Introduction: The familial short QT syndrome (SQTS) is a rare channelopathies associated with an increased risk of cardiac arrhythmia and sudden cardiac death (SCD) or sudden infant death syndrome (SIDS). Here, we report phenotypic and function expression of another apparent hotspot in KCNH2 associated with SQTS. Methods: Probands from the United States, Canada, Europe and Asia diagnosed with SQTS and their family members were evaluated clinically and by genetic screening. KCNH2 wild- type (WT) and mutated genes were cloned and transiently expressed in HEK293 cells and currents were recorded using whole cell patch-clamp and action potential (AP) clamp recording techniques. Results: KCNH2-T618I, a previously reported variant, was identified in 13 patients of 5 unrelated families (61.5% males, age 27.2±3.7 years). All carriers were clinically diagnosed as SQTS, showing 100% penetrance with variable expressivity. Eight members of the 5 families experienced SCD/SIDS (50.0% males, age 34.8±6.6 years, 9 weeks to 58 years). The average QTc of probands was 298.9±10.8 ms and of all mutant carriers was 313.0±5.8 ms. A distinct U wave was evident in V3 in 11 cases (84.6%). All symptomatic patients (23.1%) were female. Three families received an ICD and one patient had ICD shocks. One family was treated and responded well to quinidine therapy. Threonine (T) at position 618 is a highly conserved residue in the pore of the channel. Functional studies showed a significant gain-of-function of IKr tail current density at -40 mV following depolarization to +50 mV compared with WT (207.5±25.8 pA/pF vs 122.7±12.2 pA/pF; n=10 respectively, P<0.01). Steady-state activation was shifted by 3.71 mV and activation kinetics was faster for mutant vs. WT channels. AP clamp recordings showed that IKr was larger and peak repolarizing current occurred earlier in mutant vs. WT channels. Conclusions: We report the most frequent mutation in KCNH2 contributing to the development of type 1 SQTS with high incidence of SCD/SIDS secondary to a gain-of-function in IKr. These findings extend our understanding of the spectrum of phenotypic and genotypic expression of hERG channel defects in SQTS.
THE SPECTRUM OF MOST FREQUENT MUTATION IN SHORT QT SYNDROME
GIUSTETTO, Carla;GAITA, Fiorenzo;
2014-01-01
Abstract
Introduction: The familial short QT syndrome (SQTS) is a rare channelopathies associated with an increased risk of cardiac arrhythmia and sudden cardiac death (SCD) or sudden infant death syndrome (SIDS). Here, we report phenotypic and function expression of another apparent hotspot in KCNH2 associated with SQTS. Methods: Probands from the United States, Canada, Europe and Asia diagnosed with SQTS and their family members were evaluated clinically and by genetic screening. KCNH2 wild- type (WT) and mutated genes were cloned and transiently expressed in HEK293 cells and currents were recorded using whole cell patch-clamp and action potential (AP) clamp recording techniques. Results: KCNH2-T618I, a previously reported variant, was identified in 13 patients of 5 unrelated families (61.5% males, age 27.2±3.7 years). All carriers were clinically diagnosed as SQTS, showing 100% penetrance with variable expressivity. Eight members of the 5 families experienced SCD/SIDS (50.0% males, age 34.8±6.6 years, 9 weeks to 58 years). The average QTc of probands was 298.9±10.8 ms and of all mutant carriers was 313.0±5.8 ms. A distinct U wave was evident in V3 in 11 cases (84.6%). All symptomatic patients (23.1%) were female. Three families received an ICD and one patient had ICD shocks. One family was treated and responded well to quinidine therapy. Threonine (T) at position 618 is a highly conserved residue in the pore of the channel. Functional studies showed a significant gain-of-function of IKr tail current density at -40 mV following depolarization to +50 mV compared with WT (207.5±25.8 pA/pF vs 122.7±12.2 pA/pF; n=10 respectively, P<0.01). Steady-state activation was shifted by 3.71 mV and activation kinetics was faster for mutant vs. WT channels. AP clamp recordings showed that IKr was larger and peak repolarizing current occurred earlier in mutant vs. WT channels. Conclusions: We report the most frequent mutation in KCNH2 contributing to the development of type 1 SQTS with high incidence of SCD/SIDS secondary to a gain-of-function in IKr. These findings extend our understanding of the spectrum of phenotypic and genotypic expression of hERG channel defects in SQTS.
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