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 Fan; Ardan 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

doi:10.1007/s12265-023-10403-8

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 journal › Journal article › Research › peer-review

2 Citations (Scopus)

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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 language	English
Journal	Journal of Cardiovascular Translational Research
Volume	16
Issue number	6
Pages (from-to)	1276-1286
ISSN	1937-5387
DOIs	https://doi.org/10.1007/s12265-023-10403-8
Publication status	Published - 2023

Bibliographical note

Publisher Copyright:
© 2023, The Author(s).

Keywords

Arrhythmia
ARVC
Composite endpoint
Desmosomal genes
Genetics
Multiple variants

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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., ... 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, 16(6), 1276-1286. https://doi.org/10.1007/s12265-023-10403-8

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; Deprez, Ronald H. Lekanne; 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.

In: Journal of Cardiovascular Translational Research, Vol. 16, No. 6, 2023, p. 1276-1286.

Research output: Contribution to journal › Journal article › Research › peer-review

Nagyova, E, Hoorntje, ET, Rijdt, WPT, Bosman, LP, Syrris, P, Protonotarios, A, Elliott, PM, Tsatsopoulou, A, Mestroni, L, Taylor, MRG, Sinagra, G, Merlo, M, Wada, Y, Horie, M, Mogensen, J, Christensen, AH, Gerull, B, Song, L, Yao, Y, Fan, S, Saguner, AM, Duru, F, Koskenvuo, JW, Cruz Marino, T, Tichnell, C, Judge, DP, Dooijes, D, Deprez, RHL, Basso, C, Pilichou, K, Bauce, B, Wilde, AAM, Charron, P, Fressart, V, van der Heijden, JF, van den Berg, MP, Asselbergs, FW, James, CA, Jongbloed, JDH, Harakalova, M & van Tintelen, JP 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

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 ; Deprez, Ronald H. Lekanne ; 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. / A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients. In: Journal of Cardiovascular Translational Research. 2023 ; Vol. 16, No. 6. pp. 1276-1286.

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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.].",

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AU - Hoorntje, Edgar T.

AU - Rijdt, Wouter P.te

AU - Bosman, Laurens P.

AU - Syrris, Petros

AU - Protonotarios, Alexandros

AU - Elliott, Perry M.

AU - Tsatsopoulou, Adalena

AU - Mestroni, Luisa

AU - Taylor, Matthew R. G.

AU - Sinagra, Gianfranco

AU - Merlo, Marco

AU - Wada, Yuko

AU - Horie, Minoru

AU - Mogensen, Jens

AU - Christensen, Alex H.

AU - Gerull, Brenda

AU - Song, Lei

AU - Yao, Yan

AU - Fan, Siyang

AU - Saguner, Ardan M.

AU - Duru, Firat

AU - Koskenvuo, Juha W.

AU - Cruz Marino, Tania

AU - Tichnell, Crystal

AU - Judge, Daniel P.

AU - Dooijes, Dennis

AU - Deprez, Ronald H. Lekanne

AU - Basso, Cristina

AU - Pilichou, Kalliopi

AU - Bauce, Barbara

AU - Wilde, Arthur A. M.

AU - Charron, Philippe

AU - Fressart, Véronique

AU - van der Heijden, Jeroen F.

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N2 - 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.].

AB - 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.].

KW - Arrhythmia

KW - ARVC

KW - Composite endpoint

KW - Desmosomal genes

KW - Genetics

KW - Multiple variants

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JF - Journal of Cardiovascular Translational Research

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