This Article Figures Only Full Text Full Text (PDF) Online Appendix Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Shimizu, W. Articles by McNitt, S. PubMed Articles by Shimizu, W. Articles by McNitt, S. Related Collections Related Article

QUARTERLY FOCUS ISSUE: HEART RHYTHM DISORDERS

Genotype-Phenotype Aspects of Type 2 Long QT Syndrome

Wataru Shimizu, MD, PhD^_*,_*, Arthur J. Moss, MD, Arthur A.M. Wilde, MD, PhD^||, Jeffrey A. Towbin, MD^#, Michael J. Ackerman, MD, PhD^_**, Craig T. January, MD, PhD, David J. Tester, BS^_**, Wojciech Zareba, MD, PhD, Jennifer L. Robinson, MS, Ming Qi, PhD, G. Michael Vincent, MD, Elizabeth S. Kaufman, MD, Nynke Hofman, MSc^¶, Takashi Noda, MD, PhD^_*, Shiro Kamakura, MD, PhD^_*, Yoshihiro Miyamoto, MD, PhD, Samit Shah, BA, Vinit Amin, MA, Ilan Goldenberg, MD, Mark L. Andrews, BBA and Scott McNitt, MS

^_* Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan
Laboratory of Molecular Genetics, National Cardiovascular Center, Suita, Osaka, Japan
Cardiology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, New York
^|| Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands
^¶ Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands
^# Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas
^_** Departments of Medicine, Pediatrics, and Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, Minnesota
Departments of Medicine and Physiology, University of Wisconsin-Madison, Madison, Wisconsin
University of Utah, School of Medicine, Salt Lake City, Utah
Heart and Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio

Manuscript received May 31, 2009; revised manuscript received August 14, 2009, accepted August 24, 2009.

^_* Reprint requests and correspondence: Dr. Wataru Shimizu, Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan (Email: wshimizu{at}hsp.ncvc.go.jp).

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 -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.

Key Words: arrhythmia • electrocardiography • long QT syndrome • genetics • syncope

Abbreviations and Acronyms   ECG = electrocardiogram   IKr = rapid component of the delayed rectifier repolarizing current   LQTS = long QT syndrome   NMD = nonsense-mediated decay   QTc = corrected QT

Related Article

Genotype–Phenotype Relationship in the Long QT Syndrome: Brimming With Knowledge but Thirsting for a Therapeutic Solution

Koonlawee Nademanee
J. Am. Coll. Cardiol. 2009 54: 2063-2064. [Full Text] [PDF]

This article has been cited by other articles:

				K. Nademanee Genotype-Phenotype Relationship in the Long QT Syndrome Brimming With Knowledge but Thirsting for a Therapeutic Solution. J. Am. Coll. Cardiol., November 24, 2009; 54(22): 2063 - 2064. [Full Text] [PDF]