A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients
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; 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, Magdalena; van Tintelen, J Peter
(2023) Journal of Cardiovascular Translational Research, volume 16, issue 6, pp. 1276 - 1286
(Article)
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
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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.].
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Keywords: Arrhythmia, ARVC, Composite endpoint, Desmosomal genes, Genetics, Multiple variants, Cardiology and Cardiovascular Medicine, Genetics(clinical), Genetics, Molecular Medicine, Pharmaceutical Science, Journal Article
ISSN: 1937-5387
Publisher: Springer New York
Note: Funding Information: AMS received educational grants through his institution from Abbott, Bayer Healthcare, Biosense Webster, Biotronik, Boston Scientific, BMS/Pfizer, and Medtronic, and speaker fees from Bayer Healthcare, Daiichi-Sankyo, and Novartis. DPJ reports payments as a consultant from 4D Molecular Therapeutics, ADRx, Inc., Cytokinetics, Pfizer, and Tenaya Therapeutics outside of the scope of this work. CAJ receives salary support on a grant from Boston Scientific Corp through her institution and payment as a consultant from Pfizer and StrideBio, Inc. Consultant LQT Therapeutics (AW). Funding Information: The work was financially supported by the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CardioVasculair Onderzoek Nederland (CVON) projects 2014–40 DOSIS, 2020B005 Double Dose, 2015–30 eDETECT and 2018–30 PREDICT2 (MH, WPtR, FWA, AW, PvT), NWO VENI grant [no. 016.176.136 to MH], The Independent Research Fund Denmark (Grant 0134-00363B, AHC), the Canadian Institute for Health Research (grant no. FRN: 123351, BG) and the Leducq Foundation CURE-PLaN project 18CVD01 (MH, WPtR, FWA, PvT) and the Netherlands Organisation for Scientific Research (NWO) 040.11.586, visitor’s travel grant to C.A. James. The Zurich ARVC Program is supported by generous grants from the Georg and Bertha Schwyzer-Winiker-Stiftung, National Institute of Health (NIH) grants: R01HL69071, R01HL116906, R01HL147064 (LM, MRGT), R01HL109209 (MRGT), CRTrieste Foundation, Baugarten and Cassa di Risparmio of Gorizia Foundation, Leonie-Wild Foundation, Swiss Heart Foundation, and Swiss National Science Foundation. The Johns Hopkins ARVC Program is supported by the Leonie-Wild Foundation, the Leyla Erkan Family Fund for ARVD Research, the Dr. Francis P. Chiramonte Private Foundation, the Dr. Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation, the Campanella Family, the Patrick J. Harrison Family, the Peter French Memorial Foundation, and the Wilmerding Endowments (GS), Foundation Leducq 14-CVD03 Trans-Atlantic Network of Excellence (LM, MRGT, GS). Publisher Copyright: © 2023, The Author(s). Publisher Copyright: © 2023, The Author(s).
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