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