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(Circulation. 2007;116:2366-2375.)
© 2007 American Heart Association, Inc.

Arrhythmia/Electrophysiology

The Common Long-QT Syndrome Mutation KCNQ1/A341V Causes Unusually Severe Clinical Manifestations in Patients With Different Ethnic Backgrounds

Toward a Mutation-Specific Risk Stratification

Lia Crotti, MD; Carla Spazzolini, DVM; Peter J. Schwartz, MD; Wataru Shimizu, MD; Isabelle Denjoy, MD; Eric Schulze-Bahr, MD; Elena V. Zaklyazminskaya, MD, PhD; Heikki Swan, MD; Michael J. Ackerman, MD, PhD; Arthur J. Moss, MD; Arthur A.M. Wilde, MD; Minoru Horie, MD; Paul A. Brink, MD, PhD; Roberto Insolia, PhD; Gaetano M. De Ferrari, MD; Gabriele Crimi, MD

From the Section of Cardiology, Department of Lung, Blood and Heart, University of Pavia, Pavia, Italy (L.C., C.S., P.J.S., G.C.); Department of Cardiology (L.C., C.S., P.J.S., G.M.D.F., G.C.) and Molecular Cardiology Laboratory (L.C., P.J.S., R.I.), IRCCS Fondazione Policlinico S. Matteo, Pavia, Italy; Department of Medicine, University of Stellenbosch, South Africa (P.J.S., P.A.B.); Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico, Milan, Italy (P.J.S.); Cardiovascular Genetics Laboratory, Hatter Institute for Cardiovascular Research, Department of Medicine, University of Cape Town, Cape Town, South Africa (P.J.S.); Division of Cardiology, Department of Internal Medicine, National Cardiovascular Center, Osaka, Japan (W.S.); Service de Cardiologie, Hôpital Lariboisière, and Inserm U582, Paris, France (I.D.); Med Klinik und Poliklinik C (Kardiologie/Angiologie), Molekulare Genetik und Spezialambulanz für Patienten mit angeborenen, arrhythmogenen Erkrankungen, Universitätsklinikum Münster, Münster, Germany (E.S.-B.); Research Center of Medical Genetics, Laboratory of DNA Research, Moscow, Russia (E.V.Z.); Helsinki University Hospital, Department of Cardiology, Helsinki, Finland (H.S.); Departments of Medicine, Pediatrics, and Molecular Pharmacology and Experimental Therapeutics, Divisions of Cardiovascular Diseases and Pediatric Cardiology, Mayo Clinic College of Medicine, Rochester, Minn (M.J.A.); Cardiology Division, Department of Medicine, University of Rochester Medical Center, Rochester, NY (A.J.M.); Departments of Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (A.A.M.W.); and Department of Cardiology, Shiga University of Medical Sciences, Ohtsu, Japan (M.H.).

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

Received April 18, 2007; accepted August 28, 2007.

Background— The impressive clinical heterogeneity of the long-QT syndrome (LQTS) remains partially unexplained. In a South African (SA) founder population, we identified a common LQTS type 1 (LQT1)–causing mutation (KCNQ1-A341V) associated with high clinical severity. We tested whether the arrhythmic risk was caused directly by A341V or by its presence in the specific ethnic setting of the SA families.

Methods and Results— Seventy-eight patients, all with a single KCNQ1-A341V mutation, from 21 families and 8 countries were compared with 166 SA patients with A341V and with 205 non-A341V LQT1 patients. In the 2 A341V populations (SA and non-SA), the probability of a first event through 40 years of age was similar (76% and 82%), and the QTc was 484±42 versus 485±45 ms (P=NS). Compared with the 205 non-A341V patients with the same median follow-up (30 versus 32 years), the 244 A341V patients were more likely to have cardiac events (75% versus 24%), were younger at first event (6 versus 11 years), and had a longer QTc (485±43 versus 465±38 ms) (all P<0.001). Arrhythmic risk remained higher (P<0.0001) even when the A341V patients were compared with non-A341V patients with mutations either localized to transmembrane domains or exhibiting a dominant-negative effect. A341V patients had more events despite β-blocker therapy.

Conclusions— The hot spot KCNQ1-A341V predicts high clinical severity independently of the ethnic origin of the families. This higher risk of cardiac events also persists when compared with LQT1 patients with either transmembrane or dominant-negative mutations. The identification of this high-risk mutation and possibly others may improve the risk stratification and management of LQTS.

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