Biallelic Genetic Variant in the DSG2 Gene Associated with Arrhythmogenic Right Ventricular Cardiomyopathy

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disorder characterized by fibrous or fibro-fatty myocardial tissue replacement leading to the life-threatening ventricular arrhythmias and progressive heart failure (HF). Most of the known genetic subtypes of ARVC, including the DSG2-associated form, are characterized by an autosomal dominant pattern of inheritance. Cases of compound heterozygous and digenic forms of ARVC are relatively rare and typically manifest in childhood or adolescence. The aim of this study is to characterize a rare biallelic form of ARVC caused by a homozygous mutation c.581C>T (p.Ser194Leu) in the DSG2 gene based on our own and published data. Methods: The study cohort included 80 probands who underwent clinical examination and genetic testing using NGS of 16 genes. Haplotype analysis was performed for the probands homozygous for the DSG2 c.581C>T (p.Ser194Leu) variant. Results: The rare form of ARVC was identified in three probands originating from the Republic of Dagestan and representing Dargin ethnic group. We assessed the frequency of the minor T allele in groups of 150 healthy volunteers, including 20 from the Republic of Dagestan, and 300 cardiomyopathy patients who are presumably natives of the North Caucasian Highland Region. The c.581C>T (p.Ser194Leu) variant was not detected in any of the DNA samples analyzed, indicating the rarity of this form of ARVC. The fact that three probands with the rare form of ARVC originate from the same minor ethnicity (Dargins) with a high rate of consanguineous marriages suggests a common ancestor for these families. All three probands shared a haplotype of approximately 4.01 Mb surrounding DSG2 c.581C>T. Conclusions: Our study contributes to expanding the knowledge of the molecular causes of cardiomyopathies in poorly studied populations, underrepresented in international databases, and to establishing genotype–phenotypic correlations.