Key result
PKP2 c.1211dup variant linked to right-dominant ACM and sustained ventricular arrhythmias in ~27% of carriers.
Why the study?
The arrhythmogenic cardiomyopathy phenotype varies by genetic etiology, and the phenotype associated with the PKP2 c.1211dup variant was not well characterized compared to other Dutch PKP2 founder variants.
What is the arrhythmogenic cardiomyopathy phenotype associated with the PKP2 c.1211dup variant compared to other Dutch PKP2 founder variants?
Cohort (n=106)
Yes
What is the arrhythmogenic cardiomyopathy phenotype associated with the PKP2 c.1211dup variant compared to other Dutch PKP2 founder variants?
The PKP2 c.1211dup variant is a Dutch founder variant associated with a typical right-dominant ACM phenotype, left ventricular involvement, and potentially greater severity than other Dutch PKP2 founder variants.
Supports arrhythmia surveillance in PKP2 c.1211dup carriers; extends Dutch founder variant data but remains hypothesis-generating.
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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Bos et al. (2023) conducted a cohort in Arrhythmogenic cardiomyopathy (n=106). PKP2 c.1211dup variant vs. Other PKP2 truncating variants (c.235C>T, c.397C>T, c.2489+1G>A) was evaluated on Sustained ventricular arrhythmias. The PKP2 c.1211dup variant is associated with a right-dominant arrhythmogenic cardiomyopathy phenotype, with 27% of carriers experiencing sustained ventricular arrhythmias and 11% developing heart failure.
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