Overlapping LQT1 and LQT2 Phenotype in a Patient with Long QT Syndrome Associated with Loss-of-Function Variations in KCNQ1 and KCNH2

Abstract

Background: Long QT Syndrome (LQTS) is an inherited disorder characterized by prolonged QT intervals and potentially life-threatening arrhythmias. Mutations in several ion channel genes are responsible for LQTS. Here we describe a patient with LQTS who has a mutation in KCNQ1 as well as a polymorphism in KCNH2. Methods and Results: The proband (MMRL0362), a 32 yo female, exhibited multiple ventricular extrasystoles and episodes of syncope. Her ECG (QTc=518ms) showed an LQT2 morphology in leads V4-V6 and LQT1 morphology in leads V1-V2. Genomic DNA was isolated from lymphocytes. All exons and intron borders of 7 LQTS susceptibility genes were amplified and sequenced. Variations were detected predicting a novel missense mutation (V110I) in KCNQ1 as well as a common polymorphism in KCNH2 (K897T). We expressed WT or V110I KCNQ1 channels in CHO-K1 cells co-transfected with KCNE1 and performed patch clamp experiments. In addition, WT or K897T KCNH2 were studied by patch clamp. Current-voltage (I-V) relations for V110I showed a significant reduction in both developing and tail current densities compared to WT at potentials >+20 mV (p<0.05), suggesting a reduction in IKs currents. K897T-HERG channels displayed a significantly reduced tail current density compared to WT-HERG at potentials >+10 mV. Interestingly, channel availability assessed using a triple-pulse protocol was slightly greater for K897T compared to WT (V0.5=−53.1±1.13 mV and −60.7±1.15 mV for K897T and WT, respectively, p<0.05). Comparison of the fully activated I-V revealed no difference in the rectification properties between WT and K897T channels. Conclusions: We report a patient with a loss-of-function mutation in KCNQ1 and a loss-of-function polymorphism in KCNH2. Our results suggest that a reduction of both IKr and IKs underlies the combined LQT1 and LQT2 phenotype in this patient.