A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients
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Published:2023-07-07
Issue:6
Volume:16
Page:1276-1286
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ISSN:1937-5387
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Container-title:Journal of Cardiovascular Translational Research
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language:en
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Short-container-title:J. of Cardiovasc. Trans. Res.
Author:
Nagyova Emilia, Hoorntje Edgar T., te Rijdt Wouter P., Bosman Laurens P., Syrris Petros, Protonotarios Alexandros, Elliott Perry M., Tsatsopoulou Adalena, Mestroni Luisa, Taylor Matthew R. G., Sinagra Gianfranco, Merlo Marco, Wada Yuko, Horie Minoru, Mogensen Jens, Christensen Alex H., Gerull Brenda, Song Lei, Yao Yan, Fan Siyang, Saguner Ardan M., Duru Firat, Koskenvuo Juha W., Cruz Marino Tania, Tichnell Crystal, Judge Daniel P., Dooijes Dennis, Lekanne Deprez Ronald H., Basso Cristina, Pilichou Kalliopi, Bauce Barbara, Wilde Arthur A. M., Charron Philippe, Fressart Véronique, van der Heijden Jeroen F., van den Berg Maarten P., Asselbergs Folkert W., James Cynthia A., Jongbloed Jan D. H., Harakalova MagdalenaORCID, van Tintelen J. Peter
Abstract
Abstract
The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331). After reclassification, only 29% of patients remained carriers of two (likely) pathogenic variants. They reached the composite endpoint (ventricular arrhythmias, heart failure, and death) significantly earlier than patients with one or no remaining reclassified variant (hazard ratios of 1.9 and 1.8, respectively). Periodic reclassification of variants contributes to more accurate risk stratification and subsequent clinical management strategy.
Funder
Hartstichting NWO The Independent Research Fund Denmark Canadian Institute for Health Research Fondation Leducq Georg und Bertha Schwyzer-Winiker-Stiftung National Institutes of Health CRTrieste Foundation Fondazione Cassa di Risparmio di Gorizia Leonie-Wild Foundation Swiss Heart Foundation Swiss National Science Foundation Leyla Erkan Family Fund for ARVD Research Dr. Francis P. Chiramonte Private Foundation, Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins Bogle Foundation Healing Hearts Foundation Campanella Family Patrick J. Harrison Family Peter French Memorial Foundation Wilmerding Endowments
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Cardiology and Cardiovascular Medicine,Pharmaceutical Science,Genetics,Molecular Medicine
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