Nathalie Roux-Buisson1, Estelle Gandjbakhch2, Erwan Donal3, Vincent Probst4, Jean-Claude Deharo5, Philippe Chevalier6, Didier Klug7, Nicolas Mansencal8, Etienne Delacretaz9, Pierre Cosnay10, Patrice Scanu11, Fabrice Extramiana12, Dagmar Keller13, Françoise Hidden-Lucet14, Jonathan Trapani15, Pierre Fouret16, Robert Frank17, Veronique Fressart18, Julien Fauré19, Joel Lunardi19, Philippe Charron20. 1. 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. 2. 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. 3. Service de Cardiologie, Hôpital Pontchaillou, Rennes, France. 4. Service de Cardiologie, Institut du thorax, CHU de Nantes, Nantes, France. 5. Service de Cardiologie, Hôpital La Timone, Marseille, France. 6. Service de Cardiologie, Hôpital Est, Lyon, France. 7. Service de Cardiologie, Hôpital Cardiologique, Lille, France. 8. Service de Cardiologie, Université de Versailles-Saint Quentin, Hôpital Ambroise Paré, AP-HP, Boulogne, France. 9. Service de Cardiologie, Hôpital de l'Ile, Berne, Switzerland. 10. Service de Cardiologie B, Hôpital Universitaire de Tours, Tours, France. 11. Service de Cardiologie, Hôpital Côte de Nacre, Caen, France. 12. Service de Cardiologie, Hôpital Lariboisière, AP-HP, Université Paris 7, Paris, France. 13. Service de Cardiologie, Hôpital Universitaire de Bâle, Bale, Switzerland. 14. 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. 15. CHRU de Grenoble, Hopital Michallon, Biochimie et Génétique Moléculaire, Grenoble, France. 16. UPMC Université Paris-6, INSERM UMRS-1166, Paris, France; Service d'Anatomie Pathologique, APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France. 17. Département de Cardiologie et Centre de Référence pour les Maladies Cardiaques Héréditaires; APHP, Hôpital Universitaire Pitié-Salpêtrière, Paris, France. 18. 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. 19. 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. 20. 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.
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. CONCLUSION: 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.
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. CONCLUSION: 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: David J Tester; Jaeger P Ackerman; John R Giudicessi; Nicholas C Ackerman; Marina Cerrone; Mario Delmar; Michael J Ackerman Journal: JACC Clin Electrophysiol Date: 2018-11-01
Authors: C L Hertz; S L Christiansen; L Ferrero-Miliani; M Dahl; P E Weeke; G L Ottesen; R Frank-Hansen; H Bundgaard; N Morling Journal: Int J Legal Med Date: 2015-09-17 Impact factor: 2.686
Authors: Karyn M Austin; Michael A Trembley; Stephanie F Chandler; Stephen P Sanders; Jeffrey E Saffitz; Dominic J Abrams; William T Pu Journal: Nat Rev Cardiol Date: 2019-09 Impact factor: 32.419
Authors: Kobra Haghighi; George Gardner; Elizabeth Vafiadaki; Mohit Kumar; Lisa C Green; Jianyong Ma; Jeffrey S Crocker; Sheryl Koch; Demetrios A Arvanitis; Phillip Bidwell; Jack Rubinstein; Rutger van de Leur; Pieter A Doevendans; Fadi G Akar; Michael Tranter; Hong-Sheng Wang; Sakthivel Sadayappan; Deeptankar DeMazumder; Despina Sanoudou; Roger J Hajjar; Francesca Stillitano; Evangelia G Kranias Journal: J Pers Med Date: 2021-06-03