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

Emilia Nagyova^#^{1

2}, Edgar T Hoorntje^#^{3

4}, Wouter P Te Rijdt^{3

4}, Laurens P Bosman¹, Petros Syrris⁵, Alexandros Protonotarios^{5

6}, Perry M Elliott⁵, Adalena Tsatsopoulou⁶, Luisa Mestroni⁷, Matthew R G Taylor⁷, Gianfranco Sinagra⁸, Marco Merlo⁸, Yuko Wada^{9

10}, Minoru Horie¹⁰, Jens Mogensen¹¹, Alex H Christensen¹², Brenda Gerull^{13

14}, Lei Song¹⁵, Yan Yao¹⁵, Siyang Fan¹⁵, Ardan M Saguner¹⁶, Firat Duru¹⁶, Juha W Koskenvuo¹⁷, Tania Cruz Marino¹⁸, Crystal Tichnell¹⁹, Daniel P Judge²⁰, Dennis Dooijes^{21

22}, Ronald H Lekanne Deprez^{22

23}, Cristina Basso^{22

24}, Kalliopi Pilichou^{22

24}, Barbara Bauce²⁴, Arthur A M Wilde^{22

25}, Philippe Charron²⁶, Véronique Fressart²⁶, Jeroen F van der Heijden¹, Maarten P van den Berg²⁷, Folkert W Asselbergs^{1

22

28

29}, Cynthia A James¹⁹, Jan D H Jongbloed³, Magdalena Harakalova^#^{30

31

32}, J Peter van Tintelen^#^{4

22

23

21}

Affiliations

¹ Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
² Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
³ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴ Netherlands Heart Institute, Utrecht, The Netherlands.
⁵ Center for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
⁶ Nikos Protonotarios Medical Center, 84300, Naxos, Greece.
⁷ Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Cardiothoracovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.
⁹ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan.
¹¹ Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
¹² Department of Cardiology, Herlev-Gentofte and Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹³ Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada.
¹⁴ Comprehensive Heart Failure Center (CHFC) and Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
¹⁵ Arrhythmia Center and Clinical EP Laboratory, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Disease, Fuwai Hospital, Peking Union Medical College-Chinese Academy of Medical Sciences, Beijing, China.
¹⁶ Department of Cardiology, University Heart Center, Zurich, Switzerland.
¹⁷ Blueprint Genetics, Helsinki, Finland.
¹⁸ Department of Medical Biology, CIUSSS Saguenay Lac-St-Jean, Chicoutimi, QC, Canada.
¹⁹ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.
²⁰ Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, USA.
²¹ Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
²² .
²³ Department of Human Genetics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
²⁴ Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.
²⁵ Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
²⁶ APHP, Referral Center for Cardiac Hereditary Diseases, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France.
²⁷ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁸ Institute of Cardiovascular Science, Faculty of Population Health Science, University College London, London, UK.
²⁹ Health Data Research UK and Institute of Health Informatics, University College London, London, UK.
³⁰ Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. m.harakalova@umcutrecht.nl.
³¹ Netherlands Heart Institute, Utrecht, The Netherlands. m.harakalova@umcutrecht.nl.
³² Regenerative Medicine Utrecht (RMU), University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. m.harakalova@umcutrecht.nl.

^# Contributed equally.

PMID: 37418234
PMCID: PMC10721666
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 et al. J Cardiovasc Transl Res. 2023 Dec.

. 2023 Dec;16(6):1276-1286.

doi: 10.1007/s12265-023-10403-8. Epub 2023 Jul 7.

Authors

Affiliations

¹ Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands.
² Department of Molecular Biology, Faculty of Natural Sciences, Comenius University in Bratislava, Bratislava, Slovakia.
³ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴ Netherlands Heart Institute, Utrecht, The Netherlands.
⁵ Center for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, London, UK.
⁶ Nikos Protonotarios Medical Center, 84300, Naxos, Greece.
⁷ Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁸ Cardiothoracovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina (ASUGI), Trieste, Italy.
⁹ Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
¹⁰ Department of Cardiovascular Medicine, Shiga University of Medical Science, Otsu, Japan.
¹¹ Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.
¹² Department of Cardiology, Herlev-Gentofte and Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
¹³ Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada.
¹⁴ Comprehensive Heart Failure Center (CHFC) and Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
¹⁵ Arrhythmia Center and Clinical EP Laboratory, State Key Laboratory of Cardiovascular Diseases, National Center for Cardiovascular Disease, Fuwai Hospital, Peking Union Medical College-Chinese Academy of Medical Sciences, Beijing, China.
¹⁶ Department of Cardiology, University Heart Center, Zurich, Switzerland.
¹⁷ Blueprint Genetics, Helsinki, Finland.
¹⁸ Department of Medical Biology, CIUSSS Saguenay Lac-St-Jean, Chicoutimi, QC, Canada.
¹⁹ Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA.
²⁰ Division of Cardiology, Department of Medicine, Medical University of South Carolina, Charleston, USA.
²¹ Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
²² .
²³ Department of Human Genetics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
²⁴ Department of Cardiac-Thoracic-Vascular Sciences and Public Health, University of Padua, Padua, Italy.
²⁵ Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
²⁶ APHP, Referral Center for Cardiac Hereditary Diseases, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France.
²⁷ Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
²⁸ Institute of Cardiovascular Science, Faculty of Population Health Science, University College London, London, UK.
²⁹ Health Data Research UK and Institute of Health Informatics, University College London, London, UK.
³⁰ Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. m.harakalova@umcutrecht.nl.
³¹ Netherlands Heart Institute, Utrecht, The Netherlands. m.harakalova@umcutrecht.nl.
³² Regenerative Medicine Utrecht (RMU), University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands. m.harakalova@umcutrecht.nl.

^# Contributed equally.

PMID: 37418234
PMCID: PMC10721666
DOI: 10.1007/s12265-023-10403-8

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.

Keywords: ARVC; Arrhythmia; Composite endpoint; Desmosomal genes; Genetics; Multiple variants.

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Conflict of interest statement

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).

Figures

**Fig. 1**
Study workflow and scheme of publication selection with information on patients with two or more ARVC-related desmosomal variants and subsequent patient selection for the database. *61 out of the 65 articles overlapped with the systematic PubMed search, ^number of patients after including information from contacted authors. Patient groups are based on the number of (likely) pathogenic ARVC variants after reclassification; P, pathogenic variant; LP, likely pathogenic variant; VUS, variant with uncertain significance; LB, likely Benign variant; B, benign variant

**Fig. 2**
Kaplan–Meier survival analysis. Group 1 (double P/LP variant carriers), Group 2 (one P/LP variant carrier), and Group 3 (no P/LP variant carrier). A All. **B, C** All, stratified for sex. **D, E** All, stratified for proband status

**Fig. 3**
Kaplan–Meier survival analysis of homozygous Naxos and homozygous Hutterite founder variant carriers. A Kaplan–Meier curves of homozygous Naxos variant carriers, Group 2 (one P/LP variant carrier) and Group 3 (no P/LP carrier). B Kaplan–Meier curves of homozygous Hutterite variant carriers, Group 2 (one or none P/LP variant carrier), and Group 3 (no P/LP variant carrier)

See this image and copyright information in PMC

References

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

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

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