title: Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing.
abstract: BACKGROUND
  Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1).
  
  
  OBJECTIVE
  Because CPVT and concealed long QT syndrome (LQTS) phenotypically mimic one other, we sought to determine the spectrum and prevalence of RyR2 mutations in a cohort of unrelated patients who were referred specifically for LQTS genetic testing.
  
  
  METHODS
  Using denaturing high-performance liquid chromatography and direct DNA sequencing, targeted mutational analysis of 23 RyR2 exons previously implicated in CPVT1 was performed on genomic DNA from 269 unrelated patients (180 females, average age at diagnosis 24 +/- 17 years) who were referred to Mayo Clinic's Sudden Death Genomics Laboratory for LQTS genetic testing. Previously, comprehensive mutational analysis of the five LQTS-associated cardiac channel genes proved negative for this entire subset of patients now designated as "genotype-negative" LQTS referrals.
  
  
  RESULTS
  Fifteen distinct RyR2 mutations (14 missense, 1 duplication/insertion, 12 novel) were found in 17 (6.3%) of 269 patients. None of these mutations were present in 400 reference alleles. Two mutations localized to the calstabin-2 (FKBP12.6) binding domain. Upon review of the clinical records, the referral diagnosis for all 17 patients was "atypical" or "borderline" LQTS.
  
  
  CONCLUSIONS
  Putative pathogenic CPVT1-causing mutations in RyR2 were detected in 6% of unrelated, genotype-negative LQTS referrals. These findings suggest that CPVT may be underrecognized among physicians referring patients because of a suspected channelopathy. A diagnosis of "atypical LQTS" may warrant consideration of CPVT and analysis of RyR2 if the standard cardiac channel gene screen for LQTS is negative.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Kopplin
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Will
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology; D005080:Exercise Test; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D009200:Myocardial Contraction / Q000502:physiology; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D012017:Referral and Consultation; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000235:genetics / Q000503:physiopathology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel