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

Objective To determine the spectrum and prevalence of mutations in the RYR2-encoded the cardiac ryanodine receptor in cases with exertional syncope and normal QTc. Background Mutations in the 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 PCR, DHPLC, and DNA sequencing on 155 unrelated patients (49% females, 96% white, 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 (LQTS) but with QTc < 480 ms and a subsequent negative LQTS 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 one of 16 exons. Conclusions Possible CPVT1 mutations in RYR2 were identified in nearly half of this cohort. 45 of the 105 translated exons are now known to host possible mutations. Considering that ~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.