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.
METHODS AND 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.
CONCLUSION: 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.