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Open Access 28-07-2023 | Cardiomyopathy | Original Article

The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant

Authors: Thomas A. Bos, Sebastiaan R. D. Piers, Marja W. Wessels, Arjan C. Houweling, Regina Bökenkamp, Marianne Bootsma, Laurens P. Bosman, Reinder Evertz, Debby M. E. I. Hellebrekers, Yvonne M. Hoedemaekers, Jeroen Knijnenburg, Ronald Lekanne Deprez, Anneke M. van Mil, Anneline S. J. M. te Riele, Marjon A. van Slegtenhorst, Arthur A. M. Wilde, Sing-Chien Yap, Dennis Dooijes, Tamara T. Koopmann, J. Peter van Tintelen, Daniela Q. C. M. Barge-Schaapveld, European Reference Network for rare, low prevalence and complex diseases of the heart: ERN GUARD-Heart

Published in: Netherlands Heart Journal | Issue 7-8/2023

Abstract

Background

The arrhythmogenic cardiomyopathy (ACM) phenotype, with life-threatening ventricular arrhythmias and heart failure, varies according to genetic aetiology. We aimed to characterise the phenotype associated with the variant c.1211dup (p.Val406Serfs*4) in the plakophilin‑2 gene (PKP2) and compare it with previously reported Dutch PKP2 founder variants.

Methods

Clinical data were collected retrospectively from medical records of 106 PKP2 c.1211dup heterozygous carriers. Using data from the Netherlands ACM Registry, c.1211dup was compared with 3 other truncating PKP2 variants (c.235C > T (p.Arg79*), c.397C > T (p.Gln133*) and c.2489+1G > A (p.?)).

Results

Of the 106 carriers, 47 (44%) were diagnosed with ACM, at a mean age of 41 years. By the end of follow-up, 29 (27%) had experienced sustained ventricular arrhythmias and 12 (11%) had developed heart failure, with male carriers showing significantly higher risks than females on these endpoints (p < 0.05). Based on available cardiac magnetic resonance imaging and echocardiographic data, 46% of the carriers showed either right ventricular dilatation and/or dysfunction, whereas a substantial minority (37%) had some form of left ventricular involvement. Both geographical distribution of carriers and haplotype analysis suggested PKP2 c.1211dup to be a founder variant originating from the South-Western coast of the Netherlands. Finally, a Cox proportional hazards model suggested significant differences in ventricular arrhythmia–free survival between 4 PKP2 founder variants, including c.1211dup.

Conclusions

The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, but also left ventricular involvement, and a possibly more severe phenotype than other Dutch PKP2 founder variants.

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Title: The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant
Authors: Thomas A. Bos
Sebastiaan R. D. Piers
Marja W. Wessels
Arjan C. Houweling
Regina Bökenkamp
Marianne Bootsma
Laurens P. Bosman
Reinder Evertz
Debby M. E. I. Hellebrekers
Yvonne M. Hoedemaekers
Jeroen Knijnenburg
Ronald Lekanne Deprez
Anneke M. van Mil
Anneline S. J. M. te Riele
Marjon A. van Slegtenhorst
Arthur A. M. Wilde
Sing-Chien Yap
Dennis Dooijes
Tamara T. Koopmann
J. Peter van Tintelen
Daniela Q. C. M. Barge-Schaapveld
European Reference Network for rare, low prevalence and complex diseases of the heart: ERN GUARD-Heart
Publication date: 28-07-2023
Publisher: Bohn Stafleu van Loghum
Keywords: Cardiomyopathy
Heart Failure
Ventricular Tachycardia
Published in: Netherlands Heart Journal / Issue 7-8/2023
Print ISSN: 1568-5888
Electronic ISSN: 1876-6250
DOI: https://doi.org/10.1007/s12471-023-01791-2

2024 ASCO Annual Meeting

Springer Medicine

The arrhythmogenic cardiomyopathy phenotype associated with PKP2 c.1211dup variant

Abstract

Background

Methods

Results

Conclusions

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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