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

Audain E, Wilsdon A, Breckpot J, Izarzugaza JM, Fitzgerald TW, Kahlert AK, Sifrim A, Wünnemann F, Perez-Riverol Y, Abdul-Khaliq H, Bak M, Bassett AS, Benson WD, Berger F, Daehnert I, Devriendt K, Dittrich S, Daubeney PE, Garg V, Hackmann K, Hoff K, Hofmann P, Dombrowsky G, Pickardt T, Bauer U, Keavney BD, Klaassen S, Kramer HH, Marshall CR, Milewicz DM, Lemaire S, Coselli JS, Mitchell ME, Tomita-Mitchell A, Prakash SK, Stamm K, Stewart AF, Silversides CK, Siebert R, Stiller B, Rosenfeld JA, Vater I, Postma AV, Caliebe A, Brook JD, Andelfinger G, Hurles ME, Thienpont B, Larsen LA, Hitz MP (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Book Volume: 17

Article Number: e1009679

Journal Issue: 7

DOI: 10.1371/journal.pgen.1009679

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 parentoffspring 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. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Max-Delbrück-Centrum für Molekulare Medizin / Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch Germany (DE) University of Copenhagen Denmark (DK) Royal Brompton Hospital United Kingdom (GB) University of Toronto Canada (CA) Medical College of Wisconsin (MCW) United States (USA) (US) Universitätsklinikum Ulm Germany (DE) University of Amsterdam Netherlands (NL) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Deutsches Herzzentrum Berlin Germany (DE) Universitätsklinikum Carl Gustav Carus Dresden Germany (DE) University of Nottingham United Kingdom (GB) European Molecular Biology Laboratory (EMBL) United Kingdom (GB) Institut de Cardiologie de Montréal Canada (CA) Baylor College of Medicine United States (USA) (US) University of Texas Health Science Center at Houston (UTHealth) United States (USA) (US) Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH Germany (DE) Competence Network for Congenital Heart Defects Germany (DE) Nationwide Children's Hospital United States (USA) (US) Universitätsklinikum des Saarlandes (UKS) Germany (DE) The European Bioinformatics Institute (EBI) United Kingdom (GB) Centre hospitalier de l'Université de Montréal (CHUM) Canada (CA) Universität Leipzig Germany (DE) Technical University of Denmark / Danmarks Tekniske Universitet (DTU) Denmark (DK) University of Ottawa Canada (CA) Wellcome Trust Sanger Institute - Genome Research Limited United Kingdom (GB)

How to cite

APA:

Audain, E., Wilsdon, A., Breckpot, J., Izarzugaza, J.M., Fitzgerald, T.W., Kahlert, A.K.,... Hitz, M.P. (2021). Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease. PLoS Genetics, 17(7). https://doi.org/10.1371/journal.pgen.1009679

MLA:

Audain, Enrique, et al. "Integrative analysis of genomic variants reveals new associations of candidate haploinsufficient genes with congenital heart disease." PLoS Genetics 17.7 (2021).

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