Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.

Cambridge Suda Genomic Research Center Soochow University Suzhou China

CNR Institute of Biochemistry and Cell Biology Monterotondo Rome Italy

Czech Centre for Phenogenomics Institute of Molecular Genetics of the Czech Academy of Sciences Prague Czech Republic

Department of Congenital Heart Defects and Pediatric Cardiology German Heart Center Munich Technical University Munich Munich Germany

Department of Congenital Heart Disease and Pediatric Cardiology University Hospital of Schleswig Holstein Kiel Germany

Department of Developmental Genetics TUM School of Life Sciences Technische Universität Munich Freising Germany

Department of Experimental Genetics TUM School of Life Science Technische Universität Munich Freising Germany

Department of Internal Medicine Division of Translational Informatics and Center of Biomedical Research Excellence in Autophagy Inflammation and Metabolism UNM Health Sciences Center and UNM Comprehensive Cancer Center Albuquerque NM USA

Department of Molecular Physiology and Biophysics Baylor College of Medicine Houston TX USA

Department of Rheumatology and Inflammation Research Institute of Medicine Sahlgrenska Academy at University of Gothenburg Gothenburg Sweden

Department of Surgery School of Medicine University of California Davis Davis CA USA

Deutsches Institut für Neurodegenerative Erkrankungen Site Munich Munich Germany

DZHK partner site Munich Heart Alliance Munich Germany

DZHK partner site Munich Munich Germany

European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Trust Genome Campus Hinxton UK

Experimental and Molecular Pediatric Cardiology German Heart Center Munich Technical University Munich Munich Germany

German Center for Cardiovascular Research Kiel Germany

German Center for Diabetes Research Neuherberg Germany

Institut für Humangenetik Technische Universität Munich Munich Germany

Institute of Developmental Genetics Helmholtz Zentrum Munich German Research Center for Environmental Health GmbH Neuherberg Germany

Institute of Experimental Genetics German Mouse Clinic Helmholtz Center Munich German Research Center for Environmental Health Neuherberg Germany

Institute of Molecular Animal Breeding and Biotechnology Gene Center Ludwig Maximilians University Munich Munich Germany

Institute of Translational Genomics Helmholtz Zentrum München German Research Center for Environmental Health Neuherberg Germany

Klinik und Poliklinik Innere Medizin 1 Klinikum Rechts der Isar Technical University of Munich Munich Germany

Korea Mouse Phenotyping Consortium and BK21 Program for Veterinary Science Research Institute for Veterinary Science College of Veterinary Medicine Seoul National University Seoul South Korea

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto Ontario Canada

Mammalian Genetics Unit and Mary Lyon Centre Medical Research Council Harwell Institute Harwell UK

Mouse Biology Program University of California Davis Davis CA USA

Munich Cluster for Systems Neurology Adolf Butenandt Institut Ludwig Maximilians Universität Munich Munich Germany

Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen Denmark

Oxford Centre for Diabetes Endocrinology and Metabolism Radcliffe Department of Medicine University of Oxford Oxford UK

Research Unit of Molecular Epidemiology Institute of Epidemiology 2 Helmholtz Zentrum Munich Munich Germany

RIKEN BioResource Center Tsukuba Japan

SKL of Pharmaceutical Biotechnology and Model Animal Research Center Collaborative Innovation Center for Genetics and Development Nanjing Biomedical Research Institute Nanjing University Nanjing China

The Centre for Phenogenomics Toronto Ontario Canada

The Hospital for Sick Children Toronto Ontario Canada

The Jackson Laboratory Bar Harbor ME USA

TUM School of Medicine Technical University of Munich and Klinikum Rechts der Isar Munich Germany

Université de Strasbourg CNRS INSERM IGBMC Institut Clinique de la Souris PHENOMIN ICS Illkirch France

Université de Strasbourg CNRS INSERM Institut de Génétique Biologie Moléculaire et Cellulaire IGBMC Illkirch France

Wellcome Centre for Human Genetics Nuffield Department of Medicine University of Oxford Oxford UK

Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK

William Harvey Research Institute Charterhouse Square Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK

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Nat Cardiovasc Res. 2022 May;1(5):529-531. doi: 10.1038/s44161-022-00072-2. PubMed

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Comprehensive ECG reference intervals in C57BL/6N substrains provide a generalizable guide for cardiac electrophysiology studies in mice