A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients
Publication date
2023-12
Authors
Nagyova, Emilia
Hoorntje, Edgar T
Rijdt, Wouter P Te
Bosman, Laurens P.
Syrris, Petros
Protonotarios, Alexandros
Elliott, Perry M
Tsatsopoulou, Adalena
Mestroni, Luisa
Taylor, Matthew R G
Editors
Advisors
Supervisors
Document Type
Article
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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.].
Keywords
Arrhythmia, ARVC, Composite endpoint, Desmosomal genes, Genetics, Multiple variants, Cardiology and Cardiovascular Medicine, Genetics(clinical), Genetics, Molecular Medicine, Pharmaceutical Science, Journal Article
Citation
Nagyova, E, Hoorntje, E T, Rijdt, W P T, Bosman, L P, Syrris, P, Protonotarios, A, Elliott, P M, Tsatsopoulou, A, Mestroni, L, Taylor, M R G, Sinagra, G, Merlo, M, Wada, Y, Horie, M, Mogensen, J, Christensen, A H, Gerull, B, Song, L, Yao, Y, Fan, S, Saguner, A M, Duru, F, Koskenvuo, J W, Cruz Marino, T, Tichnell, C, Judge, D P, Dooijes, D, Lekanne Deprez, R H, Basso, C, Pilichou, K, Bauce, B, Wilde, A A M, Charron, P, Fressart, V, van der Heijden, J F, van den Berg, M P, Asselbergs, F W, James, C A, Jongbloed, J D H, Harakalova, M & van Tintelen, J P 2023, 'A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients', Journal of Cardiovascular Translational Research, vol. 16, no. 6, pp. 1276-1286. https://doi.org/10.1007/s12265-023-10403-8