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(Circulation. 2004;109:1834-1841.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Compound Mutations

A Common Cause of Severe Long-QT Syndrome

Peter Westenskow, BS; Igor Splawski, PhD; Katherine W. Timothy, BS; Mark T. Keating, MD; Michael C. Sanguinetti, PhD

From the Departments of Physiology (P.W., M.C.S.) and Human Genetics (K.T.W.), University of Utah, Salt Lake City, and Department of Cardiology, Children’s Hospital, and Departments of Pediatrics and Cell Biology, HMS, HHMI, Boston, Mass (I.S., M.T.K.).

Correspondence to Michael C. Sanguinetti, Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112-5000. E-mail sanguinetti{at}cvrti.utah.edu

Received January 3, 2003; de novo received October 1, 2003; revision received December 12, 2003; accepted January 15, 2004.

Background— Long QT syndrome (LQTS) predisposes affected individuals to sudden death from cardiac arrhythmias. Although most LQTS individuals do not have cardiac events, significant phenotypic variability exists within families. Probands can be very symptomatic. The mechanism of this phenotypic variability is not understood.

Methods and Results— Genetic analyses of KVLQT1, HERG, KCNE1, KCNE2, and SCN5A detected compound mutations in 20 of 252 LQTS probands (7.9%). Carriers of 2 mutations had longer QTc intervals (527±54 versus 489±44 ms; P<0.001); all had experienced cardiac events (20 of 20 [100%] versus 128 of 178 [72%]; P<0.01) and were 3.5-fold more likely to have cardiac arrest (9 of 16 [56%] versus 45 of 167 [27%]; P<0.01; OR, 3.5; 95% CI, 1.2 to 9.9) compared with probands with 1 or no identified mutation. Two-microelectrode voltage clamp of Xenopus oocytes was used to characterize the properties of variant slow delayed rectifier potassium (I_Ks) channels identified in 7 of the probands. When wild-type and variant subunits were coexpressed in appropriate ratios to mimic the genotype of the proband, the reduction in I_Ks density was equivalent to the additive effects of the single mutations.

Conclusions— LQTS-associated compound mutations cause a severe phenotype and are more common than expected. Individuals with compound mutations need to be identified, and their management should be tailored to their increased risk for arrhythmias.

Key Words: arrhythmia • electrophysiology • long-QT syndrome • potassium

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