title: Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes.
abstract: Marked prolongation of the QT interval and polymorphic ventricular tachycardia following medication (drug-induced long QT syndrome, diLQTS) is a severe adverse drug reaction (ADR) that phenocopies congenital long QT syndrome (cLQTS) and is one of the leading causes for drug withdrawal and relabeling. We evaluated the frequency of rare non-synonymous variants in genes contributing to the maintenance of heart rhythm in cases of diLQTS using targeted capture coupled to next-generation sequencing. Eleven of 31 diLQTS subjects (36%) carried a novel missense mutation in genes with known congenital arrhythmia associations or with a known cLQTS mutation. In the 26 Caucasian subjects, 23% carried a highly conserved rare variant predicted to be deleterious to protein function in these genes compared with only 2-4% in public databases (P<0.003). We conclude that the rare variation in genes responsible for congenital arrhythmia syndromes is frequent in diLQTS. Our findings demonstrate that diLQTS is a pharmacogenomic syndrome predisposed by rare genetic variants.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Ramirez
authors.forename: C M
authors.initials: CM
authors.lastname: Shaffer
authors.forename: J T
authors.initials: JT
authors.lastname: Delaney
authors.forename: D P
authors.initials: DP
authors.lastname: Sexton
authors.forename: S E
authors.initials: SE
authors.lastname: Levy
authors.forename: M J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: D A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: A L
authors.initials: AL
authors.lastname: George
authors.forename: D M
authors.initials: DM
authors.lastname: Roden
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000150:complications / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics* / Q000473:pathology; D004562:Electrocardiography; D005260:Female; D005787:Gene Frequency; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000150:complications / Q000235:genetics