Published Online
on April 30, 2007

A more recent version of this article appeared on May 15, 2007

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Submitted on September 17, 2006
Accepted on March 2, 2007

Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene

Arthur J. Moss MD^*, Wataru Shimizu MD, PhD, Arthur A.M. Wilde MD, PhD, Jeffrey A. Towbin MD, Wojciech Zareba MD, PhD, Jennifer L. Robinson MS, Ming Qi PhD, G. Michael Vincent MD, Michael J. Ackerman MD, PhD, Elizabeth S. Kaufman MD, Nynke Hofman MSc, Rahul Seth MD, Shiro Kamakura MD, PhD, Yoshihiro Miyamoto MD, PhD, Ilan Goldenberg MD, Mark L. Andrews BBA, and Scott McNitt MS

From the Cardiology Division (A.J.M., W.Z., J.L.R., I.G., M.L.A., S.M., R.S.) of the Department of Medicine and the Department of Pathology (M.Q.), University of Rochester School of Medicine and Dentistry, Rochester, NY; Division of Cardiology, Department of Internal Medicine (W.S., S.K.) and Laboratory of Molecular Genetics (Y.M.), National Cardiovascular Center, Suita, Japan; Departments of Clinical and Experimental Cardiology (A.A.M.W.) and Clinical Genetics (N.H.), Academic Medical Center, Amsterdam, the Netherlands; Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston (J.A.T.); School of Medicine, University of Utah, Salt Lake City (G.M.V.); Departments of Medicine, Pediatrics, and Molecular Pharmacology, Mayo Clinic College of Medicine, Rochester, Minn (M.J.A.); and Heart and Vascular Research Center, MetroHealth Campus of Case Western Reserve University, Cleveland, Ohio (E.S.K.).

^* To whom correspondence should be addressed. E-mail: heartajm{at}heart.rochester.edu.

Background--Type-1 long-QT syndrome (LQTS) is caused by loss-of-function mutations in the KCNQ1-encoded I_Ks cardiac potassium channel. We evaluated the effect of location, coding type, and biophysical function of KCNQ1 mutations on the clinical phenotype of this disorder.

Methods and Results--We investigated the clinical course in 600 patients with 77 different KCNQ1 mutations in 101 proband-identified families derived from the US portion of the International LQTS Registry (n=425), the Netherlands’ LQTS Registry (n=93), and the Japanese LQTS Registry (n=82). The Cox proportional hazards survivorship model was used to evaluate the independent contribution of clinical and genetic factors to the first occurrence of time-dependent cardiac events from birth through age 40 years. The clinical characteristics, distribution of mutations, and overall outcome event rates were similar in patients enrolled from the 3 geographic regions. Biophysical function of the mutations was categorized according to dominant-negative (>50%) or haploinsufficiency (50%) reduction in cardiac repolarizing I_Ks potassium channel current. Patients with transmembrane versus C-terminus mutations (hazard ratio, 2.06; P<0.001) and those with mutations having dominant-negative versus haploinsufficiency ion channel effects (hazard ratio, 2.26; P<0.001) were at increased risk for cardiac events, and these genetic risks were independent of traditional clinical risk factors.

Conclusions--This genotype-phenotype study indicates that in type-1 LQTS, mutations located in the transmembrane portion of the ion channel protein and the degree of ion channel dysfunction caused by the mutations are important independent risk factors influencing the clinical course of this disorder.

Key words: electrocardiography • genetics • long-QT syndrome

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