Compound mutations: A common cause of severe long-Qt syndrome

• Published in: Circulation (New York, N.Y.) Vol. 109; no. 15; pp. 1834 - 1841
• Main Authors: WESTENSKOW, Peter, SPLAWSKI, Igor, TIMOTHY, Katherine W, KEATING, Mark T, SANGUINETTI, Michael C
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 20.04.2004
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Electric Conductivity; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Female; Humans; Ion Channels - genetics; KCNQ Potassium Channels; KCNQ1 Potassium Channel; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Male; Medical sciences; Mutagenesis, Site-Directed; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Pedigree; Potassium Channels - genetics; Potassium Channels - physiology; Potassium Channels, Voltage-Gated; Sodium Channels - genetics; Xenopus laevis; Arrhythmia; Heart disease; Electrophysiology; Cardiovascular disease; Mutation; Compounds; Inorganic element; Potassium; long-QT syndrome
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000125524.34234.13

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. 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. 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.