The Phenotypic Spectrum of a Mutation Hotspot Responsible for the Short QT Syndrome

OBJECTIVES: This study sought to evaluate the phenotypic and functional expression of an apparent hotspot mutation associated with short QT syndrome (SQTS). BACKGROUND: SQTS is a rare channelopathy associated with a high risk of life-threatening arrhythmias and sudden cardiac death (SCD). METHODS: Probands diagnosed with SQTS and their family members were evaluated clinically and genetically. KCNH2 wild-type (WT) and mutant genes were transiently expressed in HEK293 cells, and currents were recorded using whole-cell patch clamp and action potential (AP) clamp techniques. RESULTS: KCNH2-T618I was identified in 18 members of 7 unrelated families (10 men; median age: 24.0 years). All carriers showed 100% penetrance with variable expressivity. Eighteen members in 7 families had SCD. The average QTc intervals of probands and all carriers was 294.1 ± 23.8 ms and 313.2 ± 23.8 ms, respectively. Seven carriers received an implantable cardioverter-defibrillator. Quinidine with adequate plasma levels was effective in prolonging QTc intervals among 5 cases, but 3 cases still had premature ventricular contraction or nonsustained ventricular tachycardia. Bepridil successfully prevented drug-refractory ventricular fibrillation in 1 case with 19-ms prolongation of the QTc interval. Functional studies with KCNE2 revealed a significant increase of I_Kr (rapidly activating delayed rectifier potassium channel) tail-current density in homozygous (119.0%) and heterozygous (74.6%) expression compared with WT. AP clamp recordings showed I_Kr was larger, and peak repolarizing current occurred earlier in mutant versus WT channels. CONCLUSIONS: We reported the clinical characteristics and biophysical properties of the highly frequent mutation that contributes to genetically identified SQTS probands. These findings extend our understanding of the spectrum of KCNH2 channel defects in SQTS.