title: Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing.
abstract: BACKGROUND
  Mutations in the RyR2-encoded cardiac ryanodine receptor/calcium release channel and in CASQ2-encoded calsequestrin cause catecholaminergic polymorphic ventricular tachycardia (CPVT1 and CPVT2, respectively).
  
  
  OBJECTIVE
  The purpose of this study was to evaluate the extent of genotypic and phenotypic heterogeneity among referrals for CPVT genetic testing.
  
  
  METHODS
  Using denaturing high-performance liquid chromatography and DNA sequencing, mutational analysis of 23 RyR2 exons previously implicated in CPVT1, comprehensive analysis of all translated exons in CASQ2 (CPVT2), KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), KCNE2 (LQT6), and KCNJ2 (Andersen-Tawil syndrome [ATS1], also annotated LQT7), and analysis of 10 ANK2 exons implicated in LQT4 were performed on genomic DNA from 11 unrelated patients (8 females) referred to Mayo Clinic's Sudden Death Genomics Laboratory explicitly for CPVT genetic testing.
  
  
  RESULTS
  Overall, putative disease causing mutations were identified in 8 patients (72%). Only 4 patients (3 males) hosted CPVT1-associated RyR2 mutations: P164S, V186M, S3938R, and T4196A. Interestingly, 4 females instead possessed either ATS1- or LQT5-associated mutations. Mutations were absent in >400 reference alleles.
  
  
  CONCLUSIONS
  Putative CPVT1-causing mutations in RyR2 were seen in <40% of unrelated patients referred with a diagnosis of CPVT and preferentially in males. Phenotypic mimicry is evident with the identification of ATS1- and LQT5-associated mutations in females displaying a normal QT interval and exercise-induced bidirectional VT, suggesting that observed exercise-induced polymorphic VT in patients may reflect disorders other than CPVT. Clinical consideration for either Andersen-Tawil syndrome or long QT syndrome and appropriate genetic testing may be warranted for individuals with RyR2 mutation-negative CPVT, particularly females.
authors.affiliation: Department of Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Puneeta
authors.initials: P
authors.lastname: Arya
authors.forename: Melissa
authors.initials: M
authors.lastname: Will
authors.forename: Carla M
authors.initials: CM
authors.lastname: Haglund
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Farley
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
mesh_terms: D000293:Adolescent; D000328:Adult; D002395:Catecholamines / Q000378:metabolism*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000175:diagnosis* / Q000235:genetics*
chemical_list: D002395:Catecholamines; D019837:Ryanodine Receptor Calcium Release Channel; D004247:DNA