Screening of whole RYR 2 gene in arrhythmogenic right ventricular cardiomyopahy/dysplasia

Abstract

Introduction: Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia (ARVC/D) is predominantly caused by desmosomal gene mutations, that account for only ∼50% of ARVC/D cases. RYR2 gene mutations usually cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) but have been associated with atypical phenotype of ARVC/D. In addition RYR2 is a large gene, therefore usually not analysed in routine. We aim to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population. Methods and results: We analyzed the whole RyR2 coding sequence (105 exons and related splice sites) in a population of 64 ARVC/D probands without desmosomal gene mutations. We identified six heterozygous putative missense mutations in six unrelated probands. Two (p.Pro1583Ser and p.Leu4670Val) were considered as disease-causing mutations and four (p.Ala2213Ser, p.Gly2367Arg, p.Tyr2932His, p.Val3219Me) were considered as genetic variants of unknown significance (GVUS). Phenotype associated with RYR2 variants was unremarkable, associating typical ECG abnormalities, frequent monomorphic ventricular tachycardia with only a minority developing polymorphic ventricular arrhythmias. All displayed typical right ventricular (RV) abnormalities associating RV dilatation and wall motion abnormalities. Fibro-fatty replacement was demonstrated when tissue available for analysis. Conclusion: In this first systematic screening of the whole RyR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we observed that (i) putative mutations were not infrequent (9% of ARVC/D probands) and (i) were predominantly associated with a conventional phenotype of ARVC/D, not overlapping with CPVT, in contrast with previous findings. Therefore, we propose that RYR2 gene should be added to the panel of genes analysed in patients with ARVC/D.