Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: results of a systematic screening.

Nathalie Roux-Buisson 1, 2, 3, * Estelle Gandjbakhch 4, 5 Erwan Donal 6, 7 Vincent Probst 8 Jean-Claude Deharo 9 Philippe Chevalier 10 Didier Klug 11 Nicolas Mansencal 12 Etienne Delecretaz 13 Pierre Cosnay 14 Patrice Scanu 15 Fabrice Extramiana 16 Dagmar Keller 17 Françoise Hidden-Lucet 5, 4 Jonathan Trapani 2 Pierre Fouret 5, 4 Robert Frank 5 Véronique Fressart 18, 5 Julien Fauré 1, 2, 3 Joel Lunardi 1, 2, 3 Philippe Charron 5, 13, 4
Abstract : Background Arrhythmogenic right ventricular Cardiomyopathy/Dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. RYR2 gene mutations usually cause Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) but have been associated with peculiar phenotype named ARVC2. Objectives We aim to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population. Methods We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations. Results We have identified six rare missense variants p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M and p.L4670V. It corresponds to a prevalence of 9% of rare RYR2 variants in ARVC/D population (6 probands/64) that is significantly higher than the estimated rate of rare RYR2 variants in control (Fisher test, p=0.03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical ECG abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities and fibro-fatty replacement when histopathological examination was available.
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Heart Rhythm, Elsevier, 2014, pp.1999-2009
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Nathalie Roux-Buisson, Estelle Gandjbakhch, Erwan Donal, Vincent Probst, Jean-Claude Deharo, et al.. Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: results of a systematic screening.. Heart Rhythm, Elsevier, 2014, pp.1999-2009. 〈inserm-01120324〉

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