ArticlePLoS genetics2021
Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease.
Erratum issuedOpen access · goldAbstract read
In one paragraph
Article in PLoS genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 26 papers, 1 of them a synthesis that pooled it.
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26citing papers in PubMed, 1 pooled it
2.2field-weighted citation impact, top 11% of its field
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Who cites it
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
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- Assessing the contribution of rare variants to congenital heart disease through a large-scale case-control exome study.NPJ genomic medicine · 2026Article
- Spectrum of Copy Number Variants in Fetal Congenital Heart Disease and Their Clinical Implications: A Retrospective Study from a Tertiary Care Center.Diagnostics (Basel, Switzerland) · 2026Article
- DNA methylation analysis of NOTCH1 variants reveals the first episignature for non-syndromic congenital heart defects.Genome medicine · 2026Article
- Congenital heart disease missense mutations in the TBX5 DNA-binding domain alter thermal stability and DNA-binding affinity.G3 (Bethesda, Md.) · 2025Article
- Current and future diagnostics of congenital heart disease (CHD).Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Notch3 is an asymmetric gene and a modifier of heart looping defects in Nodal mouse mutants.PLoS biology · 2025Article
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- STIGMA: Single-cell tissue-specific gene prioritization using machine learning.American journal of human genetics · 2024Article
- Discovery ofAmerican journal of translational research · 2024Article
- Human Genetics of Congenital Heart Defects.Advances in experimental medicine and biology · 2024Review
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- Heart Disease and Stroke Statistics-2023 Update: A Report From the American Heart Association.Circulation · 2023Review
- The implication of chromosomal abnormalities in the surgical outcomes of Chinese pediatric patients with congenital heart disease.Frontiers in cardiovascular medicine · 2023Article
- Prospects for precision genetic medicine in congenital heart disease.Current opinion in genetics & development · 2022Review
Corrections and comments
- Erratum issued
Authors and funding
50 authors at 20 institutions in 7 countries.
Enrique AudainDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.ORCID 0000-0002-9201-7840
Anna WilsdonSchool of Life Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.ORCID 0000-0003-2686-1039
Jeroen BreckpotCentre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.
Jose M G IzarzugazaDepartment of Health Technology, Technical University of Denmark, Lyngby, Denmark.
Tomas W FitzgeraldEuropean Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Cambridge, United Kingdom.ORCID 0000-0002-2370-8496
Anne-Karin KahlertDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.
Alejandro SifrimDepartment of Human Genetics, University of Leuven, KU Leuven, Leuven, Belgium.ORCID 0000-0001-8247-4020
Florian WünnemannMontreal Heart Institute, Université de Montréal, Québec, Canada.ORCID 0000-0002-0978-6076
Yasset Perez-RiverolEuropean Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.ORCID 0000-0001-6579-6941
Hashim Abdul-KhaliqClinic for Pediatric Cardiology-University Hospital of Saarland, Homburg (Saar), Germany.
Mads BakDepartment of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.ORCID 0000-0003-2762-1002
Anne S BassettToronto Congenital Cardiac Centre for Adults, and Division of Cardiology, Department of Medicine, University Health Network, Toronto, Canada.ORCID 0000-0002-0681-7279
D Woodrow BensonDepartment of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Felix BergerDepartment of Congenital Heart Disease-Pediatric Cardiology, German Heart Center Berlin, Berlin, Germany.ORCID 0000-0001-7881-1557
Ingo DaehnertDepartment of Pediatric Cardiology and Congenital Heart Disease, Heart Center, University of Leipzig, Leipzig, Germany.ORCID 0000-0002-2773-689X
Koenraad DevriendtCentre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.ORCID 0000-0002-3651-2548
Sven DittrichDepartment of Pediatric Cardiology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany.ORCID 0000-0002-8455-3416
Piers Ef DaubeneyDivision of Paediatric Cardiology, Royal Brompton Hospital, London, United Kingdom.ORCID 0000-0001-7573-8235
Vidu GargThe Heart Center, Nationwide Children's Hospital, Columbus, Ohio, United States of America.ORCID 0000-0002-3778-5927
Karl HackmannInstitute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.ORCID 0000-0003-4181-2120
Kirstin HoffDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.ORCID 0000-0002-3259-2536
Philipp HofmannDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.
Gregor DombrowskyDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.ORCID 0000-0003-2591-2682
Thomas PickardtCompetence Network for Congenital Heart Defects, Berlin, Germany.ORCID 0000-0003-0019-6325
Ulrike BauerCompetence Network for Congenital Heart Defects, Berlin, Germany.
Bernard D KeavneyDivision of Cardiovascular Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, United Kingdom.ORCID 0000-0001-9573-0812
Sabine KlaassenExperimental and Clinical Research Center (ECRC), a joint cooperation between the Charité Medical Faculty and the Max-Delbrück-Center for Molecular Medicine (MDC), Berlin, Germany.
Hans-Heiner KramerDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.
Christian R MarshallThe Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Canada.
Dianna M MilewiczDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.ORCID 0000-0002-7806-0068
Scott LemaireMichael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, United States of America.
Joseph S CoselliDepartment of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Michael E MitchellDepartment of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Aoy Tomita-MitchellDepartment of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.
Siddharth K PrakashDepartment of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, United States of America.ORCID 0000-0001-6341-9624
Karl StammDepartment of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.ORCID 0000-0002-7844-7326
Alexandre F R StewartRuddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada.ORCID 0000-0003-2673-9164
Candice K SilversidesToronto Congenital Cardiac Centre for Adults, and Division of Cardiology, Department of Medicine, University Health Network, Toronto, Canada.
Reiner SiebertInstitute of Human Genetics, University Hospital Ulm, Ulm, Germany.
Brigitte StillerDepartment of Congenital Heart Disease and Pediatric Cardiology, University Heart Center Freiburg-Bad Krozingen, Freiburg, Germany.ORCID 0000-0002-7657-4647
Jill A RosenfeldDepartment of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America.ORCID 0000-0001-5664-7987
Inga VaterDepartment of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.
Alex V PostmaDepartment of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Almuth CaliebeDepartment of Human Genetics, University Medical Center Schleswig-Holstein (UKSH), Kiel, Germany.ORCID 0000-0003-2157-425X
J David BrookSchool of Life Sciences, University of Nottingham, University Park, Nottingham, United Kingdom.
Gregor AndelfingerCardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Saint-Justine Research Centre, Université de Montréal, Montreal, Canada.ORCID 0000-0002-9047-0502
Matthew E HurlesWellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.ORCID 0000-0002-2333-7015
Bernard ThienpontCentre for Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium.ORCID 0000-0002-8772-6845
Lars Allan LarsenDepartment of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.ORCID 0000-0002-7536-1172
Marc-Phillip HitzDepartment of Congenital Heart Disease and Pediatric Cardiology, University Hospital of Schleswig-Holstein, Kiel, Germany.
University Hospital Schleswig-Holstein · DEMedical College of Wisconsin · USKU Leuven · BEWellcome Sanger Institute · GBDeutsches Herzzentrum München · DEEuropean Bioinformatics Institute · GBThe University of Texas Health Science Center at Houston · USUniversity Health Network · CAUniversity of Copenhagen · DKUniversity of Nottingham · GBAmsterdam University Medical Centers · NLBaylor College of Medicine · USCentre Hospitalier Universitaire Sainte-Justine · CADeutsches Herzzentrum der Charité · DEFriedrich-Alexander-Universität Erlangen-Nürnberg · DEHospital for Sick Children · CALeipzig Heart Institute · DEMax Delbrück Center · DEMontreal Heart Institute · CANationwide Children's Hospital · US
Funding
Genetic Basis of Early Onset Bicuspid Aortic Valve DiseaseR01HL137028 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI PRAKASH, SIDDHARTH KUMAR · 2017 to 2020
$1.5MBritish Heart Foundation CH/13/2/30154British Heart Foundation FS/14/51/30879British Heart Foundation RG/13/10/30376British Heart Foundation RG/15/12/31616British Heart Foundation RG/F/21/110050NHLBI NIH HHS R01 HL137028
Abstract
Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.
Indexed as
Databases, GeneticDNA Copy Number VariationsGene ExpressionGene Expression ProfilingGenetic Predisposition to DiseaseGenomicsHaploinsufficiencyHeart Defects, CongenitalHumansIon ChannelsMembrane ProteinsPolymorphism, Single NucleotideTranscriptomeIon ChannelsMembrane Proteins
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