Arrhythmogenic Cardiomyopathy PKP2-Related: Clinical and Functional Characterization of a Pathogenic Variant Detected in Two Italian Families

Background/Objectives: PKP2 (MIM *602861) is the most commonly gene associated with Arrhythmogenic Cardiomyopathy (ACM), an inherited cardiac muscle disorder. The aim of this study was to characterize the phenotypical effect of a heterozygous pathogenic c.2443_2448delAACACCinsGAAA variant in PKP2 gene (NM_004572), detected in two Italian families. Methods: Next Generation Sequencing (NGS) analysis was carried out on two probands, testing a multigenic targeted panel. Segregation analysis through Sanger sequencing detected other three and six positive members, in Family 1 and 2, respectively. Thus, eleven positive patients were identified overall. A deep clinical evaluation was performed according to age groups and clinical parameters (symptoms, electrocardiogram, imaging, and devices). To investigate the molecular effect of the identified variant on PKP2 expression level, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) and quantitative RT-polymerase chain reaction was performed. PKP2 expression at the protein level was analyzed on PBMCs by Western blot analysis. Results: PKP2 transcriptional levels resulted to be reduced by 48% in cells carrying c.2443_2448delAACACCinsGAAA variant compared to WT cells (p = 0.00015). Importantly, Western blot confirmed the reduced level of PKP2 protein in two heterozygous carriers of the variant, confirming the haploinsufficiency effect. Conclusions: The clinical onset of ACM can be Sudden Cardiac Death, and hence, it is recommended to perform a segregation test on first-degree relatives of pathogenic variant carriers, even if they are asymptomatic, with the purpose of promptly detecting those at risk.