title: Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia.
abstract: BACKGROUND
  Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth.
  
  
  OBJECTIVE
  We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation.
  
  
  METHODS
  Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload-induced calcium release activity of the mutant channel in HEK293 cells.
  
  
  RESULTS
  We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload-induced calcium release activity under conditions that mimic catecholaminergic stress.
  
  
  CONCLUSIONS
  Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation.
authors: Cardiavant, Centro Médico Cardiológico, Las Palmas de Gran Canaria, Spain.
authors: Fernando
authors: F
authors: Wangüemert
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain.
authors: Cristina
authors: C
authors: Bosch Calero
authors: Cardiavant, Centro Médico Cardiológico, Las Palmas de Gran Canaria, Spain.
authors: Carmelo
authors: C
authors: Pérez
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain; Department of Medical Sciences, Universitat de Girona, Girona, Spain.
authors: Oscar
authors: O
authors: Campuzano
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain; Department of Medical Sciences, Universitat de Girona, Girona, Spain.
authors: Pedro
authors: P
authors: Beltran-Alvarez
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain; Department of Medical Sciences, Universitat de Girona, Girona, Spain.
authors: Fabiana S
authors: FS
authors: Scornik
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain; Department of Medical Sciences, Universitat de Girona, Girona, Spain.
authors: Anna
authors: A
authors: Iglesias
authors: Institut Clínic del Tòrax, Universitat de Barcelona, Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Paola
authors: P
authors: Berne
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain.
authors: Catarina
authors: C
authors: Allegue
authors: Cardiavant, Centro Médico Cardiológico, Las Palmas de Gran Canaria, Spain.
authors: Pablo M
authors: PM
authors: Ruiz Hernandez
authors: Institut Clínic del Tòrax, Universitat de Barcelona, Hospital Clínic de Barcelona, Barcelona, Spain.
authors: Josep
authors: J
authors: Brugada
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain; Department of Medical Sciences, Universitat de Girona, Girona, Spain. Electronic address: guillermo.perez@udg.edu.
authors: Guillermo J
authors: GJ
authors: Pérez
authors: Centre de Genètica Cardiovascular Universitat de Girona-IDIBGI, Girona, Spain; Institut Clínic del Tòrax, Universitat de Barcelona, Hospital Clínic de Barcelona, Barcelona, Spain; Hospital Universitari Josep Trueta, Girona, Spain.
authors: Ramon
authors: R
authors: Brugada
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000328:Adult; D002648:Child; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control; D017147:Defibrillators, Implantable; D015716:Electrocardiography, Ambulatory / Q000379:methods; D005080:Exercise Test / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D018570:Risk Assessment; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D013030:Spain; D017180:Tachycardia, Ventricular / Q000150:complications / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D016896:Treatment Outcome; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000319:Adrenergic beta-Antagonists; D019837:Ryanodine Receptor Calcium Release Channel
keywords: Arrhythmias; CPVT; Genetic testing; RyR2; SOICR; Sudden cardiac death