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(Circulation. 2005;112:2602-2610.)
© 2005 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Phenotypic Variability and Unusual Clinical Severity of Congenital Long-QT Syndrome in a Founder Population

Paul A. Brink, MD, PhD; Lia Crotti, MD; Valerie Corfield, PhD; Althea Goosen, RN; Glenda Durrheim, MSc; Paula Hedley, MSc; Marshall Heradien, MD; Gerhard Geldenhuys, PhD; Emilio Vanoli, MD; Sara Bacchini, MD; Carla Spazzolini, DVM; Andrew L. Lundquist, PhD; Dan M. Roden, MD; Alfred L. George, Jr, MD; Peter J. Schwartz, MD

From the Department of Internal Medicine (P.A.B., A.G., M.H., P.J.S.), the US/MRC Centre for Molecular and Cellular Biology (V.C., G.D., P.H.), and the Bureau for Industrial Mathematics (G.G.), University of Stellenbosch, South Africa; the Department of Cardiology, University of Pavia and IRCCS Policlinico S. Matteo (L.C., E.V., S.B., C.S., P.J.S.), and the Molecular Cardiology Laboratory, IRCCS Policlinico S. Matteo (L.C., P.J.S.), Pavia, Italy; and the Departments of Pharmacology (A.L.L., D.M.R., A.L.G.) and Medicine (D.M.R., A.L.G.), Vanderbilt University, Nashville, Tenn.

Correspondence to Peter J. Schwartz, MD, Professor and Chairman, Department of Cardiology, IRCCS Policlinico S. Matteo, Viale Golgi 19, 27100 Pavia, Italy. E-mail pjqt{at}compuserve.com

Received July 1, 2005; accepted July 29, 2005.

Background— In the congenital long-QT syndrome (LQTS), there can be a marked phenotypic heterogeneity. Founder effects, by which many individuals share a mutation identical by descent, represent a powerful tool to further understand the underlying mechanisms and to predict the natural history of mutation-associated effects. We are investigating one such founder effect, originating in South Africa in approximately AD 1700 and segregating the same KCNQ1 mutation (A341V).

Methods and Results— The study population involved 320 subjects, 166 mutation carriers (MCs) and 154 noncarriers. When not taking ß-blocker therapy, MCs had a wide range of QTc values (406 to 676 ms), and 12% of individuals had a normal QTc (440 ms). A QTc >500 ms was associated with increased risk for cardiac events (OR=4.22; 95% CI, 1.12 to 15.80; P=0.033). We also found that MCs with a heart rate <73 bpm were at significantly lower risk (OR=0.23; 95% CI, 0.06 to 0.86; P=0.035). This study also unexpectedly determined that KCNQ1-A341V is associated with greater risk than that reported for large databases of LQT1 patients: A341V MCs are more symptomatic by age 40 years (79% versus 30%) and become symptomatic earlier (7±4 versus 13±9 years, both P<0.001). Accordingly, functional studies of KCNQ1-A341V in CHO cells stably expressing IK_s were conducted and identified a dominant negative effect of the mutation on wild-type channels.

Conclusions— KCNQ1-A341V is a mutation associated with an unusually severe phenotype, most likely caused by the dominant negative effect of the mutation. The availability of an extended kindred with a common mutation allowed us to identify heart rate, an autonomic marker, as a novel risk factor.

Key Words: arrhythmia • death, sudden • genetics • long-QT syndrome • nervous system, autonomic

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