title: Genotype-phenotype aspects of type 2 long QT syndrome.
abstract: 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.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan. wshimizu@hsp.ncvc.go.jp
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Moss
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.forename: Craig T
authors.initials: CT
authors.lastname: January
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.forename: Wojciech
authors.initials: W
authors.lastname: Zareba
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Robinson
authors.forename: Ming
authors.initials: M
authors.lastname: Qi
authors.forename: G Michael
authors.initials: GM
authors.lastname: Vincent
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Kaufman
authors.forename: Nynke
authors.initials: N
authors.lastname: Hofman
authors.forename: Takashi
authors.initials: T
authors.lastname: Noda
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Samit
authors.initials: S
authors.lastname: Shah
authors.forename: Vinit
authors.initials: V
authors.lastname: Amin
authors.forename: Ilan
authors.initials: I
authors.lastname: Goldenberg
authors.forename: Mark L
authors.initials: ML
authors.lastname: Andrews
authors.forename: Scott
authors.initials: S
authors.lastname: McNitt
mesh_terms: 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
chemical_list: D018389:Codon, Nonsense; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human