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.
Placental chorangiomas can cause a high-output fetal state and increase neonatal morbidity and mortality. There is a paucity of data published describing the optimal treatment of these cases, and methods for occlusion to date include placement of vascular clips, bipolar cautery, injection of alcohol or surgical glue, interstitial laser, and microcoil embolization. We report 2 cases of prenatally diagnosed chorangiomas that caused a high-output fetal state and were successfully treated with microcoil embolization. This case series describes our technique and supports microcoil embolization as a potentially safe and effective antenatal treatment option in symptomatic chorangiomas.
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