title: Coexisting mutations/polymorphisms of the long QT syndrome genes in patients with repaired Tetralogy of Fallot are associated with the risks of life-threatening events.
abstract: Coexisting long QT gene mutations/polymorphisms in Tetralogy of Fallot (TOF) patients may aggravate the repolarization abnormality from cardiac repair. We investigated the impact of these genes on the risk of life-threatening events. Genetic variants of the three common long QT genes were identified from patients with repaired TOF. Life-threatening events were defined as sudden cardiac death and hemodynamic unstable ventricular arrhythmia. Biophysical characterization of the alleles of the genetic variants was performed using a whole-cell voltage clamp with expression in Xenopus oocytes. A total of 84 patients (56.0 % male with 1,215 patients-year follow-up) were enrolled. Six rare variants and six non-synonymous single nucleotide polymorphisms (SNPs) were found in 40 (47.6 %) patients. Life-threatening events occurred in five patients; four received implantable cardioverter defibrillator and one died of sudden cardiac death. Life-threatening events occurred more often in those with genetic variants than those without (5/40 vs. 0/44, P = 0.021); particularly, the hERG or SCN5A gene mutations/polymorphisms (2/5 vs. 3/79, P = 0.027 and 5/27 vs. 0/57, P = 0.003, respectively). Among the five patients with life-threatening events, three had compound variants (hERG p.M645R/SCN5A p.R1193Q, hERG p.K897T/SCN5A p.H558R, and KVLQT1 p.G645S/SCN5A p.P1090L), that also increased the risk of events. Their QTc and JTc were all prolonged. Functional study of the novel variant (hERG gene p.M645R) from patients with life-threatening events revealed a dominant negative effect. In conclusion, in repaired TOF patients, coexisting long QT mutations/polymorphisms might have additive effects on the repolarization abnormality from surgery and thereby increase the risks of life-threatening events.
authors.affiliation: Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
authors.forename: Shuenn-Nan
authors.initials: SN
authors.lastname: Chiu
authors.forename: Mei-Hwan
authors.initials: MH
authors.lastname: Wu
authors.forename: Ming-Jai
authors.initials: MJ
authors.lastname: Su
authors.forename: Jou-Kou
authors.initials: JK
authors.lastname: Wang
authors.forename: Ming-Tai
authors.initials: MT
authors.lastname: Lin
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chang
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Hsu
authors.forename: Ching-Tsuen
authors.initials: CT
authors.lastname: Shen
authors.forename: Olivier
authors.initials: O
authors.lastname: Thériault
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D008133:Long QT Syndrome / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic; D013771:Tetralogy of Fallot / Q000235:genetics* / Q000503:physiopathology; D014981:Xenopus
chemical_list: D017931:DNA Primers