Genotype-phenotype aspects of type 2 long QT syndrome.
OBJECTIVE
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).


BACKGROUND
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 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.


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 (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).


CONCLUSIONS
The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.
Shimizu
Wataru
W
Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan. wshimizu@hsp.ncvc.go.jp
Moss
Arthur J
AJ
Wilde
Arthur A M
AA
Towbin
Jeffrey A
JA
Ackerman
Michael J
MJ
January
Craig T
CT
Tester
David J
DJ
Zareba
Wojciech
W
Robinson
Jennifer L
JL
Qi
Ming
M
Vincent
G Michael
GM
Kaufman
Elizabeth S
ES
Hofman
Nynke
N
Noda
Takashi
T
Kamakura
Shiro
S
Miyamoto
Yoshihiro
Y
Shah
Samit
S
Amin
Vinit
V
Goldenberg
Ilan
I
Andrews
Mark L
ML
McNitt
Scott
S
D000293:Adolescent; D000328:Adult; D002648:Child; D018389:Codon, Nonsense; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D008564:Membrane Potentials; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D016016:Proportional Hazards Models; D017433:Protein Structure, Secondary / Q000235:genetics; D012189:Retrospective Studies; D055815:Young Adult
D018389:Codon, Nonsense; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human