Abstract 2736: Mutations In The Nonpore Region of The HERG Gene Are at Risk of Acquired Long QT Syndrome

Introduction : Mutations involving the KCNH2 gene in HERG channel are responsible for type2 LQTS. Previous study showed patients with mutations in the pore region of the HERG gene are markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations. However, a few data exist regarding mode of onset and frequency in arrhythmic events of mutations in the nonpore regions of the HERG channel. Hypothesis :We hypothesized that patients with mutations in the nonpore regions of the HERG gene increase risk for cardiac events under a specific condition. Methods: We examined 104 unrelated subjects with LQTS. Genetic analysis of KCNH2 gene was performed using standard genetic tests for probands and families of genotyped ones.Between subjects with and without pore mutations,difference in clinical characteristics such as QTc intervals, LQT score and major cardiac events are evaluated by standard statistical methods. Result: We identified 7 LQT2 patients with 3 pore mutations and 17 patients with 7 nonpore mutation, and evaluated clinical characteristics and characterized the electrophysiological properties of these mutations. The baseline QTc intervals were significantly longer with pore than with nonpore mutations (513 ± 60ms vs. 479 ± 21ms, p<0.01). The LQTS scores determined by Schwartz’s criteria were also significantly higher with pore mutations (4.5 ± 1.2 vs. 2.9 ± 1.2, p<0.01). However the frequency of LQTS-related cardiac events with nonpore mutaion was as high as with pore mutations (57 % vs. 30 %, N.S). Significantly 4 of 5 cardiac events with nonpore mutations occurred under medications (Probucol) or conditions (Hypokalemia) known to favor QT prolongation, although only 1 of 4 cardiac events with pore mutations did. Electrophysiological study revealed that the tail current amplitude through one nonpore mutant channel(M124T)was significantly decreased as compared that of WT HERG channel and Probucol significantly inhibited M124T HERG channels. Conclusions: These data demonstrate that LQT2 patients with nonpore mutations are also at high risk of arrhythmia-related events in the presence of drugs or other environmental stressors.