Genotype-Phenotype Aspects of Type 2 Long QT Syndrome

Wataru Shimizu, Arthur J. Moss, Arthur A.M. Wilde, Jeffrey A. Towbin, Michael J. Ackerman, Craig T. January, David J. Tester, Wojciech Zareba, Jennifer L. Robinson, Ming Qi, G. Michael Vincent, Elizabeth S. Kaufman, Nynke Hofman, Takashi Noda, Shiro Kamakura, Yoshihiro Miyamoto, Samit Shah, Vinit Amin, Ilan Goldenberg, Mark L. AndrewsScott McNitt

Research output: Contribution to journalArticlepeer-review

180 Scopus citations


Objectives: 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 α-helical domains than in subjects 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: The KCNH2 missense mutations located in the transmembrane S5-loop-S6 region are associated with the greatest risk.

Original languageEnglish (US)
Pages (from-to)2052-2062
Number of pages11
JournalJournal of the American College of Cardiology
Issue number22
StatePublished - Nov 24 2009


  • arrhythmia
  • electrocardiography
  • genetics
  • long QT syndrome
  • syncope

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Genotype-Phenotype Aspects of Type 2 Long QT Syndrome'. Together they form a unique fingerprint.

Cite this