Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease

• Enrique Audain ,

  Contributed equally to this work with: Enrique Audain, Anna Wilsdon

  Roles Conceptualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing

  Affiliations Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany, German Center for Cardiovascular Research (DZHK), Kiel, Germany

  https://orcid.org/0000-0002-9201-7840

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• Anna Wilsdon ,

  Contributed equally to this work with: Enrique Audain, Anna Wilsdon

  Roles Data curation, Investigation, Writing – original draft

  Affiliation School of Life Sciences, University of Nottingham, University Park, Nottingham, United Kingdom

  https://orcid.org/0000-0003-2686-1039

  ⨯
• Jeroen Breckpot,

  Roles Data curation, Investigation, Writing – review & editing

  Affiliation Centre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

  ⨯
• Jose M. G. Izarzugaza,

  Roles Data curation, Formal analysis

  Affiliation Department of Health Technology, Technical University of Denmark, Lyngby, Denmark

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• Tomas W. Fitzgerald,

  Roles Methodology, Writing – review & editing

  Affiliation European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom

  https://orcid.org/0000-0002-2370-8496

  ⨯
• Anne-Karin Kahlert,

  Roles Data curation, Writing – review & editing

  Affiliations Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany, German Center for Cardiovascular Research (DZHK), Kiel, Germany, Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany

  ⨯
• Alejandro Sifrim,

  Roles Formal analysis, Methodology

  Affiliations Department of Human Genetics, University of Leuven, KU Leuven, Leuven, Belgium, Sanger Institute-EBI Single-Cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, United Kingdom

  https://orcid.org/0000-0001-8247-4020

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• Florian Wünnemann,

  Roles Methodology, Writing – review & editing

  Affiliation Montreal Heart Institute, Université de Montréal, Québec, Canada

  https://orcid.org/0000-0002-0978-6076

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• Yasset Perez-Riverol,

  Roles Methodology, Writing – review & editing

  Affiliation European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom

  https://orcid.org/0000-0001-6579-6941

  ⨯
• Hashim Abdul-Khaliq,

  Roles Data curation, Writing – review & editing

  Affiliation Clinic for Pediatric Cardiology—University Hospital of Saarland, Homburg (Saar), Germany

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• Mads Bak,

  Roles Data curation, Writing – review & editing

  Affiliations Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark, Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

  https://orcid.org/0000-0003-2762-1002

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• Anne S. Bassett,

  Roles Data curation, Writing – review & editing

  Affiliations Toronto Congenital Cardiac Centre for Adults, and Division of Cardiology, Department of Medicine, University Health Network, Toronto, Canada, Department of Psychiatry, University of Toronto, Toronto, Canada

  https://orcid.org/0000-0002-0681-7279

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• Woodrow D. Benson,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America

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• Felix Berger,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Congenital Heart Disease—Pediatric Cardiology, German Heart Center Berlin, Berlin, Germany

  https://orcid.org/0000-0001-7881-1557

  ⨯
• Ingo Daehnert,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Pediatric Cardiology and Congenital Heart Disease, Heart Center, University of Leipzig, Leipzig, Germany

  https://orcid.org/0000-0002-2773-689X

  ⨯
• Koenraad Devriendt,

  Roles Data curation, Writing – review & editing

  Affiliation Centre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium

  https://orcid.org/0000-0002-3651-2548

  ⨯
• Sven Dittrich,

  Roles Data curation

  Affiliation Department of Pediatric Cardiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany

  https://orcid.org/0000-0002-8455-3416

  ⨯
• Piers EF Daubeney,

  Roles Data curation

  Affiliation Division of Paediatric Cardiology, Royal Brompton Hospital, London, United Kingdom

  https://orcid.org/0000-0001-7573-8235

  ⨯
• Vidu Garg,

  Roles Data curation, Writing – review & editing

  Affiliations The Heart Center, Nationwide Children’s Hospital, Columbus, Ohio, United States of America, Department of Molecular Genetics, The Ohio State University, Columbus, Ohio, United States of America, Center for Cardiovascular Research, Nationwide Children’s Hospital, Columbus, Ohio, United States of America, Department of Pediatrics, The Ohio State University, Columbus, Ohio, United States of America

  https://orcid.org/0000-0002-3778-5927

  ⨯
• Karl Hackmann,

  Roles Data curation, Writing – review & editing

  Affiliation Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany

  https://orcid.org/0000-0003-4181-2120

  ⨯
• Kirstin Hoff,

  Roles Data curation, Writing – review & editing

  Affiliations Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany, German Center for Cardiovascular Research (DZHK), Kiel, Germany

  https://orcid.org/0000-0002-3259-2536

  ⨯
• Philipp Hofmann,

  Roles Data curation, Writing – review & editing

  Affiliations Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany, German Center for Cardiovascular Research (DZHK), Kiel, Germany

  ⨯
• Gregor Dombrowsky,

  Roles Data curation, Writing – review & editing

  Affiliations Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany, German Center for Cardiovascular Research (DZHK), Kiel, Germany

  https://orcid.org/0000-0003-2591-2682

  ⨯
• Thomas Pickardt,

  Roles Data curation, Resources

  Affiliation Competence Network for Congenital Heart Defects, Berlin, Germany

  https://orcid.org/0000-0003-0019-6325

  ⨯
• Ulrike Bauer,

  Roles Resources

  Affiliation Competence Network for Congenital Heart Defects, Berlin, Germany

  ⨯
• Bernard D. Keavney,

  Roles Data curation, Writing – review & editing

  Affiliations Division of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom, Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom

  https://orcid.org/0000-0001-9573-0812

  ⨯
• Sabine Klaassen,

  Roles Data curation, Writing – review & editing

  Affiliations Experimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Pediatric Cardiology, Berlin, Germany, DZHK (German Centre for Cardiovascular Research), partner site Berlin, Berlin, Germany

  ⨯
• Hans-Heiner Kramer,

  Roles Funding acquisition, Resources, Writing – review & editing

  Affiliations Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany, German Center for Cardiovascular Research (DZHK), Kiel, Germany

  ⨯
• Christian R. Marshall,

  Roles Data curation, Writing – review & editing

  Affiliations The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada, Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada

  ⨯
• Dianna M. Milewicz,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America

  https://orcid.org/0000-0002-7806-0068

  ⨯
• Scott Lemaire,

  Roles Data curation, Writing – review & editing

  Affiliation Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America

  ⨯
• Joseph S. Coselli,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America

  ⨯
• Michael E. Mitchell,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America

  ⨯
• Aoy Tomita-Mitchell,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America

  ⨯
• Siddharth K. Prakash,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America

  https://orcid.org/0000-0001-6341-9624

  ⨯
• Karl Stamm,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America

  https://orcid.org/0000-0002-7844-7326

  ⨯
• Alexandre F. R. Stewart,

  Roles Data curation, Writing – review & editing

  Affiliation Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada

  https://orcid.org/0000-0003-2673-9164

  ⨯
• Candice K. Silversides,

  Roles Data curation, Writing – review & editing

  Affiliation Toronto Congenital Cardiac Centre for Adults, and Division of Cardiology, Department of Medicine, University Health Network, Toronto, Canada

  ⨯
• Reiner Siebert,

  Roles Data curation, Writing – review & editing

  Affiliations Institute of Human Genetics, University Hospital Ulm, Ulm, Germany, Department of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany

  ⨯
• Brigitte Stiller,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg—Bad Krozingen, Freiburg, Germany

  https://orcid.org/0000-0002-7657-4647

  ⨯
• Jill A. Rosenfeld,

  Roles Data curation, Writing – original draft

  Affiliation Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America

  https://orcid.org/0000-0001-5664-7987

  ⨯
• Inga Vater,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany

  ⨯
• Alex V. Postma,

  Roles Data curation, Writing – review & editing

  Affiliations Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands, Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

  ⨯
• Almuth Caliebe,

  Roles Data curation, Writing – review & editing

  Affiliation Department of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany

  https://orcid.org/0000-0003-2157-425X

  ⨯
• J. David Brook,

  Roles Writing – review & editing

  Affiliation School of Life Sciences, University of Nottingham, University Park, Nottingham, United Kingdom

  ⨯
• Gregor Andelfinger,

  Roles Methodology, Writing – review & editing

  Affiliation Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Saint-Justine Research Centre, Université de Montréal, Montreal, Canada

  https://orcid.org/0000-0002-9047-0502

  ⨯
• Matthew E. Hurles,

  Roles Conceptualization, Funding acquisition, Writing – review & editing

  Affiliation Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom

  https://orcid.org/0000-0002-2333-7015

  ⨯
• Bernard Thienpont,

  Roles Conceptualization, Writing – review & editing

  Affiliations Centre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium, Laboratory of Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium

  https://orcid.org/0000-0002-8772-6845

  ⨯
• Lars Allan Larsen ,

  Roles Conceptualization, Data curation, Formal analysis, Writing – review & editing

  * E-mail: larsal@sund.ku.dk (LAL); Marc-Phillip.Hitz@uksh.de (MPH)

  Affiliation Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

  https://orcid.org/0000-0002-7536-1172

  ⨯
•  [ ... ],
• Marc-Phillip Hitz

  Roles Conceptualization, Data curation, Formal analysis, Writing – review & editing

  * E-mail: larsal@sund.ku.dk (LAL); Marc-Phillip.Hitz@uksh.de (MPH)

  Affiliations Department of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany, German Center for Cardiovascular Research (DZHK), Kiel, Germany, Department of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom

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