Targeted next generation sequencing and multiplex ligation-dependent probe amplification analysis results in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) and the possible link with phenotype

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a well-defined hereditary disorder. Its prevalence in the adult population is 1/2000-1/5000. The most common disease causing mutations related to ARVC phenotype are reported in PKP2, DSP and DSG2 genes. However, approximately 40-50% of cases that meet the diagnostic criteria, the genetic cause cannot be identified. It has being suggested that copy number variations or yet unknown gene mutations may be responsible for these patients. Furthermore, genetic status of patients with ARVC in our country is very limited. The study cohort consists of 24 ARVC index patients and their 10 relatives. Cardiomyopathy Next Generation Sequencing (NGS) panel containing 54 genes and PKP2, DSG2, DSC2, JUP, DSP, TGFB3, and RYR2 genes' multiple ligation-induced probe amplification (MLPA) results and clinical features of the patients were analyzed retrospectively. Three pathogenic (P), six likely pathogenic (LP) and eighty six VUS (variant of unknown significance) changes were found in the study cohort with 37,5% (P, OP) detection rate. PKP2 gene mutations were found to be the most frequent pathogenic changes. PKP2 gene c.939delC, c.713del and, DSP gene c.803del mutations were novel. The PKP2 c.939delC mutation was detected in 3 unrelated cases and it was thought that it might be a founder mutation effect for our region. For this purpose, further studies are needed. No deletion or duplication was found in the MLPA analysis of index patients. This study is the first ARVC case series in our country using the NGS and MLPA methods. Genetic testing in ARVC allows family screening and to identify family members at risk. As studies increase, the genotype-phenotype correlation of ARVC will be understood better and personalized approaches in the medical practice will be possible.