title: The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis.
abstract: OBJECTIVE
  This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc).
  
  
  BACKGROUND
  Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts.
  
  
  METHODS
  Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45).
  
  
  RESULTS
  Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons.
  
  
  CONCLUSIONS
  Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Argelia
authors.initials: A
authors.lastname: Medeiros-Domingo
authors.forename: Zahurul A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Nynke
authors.initials: N
authors.lastname: Hofman
authors.forename: Hennie
authors.initials: H
authors.lastname: Bikker
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000328:Adult; D015220:Calcium Channels / Q000235:genetics; D002395:Catecholamines / Q000378:metabolism; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology; D015444:Exercise / Q000502:physiology; D005080:Exercise Test; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics; D008297:Male; D009030:Mosaicism; D016366:Open Reading Frames / Q000235:genetics*; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D013575:Syncope / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics*; D055815:Young Adult
chemical_list: D015220:Calcium Channels; D002395:Catecholamines; D019837:Ryanodine Receptor Calcium Release Channel