A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients

Emilia Nagyova, Edgar T Hoorntje, Wouter P Te Rijdt, Laurens P Bosman, Petros Syrris, Alexandros Protonotarios, Perry M Elliott, Adalena Tsatsopoulou, Luisa Mestroni, Matthew R G Taylor, Gianfranco Sinagra, Marco Merlo, Yuko Wada, Minoru Horie, Jens Mogensen, Alex H Christensen, Brenda Gerull, Lei Song, Yan Yao, Siyang FanArdan M Saguner, Firat Duru, Juha W Koskenvuo, Tania Cruz Marino, Crystal Tichnell, Daniel P Judge, Dennis Dooijes, Ronald H Lekanne Deprez, Cristina Basso, Kalliopi Pilichou, Barbara Bauce, Arthur A M Wilde, Philippe Charron, Véronique Fressart, Jeroen F van der Heijden, Maarten P van den Berg, Folkert W Asselbergs, Cynthia A James, Jan D H Jongbloed, Magdalena Harakalova*, J Peter van Tintelen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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. [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)1276-1286
Number of pages11
JournalJournal of Cardiovascular Translational Research
Volume16
Issue number6
Early online date7 Jul 2023
DOIs
Publication statusPublished - Dec 2023

Keywords

  • Arrhythmia
  • ARVC
  • Composite endpoint
  • Desmosomal genes
  • Genetics
  • Multiple variants

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