title: Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients.
abstract: Administration of specific drugs may occasionally induce acquired long QT syndrome (aLQTS), a disorder that predisposes to ventricular arrhythmias, typically of the torsade de pointes (TdP) type, and sudden cardiac death. "Forme fruste" mutations in congenital LQTS (cLQTS) genes have been reported repeatedly as the underlying cause of aLQTS, and are therefore considered as an important risk factor. We evaluated the impact of genetic susceptibility for aLQTS through mutations in cLQTS genes. Five cLQTS genes ( KCNH2, KCNQ1, SCN5A, KCNE1, KCNE2) were thoroughly screened for genetic variations in 32 drug-induced aLQTS patients with confirmed TdP and 32 healthy individuals. Missense forme frust mutations were identified in four aLQTS patients: D85N in KCNE1 (two cases), T8A in KCNE2, and P347S in KCNH2. Three other missense variations were found both in patients and controls, and are thus unlikely to significantly influence aLQTS susceptibility. In addition, 13 silent and six intronic variations were detected, four of which were found in a single aLQTS patient but not in the controls. We conclude that missense mutations in the examined cLQTS genes explain only a minority of aLQTS cases.
authors.affiliation: Department of Pharmacogenomics, Johnson & Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, Beerse, Belgium.
authors.forename: Aimée D C
authors.initials: AD
authors.lastname: Paulussen
authors.forename: Ronaldus A H J
authors.initials: RA
authors.lastname: Gilissen
authors.forename: Martin
authors.initials: M
authors.lastname: Armstrong
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.forename: Peter
authors.initials: P
authors.lastname: Verhasselt
authors.forename: Hubert J M
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Eric
authors.initials: E
authors.lastname: Schulze-Bahr
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Haverkamp
authors.forename: Günter
authors.initials: G
authors.lastname: Breithardt
authors.forename: Nadine
authors.initials: N
authors.lastname: Cohen
authors.forename: Jeroen
authors.initials: J
authors.lastname: Aerssens
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D005260:Female; D014644:Genetic Variation; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000139:chemically induced / Q000209:etiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D012307:Risk Factors; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C568320:SCN5A protein, human; D015222:Sodium Channels; C059983:potassium channel protein I(sk)