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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

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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.

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Acknowledgments

This work was supported in part by the Department of Medical Research in the National Taiwan University Hospital, and was supported by the National Science Council in Taiwan (Grant 96-2314-B-002-038).

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Authors and Affiliations

  1. Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei, 100, Taiwan

    Shuenn-Nan Chiu, Mei-Hwan Wu, Jou-Kou Wang, Ming-Tai Lin, Chien-Chih Chang & Hui-Wen Hsu

  2. Department of Pharmacology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan

    Ming-Jai Su

  3. Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan

    Ching-Tsuen Shen

  4. Centre de Recherche Université Laval Robert-Giffard, Quebec City, QC, Canada

    Olivier Thériault & Mohamed Chahine

  5. Department of Medicine, Laval University, Quebec City, QC, Canada

    Olivier Thériault & Mohamed Chahine

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  1. Shuenn-Nan Chiu
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Correspondence to Mei-Hwan Wu.

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Chiu, SN., Wu, MH., Su, MJ. et al. 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. Hum Genet 131, 1295–1304 (2012). https://doi.org/10.1007/s00439-012-1156-4

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