Belgrade, Serbia.
Borut PeterlinClinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
Rolph PfundtDepartment of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, the Netherlands.
Anna PrenticeThe 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.
Clement ProuteauDepartment of Genetics, Angers University Hospital, Angers, France.
Bethany RobinetteUniversity of Mississippi Medical Center, Department of Pediatrics, Division of Medical Genetics, Jackson, MS, USA.
Dmitrijs RotsChildren's Clinical University Hospital, Riga, Latvia; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
Gita TaurinaChildren's Clinical University Hospital, Riga, Latvia.
Marjon van SlegtenhorstDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
Ludmila VolozonokaChildren's Clinical University Hospital, Riga, Latvia.
Marja WesselsDepartment of Clinical Genetics, Erasmus Medical Center, Rotterdam, the Netherlands.
Brayden WestDepartment of Pathology, Arkansas Children's Hospital, Little Rock, AR, USA.
Ayelet ZeremGray 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.
Yinhong ZhangDepartment 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.
Baosheng ZhuDepartment 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.
Alban ZieglerDepartment of Genetics, University Hospital of Toulouse, Toulouse, France.
Cécile CourdierDepartment of Clinical Genetics, Bordeaux University Hospital, Bordeaux, France; GCS AURAGEN, 69003 Lyon, France.
Patricia FergelotDepartment of Clinical Genetics, Bordeaux University Hospital, Bordeaux, France; GCS AURAGEN, 69003 Lyon, France.
Julien Van GilsDepartment of Clinical Genetics, Bordeaux University Hospital, Bordeaux, France; GCS AURAGEN, 69003 Lyon, France.
Shannon TerekAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, CA 92656, USA.
Grace E VanNoyAmbry Genetics, 1 Enterprise Drive, Aliso Viejo, CA 92656, USA.
Brianna BerlinThe Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Alexandra G BuonomoThe Epilepsy NeuroGenetics Initiative (ENGIN), Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Jillian L McKeeThe 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.
Gregory M CooperHudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
Hui GuoCenter 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.
Funding
South-seq: DNA sequencing for newborn nurseries in the SouthU01HG007301 · NHGRI · HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY · PI BARSH, GREGORY STEFAN, COOPER, GREGORY MICHAEL · 2017 to 2021
$11.9MSleep and Circadian Dysfunction, Brain and Neurobehavioral Development in AutismP50HD103538 · NICHD · HUGO W. MOSER RES INST KENNEDY KRIEGER · PI S. Ali Fatemi, Bradley L Schlaggar · 2020 to 2026
$9.9MLong-read genome sequencing for the discovery of highly penetrant variation in rare diseasesR01HD112437 · NICHD · HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY · PI Gregory Michael Cooper, Jane Grimwood · 2024 to 2026
$1.8MGLIA-CTN Genomic Expert Curation PanelU24NS131172 · NINDS · CHILDREN'S HOSP OF PHILADELPHIA · PI VANDERVER, ADELINE LUCIE · 2023 to 2025
$1.1MNHGRI NIH HHS U01 HG007301NICHD NIH HHS P50 HD103538NICHD NIH HHS R01 HD112437NINDS NIH HHS U24 NS131172
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 collaboration, we assembled a cohort of 21 affected individuals carrying 18 unique, rare, heterozygous, protein-altering ZNF536 variants. Most variants (15/18) were predicted loss-of-function (LoF) alleles, with the remainder being missense variants. Among families with available inheritance data (17/20), most variants arose de novo (12/17), while others were inherited from mosaic or mildly affected parents (5/17). Clinically, affected individuals presented with developmental delay along with high rates of autism spectrum disorder, intellectual disability, hyperactivity, aggressive behavior, anxiety, and hyperphagia; epilepsy and sleep disturbances were also frequently observed. To assess functional consequences of a proband-associated ZNF536 variant, we generated a Zfp536
Indexed as
DNA-Binding ProteinsLoss of Function MutationNeurodevelopmental DisordersTranscription FactorsAdolescentAllelesAnimalsAutism Spectrum DisorderChildChild, PreschoolFemaleHumansMaleMiceMutation, MissensePhenotypeDNA-Binding ProteinsTranscription Factorsautism spectrum disorderGeneMatcherhaploinsufficiencyneurodevelopmentrare diseasetranscription factorZNF536
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