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

Thomas A Bos1, Sebastiaan R D Piers2, Marja W Wessels3

  • 1Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.

Netherlands Heart Journal : Monthly Journal of the Netherlands Society of Cardiology and the Netherlands Heart Foundation
|July 28, 2023
PubMed

Insights

The plakophilin-2 (PKP2) c.1211dup variant is a Dutch founder mutation linked to arrhythmogenic cardiomyopathy (ACM). This variant presents a typically right-dominant ACM phenotype, with potential left ventricular involvement and a more severe clinical course compared to other PKP2 founder variants.

Area of Science:

  • Genetics
  • Cardiology
  • Molecular Biology

Background:

  • Arrhythmogenic cardiomyopathy (ACM) exhibits variable phenotypes based on genetic causes.
  • Plakophilin-2 (PKP2) gene variants are a significant genetic etiology for ACM.
  • Understanding genotype-phenotype correlations is crucial for managing ACM.

Purpose of the Study:

  • To characterize the ACM phenotype associated with the PKP2 c.1211dup variant.
  • To compare the c.1211dup variant phenotype with other known Dutch PKP2 founder variants.
  • To investigate the founder status and origin of the PKP2 c.1211dup variant in the Netherlands.

Main Methods:

  • Retrospective analysis of clinical data from 106 PKP2 c.1211dup heterozygous carriers.
  • Comparison with three other truncating PKP2 variants using data from the Netherlands ACM Registry.
  • Haplotype analysis and geographical distribution assessment to determine founder status.

Main Results:

  • 44% of carriers were diagnosed with ACM, with a mean age of 41 years.
  • Ventricular arrhythmias and heart failure occurred in 27% and 11% of carriers, respectively, with higher risks in males.
  • Cardiac imaging revealed right ventricular involvement in 46% and left ventricular involvement in 37% of carriers.
  • The c.1211dup variant is likely a founder variant from the South-Western coast of the Netherlands.
  • Significant differences in arrhythmia-free survival were observed among four PKP2 founder variants.

Conclusions:

  • The PKP2 c.1211dup variant is a Dutch founder mutation.
  • It is associated with a predominantly right-dominant ACM phenotype, but also exhibits left ventricular involvement.
  • The c.1211dup variant may be associated with a more severe ACM phenotype compared to other Dutch PKP2 founder variants.
Abstract

Keywords:
Arrhythmogenic CardiomyopathyFounder mutationGeneticsPlakophilin‑2

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