title: Prevalence and significance of rare RYR2 variants in arrhythmogenic right ventricular cardiomyopathy/dysplasia: results of a systematic screening.
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. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2.
  
  
  OBJECTIVE
  We aimed 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 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available.
  
  
  CONCLUSIONS
  In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D.
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France; CHRU de Grenoble, Hopital Michallon, Biochimie et Génétique Moléculaire, Grenoble, France; Université Joseph Fourier, Grenoble, France; INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Roux-Buisson
authors.affiliation: UPMC Université Paris-6, INSERM UMRS-1166, Paris, France; Département de Cardiologie et Centre de Référence pour les Maladies Cardiaques Héréditaires; APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France; INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Gandjbakhch
authors.affiliation: Service de Cardiologie, Hôpital Pontchaillou, Rennes, France.
authors.forename: Erwan
authors.initials: E
authors.lastname: Donal
authors.affiliation: Service de Cardiologie, Institut du thorax, CHU de Nantes, Nantes, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Probst
authors.affiliation: Service de Cardiologie, Hôpital La Timone, Marseille, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Deharo
authors.affiliation: Service de Cardiologie, Hôpital Est, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Chevalier
authors.affiliation: Service de Cardiologie, Hôpital Cardiologique, Lille, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Klug
authors.affiliation: Service de Cardiologie, Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mansencal
authors.affiliation: Service de Cardiologie, Hôpital de l'Ile, Berne, Switzerland.
authors.forename: Etienne
authors.initials: E
authors.lastname: Delacretaz
authors.affiliation: Service de Cardiologie B, Hôpital Universitaire de Tours, Tours, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Cosnay
authors.affiliation: Service de Cardiologie, Hôpital Côte de Nacre, Caen, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Scanu
authors.affiliation: Service de Cardiologie, Hôpital Lariboisière, AP-HP, Université Paris 7, Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Extramiana
authors.affiliation: Service de Cardiologie, Hôpital Universitaire de Bâle, Bale, Switzerland.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Keller
authors.affiliation: UPMC Université Paris-6, INSERM UMRS-1166, Paris, France; Département de Cardiologie et Centre de Référence pour les Maladies Cardiaques Héréditaires; APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Hidden-Lucet
authors.affiliation: CHRU de Grenoble, Hopital Michallon, Biochimie et Génétique Moléculaire, Grenoble, France.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Trapani
authors.affiliation: UPMC Université Paris-6, INSERM UMRS-1166, Paris, France; Service d'Anatomie Pathologique, APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Fouret
authors.affiliation: Département de Cardiologie et Centre de Référence pour les Maladies Cardiaques Héréditaires; APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Frank
authors.affiliation: Département de Cardiologie et Centre de Référence pour les Maladies Cardiaques Héréditaires; APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France; Service de Biochimie, Unité de Cardiogénétique et Myogénétique, AP-HP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Fressart
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France; CHRU de Grenoble, Hopital Michallon, Biochimie et Génétique Moléculaire, Grenoble, France; Université Joseph Fourier, Grenoble, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Fauré
authors.affiliation: INSERM U836, Grenoble Institut des Neurosciences, Equipe Muscle et Pathologies, Grenoble, France; CHRU de Grenoble, Hopital Michallon, Biochimie et Génétique Moléculaire, Grenoble, France; Université Joseph Fourier, Grenoble, France.
authors.forename: Joel
authors.initials: J
authors.lastname: Lunardi
authors.affiliation: UPMC Université Paris-6, INSERM UMRS-1166, Paris, France; Département de Cardiologie et Centre de Référence pour les Maladies Cardiaques Héréditaires; APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France; Service de Cardiologie, Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne, France. Electronic address: philippe.charron@psl.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Charron
mesh_terms: D000328:Adult; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D003896:Desmosomes / Q000235:genetics; D003952:Diagnostic Imaging; D004562:Electrocardiography; D005091:Exons; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D015995:Prevalence; D011446:Prospective Studies; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D013557:Switzerland
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
keywords: Arrhythmogenic right ventricular dysplasia/cardiomyopathy; Mutation; RYR2 gene