Increased Risk of Arrhythmic Events in Long-QT Syndrome With Mutations in the Pore Region of the Human Ether-a-go-go–Related Gene Potassium Channel

Background — The hereditary long-QT syndrome is characterized by prolonged ventricular repolarization and a variable clinical course with arrhythmia-related syncope and sudden death. Mutations involving the human ether-a-go-go–related gene (HERG) channel are responsible for the LQT2 form of long-QT syndrome, and in cellular expression studies these mutations are associated with reduction in the rapid component of the delayed rectifier repolarizing current (I Kr ). We investigated the clinical features and prognostic implications of mutations involving pore and nonpore regions of the HERG channel in the LQT2 form of this disorder. Methods and Results — A total of 44 different HERG mutations were identified in 201 subjects, with 14 mutations located in the pore region (amino acid residues 550 through 650). Thirty-five subjects had mutations in the pore region and 166 in nonpore regions. Follow-up extended through age 40 years. Subjects with pore mutations had more severe clinical manifestations of the genetic disorder and experienced a higher frequency (74% versus 35%; P <0.001) of arrhythmia-related cardiac events occurring at earlier age than did subjects with nonpore mutations. Multivariate Cox proportional hazard regression analysis revealed that pore mutations dominated the risk, with hazard ratios in the range of 11 ( P <0.0001) for QTc at 500 ms, with a 16% increase in the pore hazard ratio for each 10-ms increase in QTc. Conclusion — Patients with mutations in the pore region of the HERG gene are at markedly increased risk for arrhythmia-related cardiac events compared with patients with nonpore mutations.