Genotype-Phenotype Aspects of Type 2 Long QT Syndrome

Objectives To investigate the effect of location, coding type, and topology of KCNH2(hERG) mutations on clinical phenotype in Type-2 long-QT syndrome. Backgrounds Previous studies were limited by population size in their ability to examine phenotypic effect of location, type and topology. Methods Study subjects included 858 Type-2 long-QT syndrome patients with 162 different KCNH2 mutations in 213 proband-identified families. The Cox proportional-hazards survivorship model was used to evaluate independent contribution of clinical and genetic factors to the first cardiac events. Results For patients with missense mutations, the transmembrane pore (S5-loop-S6) and N-terminus regions were a significantly greater risk than the C-terminus region (HR=2.87 and 1.86, respectively), but the transmembrane non-pore (S1-S4) region was not (HR=1.19). Additionally, the transmembrane pore region was significantly riskier than the N-terminus or transmembrane non-pore regions (HR=1.54, 2.42). However, for non-missense mutations, these other regions were no longer riskier than the C-terminus (HR=1.13, 0.77 and 0.46, respectively). Likewise, subjects with non-missense mutations were at significantly higher risk than those with missense mutations in the C-terminus region (HR=2.00), but this was not the case in other regions. This mutation location-type interaction was significant (p-value=0.008). A significantly higher risk was found in subjects with mutations located in α-helical domains than in those with mutations in β-sheet domains or other locations (HR=1.74 and 1.33, respectively). Time-dependent β-blocker use was associated with a significant 63% reduction in the risk of first cardiac events (p<0.001). Conclusions KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.