Genotype-Phenotype Aspects of Type 2 Long QT Syndrome

Wataru Shimizu, Arthur J. Moss, Arthur A.M. Wilde, Jeffrey 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. Andrews & 1 others Scott McNitt

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

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
Volume54
Issue number22
DOIs
StatePublished - Nov 24 2009
Externally publishedYes

Fingerprint

Long QT Syndrome
Genotype
Phenotype
Mutation
Missense Mutation
S 6
Aptitude
Risk Reduction Behavior
Population Density
Proportional Hazards Models
Survival Rate

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Shimizu, W., Moss, A. J., Wilde, A. A. M., Towbin, J., Ackerman, M. J., January, C. T., ... McNitt, S. (2009). Genotype-Phenotype Aspects of Type 2 Long QT Syndrome. Journal of the American College of Cardiology, 54(22), 2052-2062. https://doi.org/10.1016/j.jacc.2009.08.028

Genotype-Phenotype Aspects of Type 2 Long QT Syndrome. / Shimizu, Wataru; Moss, Arthur J.; Wilde, Arthur A.M.; Towbin, Jeffrey; Ackerman, Michael J.; January, Craig T.; Tester, David J.; Zareba, Wojciech; Robinson, Jennifer L.; Qi, Ming; Vincent, G. Michael; Kaufman, Elizabeth S.; Hofman, Nynke; Noda, Takashi; Kamakura, Shiro; Miyamoto, Yoshihiro; Shah, Samit; Amin, Vinit; Goldenberg, Ilan; Andrews, Mark L.; McNitt, Scott.

In: Journal of the American College of Cardiology, Vol. 54, No. 22, 24.11.2009, p. 2052-2062.

Research output: Contribution to journalArticle

Shimizu, W, Moss, AJ, Wilde, AAM, Towbin, J, Ackerman, MJ, January, CT, Tester, DJ, Zareba, W, Robinson, JL, Qi, M, Vincent, GM, Kaufman, ES, Hofman, N, Noda, T, Kamakura, S, Miyamoto, Y, Shah, S, Amin, V, Goldenberg, I, Andrews, ML & McNitt, S 2009, 'Genotype-Phenotype Aspects of Type 2 Long QT Syndrome', Journal of the American College of Cardiology, vol. 54, no. 22, pp. 2052-2062. https://doi.org/10.1016/j.jacc.2009.08.028
Shimizu, Wataru ; Moss, Arthur J. ; Wilde, Arthur A.M. ; Towbin, Jeffrey ; Ackerman, Michael J. ; January, Craig T. ; Tester, David J. ; Zareba, Wojciech ; Robinson, Jennifer L. ; Qi, Ming ; Vincent, G. Michael ; Kaufman, Elizabeth S. ; Hofman, Nynke ; Noda, Takashi ; Kamakura, Shiro ; Miyamoto, Yoshihiro ; Shah, Samit ; Amin, Vinit ; Goldenberg, Ilan ; Andrews, Mark L. ; McNitt, Scott. / Genotype-Phenotype Aspects of Type 2 Long QT Syndrome. In: Journal of the American College of Cardiology. 2009 ; Vol. 54, No. 22. pp. 2052-2062.
@article{f00292d326254279aa584455c5c2c7fd,
title = "Genotype-Phenotype Aspects of Type 2 Long QT Syndrome",
abstract = "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.",
author = "Wataru Shimizu and Moss, {Arthur J.} and Wilde, {Arthur A.M.} and Jeffrey Towbin and Ackerman, {Michael J.} and January, {Craig T.} and Tester, {David J.} and Wojciech Zareba and Robinson, {Jennifer L.} and Ming Qi and Vincent, {G. Michael} and Kaufman, {Elizabeth S.} and Nynke Hofman and Takashi Noda and Shiro Kamakura and Yoshihiro Miyamoto and Samit Shah and Vinit Amin and Ilan Goldenberg and Andrews, {Mark L.} and Scott McNitt",
year = "2009",
month = "11",
day = "24",
doi = "10.1016/j.jacc.2009.08.028",
language = "English (US)",
volume = "54",
pages = "2052--2062",
journal = "Journal of the American College of Cardiology",
issn = "0735-1097",
publisher = "Elsevier USA",
number = "22",

}

TY - JOUR

T1 - Genotype-Phenotype Aspects of Type 2 Long QT Syndrome

AU - Shimizu, Wataru

AU - Moss, Arthur J.

AU - Wilde, Arthur A.M.

AU - Towbin, Jeffrey

AU - Ackerman, Michael J.

AU - January, Craig T.

AU - Tester, David J.

AU - Zareba, Wojciech

AU - Robinson, Jennifer L.

AU - Qi, Ming

AU - Vincent, G. Michael

AU - Kaufman, Elizabeth S.

AU - Hofman, Nynke

AU - Noda, Takashi

AU - Kamakura, Shiro

AU - Miyamoto, Yoshihiro

AU - Shah, Samit

AU - Amin, Vinit

AU - Goldenberg, Ilan

AU - Andrews, Mark L.

AU - McNitt, Scott

PY - 2009/11/24

Y1 - 2009/11/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=71849098104&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=71849098104&partnerID=8YFLogxK

U2 - 10.1016/j.jacc.2009.08.028

DO - 10.1016/j.jacc.2009.08.028

M3 - Article

VL - 54

SP - 2052

EP - 2062

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

SN - 0735-1097

IS - 22

ER -