title: Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia.
abstract: BACKGROUND
  Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias.
  
  
  RESULTS
  We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes.
  
  
  CONCLUSIONS
  We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.
authors.affiliation: Department of Cardiology, University of Helsinki, Helsinki, Finland. annukka.marjamaa@helsinki.fi
authors.forename: Annukka
authors.initials: A
authors.lastname: Marjamaa
authors.forename: Päivi
authors.initials: P
authors.lastname: Laitinen-Forsblom
authors.forename: Annukka M
authors.initials: AM
authors.lastname: Lahtinen
authors.forename: Matti
authors.initials: M
authors.lastname: Viitasalo
authors.forename: Lauri
authors.initials: L
authors.lastname: Toivonen
authors.forename: Kimmo
authors.initials: K
authors.lastname: Kontula
authors.forename: Heikki
authors.initials: H
authors.lastname: Swan
mesh_terms: D000293:Adolescent; D000328:Adult; D002395:Catecholamines / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004562:Electrocardiography; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010641:Phenotype; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics*; D018879:Ventricular Premature Complexes / Q000235:genetics*; D055815:Young Adult
chemical_list: D002395:Catecholamines; D019837:Ryanodine Receptor Calcium Release Channel