Arrhythmogenic Cardiomyopathy: Exercise and Divergent Phenotypes in a Family With a Pathogenic PKP2 Variant.

BACKGROUND

Arrhythmogenic cardiomyopathy (ACM) is an inherited myocardial disorder characterized by progressive fibrofatty replacement of the myocardium, predisposing affected individuals to ventricular arrhythmias and sudden cardiac death. Pathogenic variants in desmosomal genes, most frequently PKP2, are the predominant genetic basis of ACM. Genotype-positive individuals demonstrate marked variability in penetrance and phenotypic expression, influenced by several modifiers, including intense exercise.

CASE SUMMARY: To illustrate the marked variability in disease expression associated with desmosomal variants, we describe a family carrying a pathogenic PKP2 splice-site variant (c.337-2A>T) demonstrating pronounced intrafamilial heterogeneity.

DISCUSSION: Despite sharing the same genetic substrate, affected family members exhibited a wide spectrum of clinical manifestations, ranging from symptomatic ventricular arrhythmias to complete absence of disease features. Specifically, the family member who engaged most consistently in regular intense exercise appeared to have the least phenotypic expression of ACM.

TAKE-HOME MESSAGE: Notably, the phenotypic pattern observed in this family challenges the prevailing perception that exercise uniformly exacerbates disease expression in PKP2-associated ACM, underscoring the complexity of gene-environment interactions in this condition.