Genotype-Phenotype Aspects of Type 2 Long QT Syndrome

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

卷:54

Article

Shimizu, Wataru¹  Moss, Arthur J.³  Wilde, Arthur A. M.⁵  Towbin, Jeffrey A.⁷  Ackerman, Michael J.^8,9,10  January, Craig T.^11,12  Tester, David J.^8,9,10  Zareba, Wojciech³  Robinson, Jennifer L.³  Qi, Ming⁴  Vincent, G. Michael¹³  Kaufman, Elizabeth S.¹⁴  Hofman, Nynke⁶  Noda, Takashi¹  Kamakura, Shiro¹  Miyamoto, Yoshihiro²  Shah, Samit³  Amin, Vinit³  Goldenberg, Ilan³  Andrews, Mark L.³  McNitt, Scott³ 

[1] Natl Cardiovasc Ctr, Dept Internal Med, Div Cardiol, Osaka 5658565, Japan

[2] Natl Cardiovasc Ctr, Mol Genet Lab, Osaka 5658565, Japan

[3] Univ Rochester, Sch Med & Dent, Dept Med, Div Cardiol, Rochester, NY 14642 USA

[4] Univ Rochester, Sch Med & Dent, Dept Pathol, Rochester, NY 14642 USA

[5] Univ Amsterdam, Acad Med Ctr, Dept Cardiol, NL-1105 AZ Amsterdam, Netherlands

[6] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, NL-1105 AZ Amsterdam, Netherlands

[7] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[8] Mayo Clin, Coll Med, Dept Med, Rochester, MN USA

[9] Mayo Clin, Coll Med, Dept Pediat, Rochester, MN USA

[10] Mayo Clin, Coll Med, Dept Mol Pharmacol, Rochester, MN USA

[11] Univ Wisconsin, Dept Med, Madison, WI USA

[12] Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA

[13] Univ Utah, Dept Med, Salt Lake City, UT 84112 USA

[14] MetroHlth Campus Case Western Reserve Univ, Heart & Vasc Res Ctr, Cleveland, OH USA

关键词: arrhythmia;    electrocardiography;    long QT syndrome;    genetics;    syncope;   

DOI  :  10.1016/j.jacc.2009.08.028

来源: Elsevier

【 摘 要 】

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 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. (J Am Coll Cardiol 2009; 54: 2052-62) (C) 2009 by the American College of Cardiology Foundation

【 授权许可】

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