Human Genetics

, Volume 131, Issue 8, pp 1295–1304 | Cite as

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

  • Shuenn-Nan Chiu
  • Mei-Hwan Wu
  • Ming-Jai Su
  • Jou-Kou Wang
  • Ming-Tai Lin
  • Chien-Chih Chang
  • Hui-Wen Hsu
  • Ching-Tsuen Shen
  • Olivier Thériault
  • Mohamed Chahine
Original Investigation

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.

Notes

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).

Conflict of interest

None declared.

Supplementary material

439_2012_1156_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 18 kb)

References

  1. Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME (2003) Ethnic differences in cardiac potassium channel variants: implications for genetic susceptibility to sudden cardiac death and genetic testing for congenital long QT syndrome. Mayo Clin Proc 78(12):1479–1487PubMedCrossRefGoogle Scholar
  2. Ackerman MJ, Splawski I, Makielski JC, Tester DJ, Will ML, Timothy KW, Keating MT, Jones G, Chadha M, Burrow CR, Stephens JC, Xu C, Judson R, Curran ME (2004) Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart Rhythm 1(5):600–607. doi:10.1016/j.hrthm.2004.07.013 PubMedCrossRefGoogle Scholar
  3. Anson BD, Ackerman MJ, Tester DJ, Will ML, Delisle BP, Anderson CL, January CT (2004) Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. Am J Physiol Heart Circ Physiol 286(6):H2434–H2441. doi:10.1152/ajpheart.00891.2003 PubMedCrossRefGoogle Scholar
  4. Chahine M, Chen LQ, Barchi RL, Kallen RG, Horn R (1992) Lidocaine block of human heart sodium channels expressed in Xenopus oocytes. J Mol Cell Cardiol 24(11):1231–1236. 0022-2828(92)93090-7[pii]PubMedCrossRefGoogle Scholar
  5. Cheung EW, Wong WH, Cheung YF (2010) Meta-analysis of pulmonary valve replacement after operative repair of tetralogy of fallot. Am J Cardiol 106(4):552–557. doi:10.1016/j.amjcard.2010.03.065 PubMedCrossRefGoogle Scholar
  6. Chiu SN, Chiu HH, Wang JK, Lin MT, Chen CA, Wu ET, Lu CW, Wu MH (2011a) Increased microvolt T-wave alternans in patients with repaired tetralogy of Fallot. Int J Cardiol. doi:10.1016/j.ijcard.2011.02.063 Google Scholar
  7. Chiu SN, Huang SC, Chang CW, Chen YS, Chen HC, Lin MT, Chen CA, Wang JK, Wu MH (2011b) The role of mechanical-electrical interaction in ventricular arrhythmia: evidence from a novel animal model for repaired tetralogy of fallot. Pediatr Res 70(3):247–252. doi:10.1203/PDR.0b013e318225fd8b PubMedCrossRefGoogle Scholar
  8. Crotti L, Lundquist AL, Insolia R, Pedrazzini M, Ferrandi C, De Ferrari GM, Vicentini A, Yang P, Roden DM, George AL Jr, Schwartz PJ (2005) KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation 112(9):1251–1258. doi:10.1161/CIRCULATIONAHA.105.549071 PubMedCrossRefGoogle Scholar
  9. Fitzgerald PT, Ackerman MJ (2005) Drug-induced torsades de pointes: the evolving role of pharmacogenetics. Heart Rhythm 2(2 Suppl):S30–S37. doi:10.1016/j.hrthm.2005.08.007 PubMedCrossRefGoogle Scholar
  10. Gatzoulis MA, Till JA, Redington AN (1997) Depolarization-repolarization inhomogeneity after repair of tetralogy of Fallot. The substrate for malignant ventricular tachycardia? Circulation 95(2):401–404PubMedCrossRefGoogle Scholar
  11. Hayashi K, Fujino N, Uchiyama K, Ino H, Sakata K, Konno T, Masuta E, Funada A, Sakamoto Y, Tsubokawa T, Nakashima K, Liu L, Higashida H, Hiramaru Y, Shimizu M, Yamagishi M (2009) Long QT syndrome and associated gene mutation carriers in Japanese children: results from ECG screening examinations. Clin Sci (Lond) 117(12):415–424. doi:10.1042/CS20080528 CrossRefGoogle Scholar
  12. Itoh H, Shimizu W, Hayashi K, Yamagata K, Sakaguchi T, Ohno S, Makiyama T, Akao M, Ai T, Noda T, Miyazaki A, Miyamoto Y, Yamagishi M, Kamakura S, Horie M (2010) Long QT syndrome with compound mutations is associated with a more severe phenotype: a Japanese multicenter study. Heart Rhythm 7(10):1411–1418. doi:10.1016/j.hrthm.2010.06.013 PubMedCrossRefGoogle Scholar
  13. Khairy P, Landzberg MJ, Gatzoulis MA, Lucron H, Lambert J, Marcon F, Alexander ME, Walsh EP (2004) Value of programmed ventricular stimulation after tetralogy of fallot repair: a multicenter study. Circulation 109(16):1994–2000. doi:10.1161/01.CIR.0000126495.11040.BD PubMedCrossRefGoogle Scholar
  14. Khairy P, Harris L, Landzberg MJ, Viswanathan S, Barlow A, Gatzoulis MA, Fernandes SM, Beauchesne L, Therrien J, Chetaille P, Gordon E, Vonder Muhll I, Cecchin F (2008) Implantable cardioverter-defibrillators in tetralogy of Fallot. Circulation 117(3):363–370. doi:10.1161/CIRCULATIONAHA.107.726372 PubMedCrossRefGoogle Scholar
  15. Khairy P, Dore A, Poirier N, Marcotte F, Ibrahim R, Mongeon FP, Mercier LA (2009) Risk stratification in surgically repaired tetralogy of Fallot. Expert Rev Cardiovasc Ther 7(7):755–762. doi:10.1586/erc.09.38 PubMedCrossRefGoogle Scholar
  16. Kubota T, Horie M, Takano M, Yoshida H, Takenaka K, Watanabe E, Tsuchiya T, Otani H, Sasayama S (2001) Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias. J Cardiovasc Electrophysiol 12(11):1223–1229PubMedCrossRefGoogle Scholar
  17. Makielski JC, Ye B, Valdivia CR, Pagel MD, Pu J, Tester DJ, Ackerman MJ (2003) A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels. Circ Res 93(9):821–828. doi:10.1161/01.RES.0000096652.14509.96 PubMedCrossRefGoogle Scholar
  18. Moss AJ, Zareba W, Kaufman ES, Gartman E, Peterson DR, Benhorin J, Towbin JA, Keating MT, Priori SG, Schwartz PJ, Vincent GM, Robinson JL, Andrews ML, Feng C, Hall WJ, Medina A, Zhang L, Wang Z (2002) Increased risk of arrhythmic events in long-QT syndrome with mutations in the pore region of the human ether-a-go–go-related gene potassium channel. Circulation 105(7):794–799PubMedCrossRefGoogle Scholar
  19. Nakazawa M, Shinohara T, Sasaki A, Echigo S, Kado H, Niwa K, Oyama K, Yokota M, Iwamoto M, Fukushima N, Nagashima M, Nakamura Y (2004) Arrhythmias late after repair of tetralogy of fallot: a Japanese Multicenter Study. Circ J 68(2):126–130PubMedCrossRefGoogle Scholar
  20. Newton-Cheh C, Guo CY, Larson MG, Musone SL, Surti A, Camargo AL, Drake JA, Benjamin EJ, Levy D, D’Agostino RB Sr, Hirschhorn JN, O’Donnell CJ (2007) Common genetic variation in KCNH2 is associated with QT interval duration: the Framingham Heart Study. Circulation 116(10):1128–1136. doi:10.1161/CIRCULATIONAHA.107.710780 PubMedCrossRefGoogle Scholar
  21. Nollert G, Fischlein T, Bouterwek S, Bohmer C, Klinner W, Reichart B (1997) Long-term survival in patients with repair of tetralogy of Fallot: 36-year follow-up of 490 survivors of the first year after surgical repair. J Am Coll Cardiol 30(5):1374–1383. S0735-1097(97)00318-5[pii]PubMedCrossRefGoogle Scholar
  22. Ozawa T, Ito M, Tamaki S, Yao T, Ashihara T, Kita Y, Okamura T, Ueshima H, Horie M (2006) Gender and age effects on ventricular repolarization abnormality in Japanese general carriers of a G643S common single nucleotide polymorphism for the KCNQ1 gene. Circ J 70(6):645–650. JST.JSTAGE/circj/70.645[pii]PubMedCrossRefGoogle Scholar
  23. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D (2003) Risk stratification in the long-QT syndrome. N Engl J Med 348(19):1866–1874. doi:10.1056/NEJMoa022147348/19/1866 PubMedCrossRefGoogle Scholar
  24. Reed GH, Wittwer CT (2004) Sensitivity and specificity of single-nucleotide polymorphism scanning by high-resolution melting analysis. Clin Chem 50(10):1748–1754. doi:10.1373/clinchem.2003.029751 PubMedCrossRefGoogle Scholar
  25. Roden DM, Viswanathan PC (2005) Genetics of acquired long QT syndrome. J Clin Invest 115(8):2025–2032. doi:10.1172/JCI25539 PubMedCrossRefGoogle Scholar
  26. Sarubbi B, Pacileo G, Ducceschi V, Russo MG, Iacono C, Pisacane C, Iacono A, Calabro R (1999) Arrhythmogenic substrate in young patients with repaired tetralogy of Fallot: role of an abnormal ventricular repolarization. Int J Cardiol 72(1):73–82. S0167-5273(99)00166-7[pii]PubMedCrossRefGoogle Scholar
  27. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, Moss AJ, Schwartz PJ, Towbin JA, Vincent GM, Keating MT (2000) Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation 102(10):1178–1185PubMedCrossRefGoogle Scholar
  28. Sun A, Xu L, Wang S, Wang K, Huang W, Wang Y, Zou Y, Ge J (2008) SCN5A R1193Q polymorphism associated with progressive cardiac conduction defects and long QT syndrome in a Chinese family. J Med Genet 45(2):127–128. doi:10.1136/jmg.2007.056333 PubMedCrossRefGoogle Scholar
  29. Tan BH, Valdivia CR, Rok BA, Ye B, Ruwaldt KM, Tester DJ, Ackerman MJ, Makielski JC (2005) Common human SCN5A polymorphisms have altered electrophysiology when expressed in Q1077 splice variants. Heart Rhythm 2(7):741–747. doi:10.1016/j.hrthm.2005.04.021 PubMedCrossRefGoogle Scholar
  30. Tester DJ, Acker MJ (2009) Single nucleotide polymorphisms and cardiac arrhythmias. In: Zipes DP, Jalife J (eds) Cardiac electrophysiology. From cell to bedside. WB Saunders, Philadelphia, pp 509–578Google Scholar
  31. Wang Q, Chen S, Chen Q, Wan X, Shen J, Hoeltge GA, Timur AA, Keating MT, Kirsch GE (2004) The common SCN5A mutation R1193Q causes LQTS-type electrophysiological alterations of the cardiac sodium channel. J Med Genet 41(5):e66PubMedCrossRefGoogle Scholar
  32. Wu MH, Hsieh FC, Wang JK, Kau ML (1999) A variant of long QT syndrome manifested as fetal tachycardia and associated with ventricular septal defect. Heart 82(3):386–388PubMedGoogle Scholar
  33. Wu MH, Chen HC, Lu CW, Wang JK, Huang SC, Huang SK (2010) Prevalence of congenital heart disease at live birth in Taiwan. J Pediatr 156(5):782–785. doi:10.1016/j.jpeds.2009.11.062 PubMedCrossRefGoogle Scholar
  34. Ye B, Valdivia CR, Ackerman MJ, Makielski JC (2003) A common human SCN5A polymorphism modifies expression of an arrhythmia causing mutation. Physiol Genomics 12(3):187–193. doi:10.1152/physiolgenomics.00117.2002 PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Shuenn-Nan Chiu
    • 1
  • Mei-Hwan Wu
    • 1
  • Ming-Jai Su
    • 2
  • Jou-Kou Wang
    • 1
  • Ming-Tai Lin
    • 1
  • Chien-Chih Chang
    • 1
  • Hui-Wen Hsu
    • 1
  • Ching-Tsuen Shen
    • 3
  • Olivier Thériault
    • 4
    • 5
  • Mohamed Chahine
    • 4
    • 5
  1. 1.Department of Pediatrics, College of MedicineNational Taiwan University Hospital, National Taiwan UniversityTaipeiTaiwan
  2. 2.Department of Pharmacology, College of MedicineNational Taiwan University Hospital, National Taiwan UniversityTaipeiTaiwan
  3. 3.Department of PediatricsCathay General HospitalTaipeiTaiwan
  4. 4.Centre de Recherche Université Laval Robert-GiffardQuebec CityCanada
  5. 5.Department of MedicineLaval UniversityQuebec CityCanada

Personalised recommendations