A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients
E. Nagyova, Edgar T. Hoorntje, Wouter P. te Rijdt, Laurens P. Bosman, Petros Syrris, Alexandros Protonotarios, Perry Elliott, Adalena Tsatsopoulou, Luisa Mestroni, Matthew R.G. Taylor, Gianfranco Sinagra, Marco Merlo, Yuko Wada, Minoru Horie, Jens Mogensen, Alex Hørby Christensen, Brenda Gerull, Lei Song, Yan Yao, Siyang Fan, Ardan M. Saguner, Fırat Duru, Juha Koskenvuo, Tania Cruz Mariño, 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, Magdaléna Harakaľová, J. Peter van Tintelen
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. Graphical Abstract.