Desmoglein-2 splice-site variant associated with arrhythmogenic right ventricular cardiomyopathy: description of ten patients and hypothesis of a founder effect

Background Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare inherited cardiomyopathy with incomplete penetrance, associated with pathogenic variants in desmosomal genes such as desmoglein-2 (DSG2) (1). Recurrent detection of identical variants within geographically restricted populations may indicate a founder effect (2). This study aimed to describe the clinical phenotype of patients carrying a previously reported DSG2 variant, assess genotype-phenotype correlations, and explore the hypothesis of a founder effect. Methods This study includes patients between 2012 and 2025 from the Multicenter Zurich ARVC Registry, carrying the c.523+2T>C splicing variant in DSG2 (2). A diagnosis of ARVC was based on the 2010 Task Force Criteria (TFC). Clinical, electrocardiographic, imaging, and outcome data were collected. Haplotype analyses are ongoing to assess a potential common founder effect. Results Ten patients were included, of whom seven met the 2010 TFC for definite ARVC. Six probands and four first-degree relatives, all born in Switzerland, were analyzed. Median age at symptom onset was 24 years. Among patients with definite ARVC, 3 exhibited a predominant right ventricular phenotype, while 4 showed biventricular involvement. All probands received an implantable cardioverter-defibrillator, one underwent heart transplantation, and two died. The more severe phenotypes are reported in homozygous patients (n=3) or patients with high sport training. This variant affects a consensus donor splice site and presents a gnomAD v4.0 allele frequency 1.25 x 10-6; compatible with the disease. No homozygote carrier is reported in GnomAD. Its clustering in Switzerland suggests local enrichment and a potential founder effect, currently being investigated by haplotype analysis. Conclusion This study highlights the phenotypic heterogeneity of patients carrying c.523+2T>C DSG2 variant, with a phenotypic severity associated with the cumulative effect of the homozygous variant or high intensity exercise. The recurrence of this variant in unrelated patients from a restricted geographic area suggests a founder effect, with implications for risk stratification, genetic diagnosis, and counseling.