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Genotype-Phenotype Correlation in Congenital LQTS: Implications for Diagnosis and Risk Stratification

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Cardiac Repolarization

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Abstract

The hereditary long QT syndrome (LQTS) is a genetic channelopathy with variable penetrance that is associated with increased propensity to syncope, polymorphic ventricular tachycardia (torsade de pointes), and sudden arrhythmic death. This inherited cardiac disorder constitutes an important cause of malignant ventricular arrhythmias and sudden cardiac death in young individuals with normal cardiac morphology. Diagnosis relies on combined assessment of ECG and clinical factors related to the patient’s personal and family history and may be difficult in approximately one quarter of LQTS subjects who present with a normal range QTc. Genetic testing is important for both diagnosis and risk assessment. Accumulating data from the International LQTS Registry have facilitated a comprehensive analysis of risk factors for aborted cardiac arrest or sudden cardiac death in prespecified age-groups, including the childhood, adolescence, adulthood, and post-40 years periods. These analyses have consistently indicated that the phenotypic expression of LQTS is time-dependent and age- and sex-specific, warranting continuous risk assessment in affected patients. Furthermore, the biophysical function, type, and location of the ion-channel mutation are currently emerging as important determinants of outcome in genotyped patients. These new data may be utilized to improve risk stratification and for the development of gene-specific therapies that may reduce the risk of life-threatening cardiac events in patients with this inherited cardiac disorder.

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References

  1. Zareba W, Moss AJ, Schwartz PJ, Vincent GM, Robinson JL, Priori SG, et al. Influence of the genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. N Engl J Med. 1998;339:960–5.

    Article  CAS  Google Scholar 

  2. Goldenberg I, Moss AJ. Long QT syndrome. J Am Coll Cardiol. 2008;51:2291–300.

    Article  Google Scholar 

  3. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, et al. Risk stratification in the long-QT syndrome. N Engl J Med. 2003;348:1866–74.

    Article  Google Scholar 

  4. Splawski I, Shen J, Timothy KW, Lehmann MH, Priori S, Robinson JL, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000;102:1178–85.

    Article  CAS  Google Scholar 

  5. Moss AJ, Schwartz PJ, Crampton RS, Tzivoni D, Locati EH, MacCluer J, et al. The long QT syndrome. Prospective longitudinal study of 328 families. Circulation. 1991;84:1136–44.

    Article  CAS  Google Scholar 

  6. Zareba W, Moss AJ, Locati EH, Lehmann MH, Peterson DR, Hall WJ, et al. Modulating effects of age and gender on the clinical course of long QT syndrome by genotype. J Am Coll Cardiol. 2003;42:103–9.

    Article  Google Scholar 

  7. Moss AJ, Shimizu W, Wilde AA, Towbin JA, Zareba W, Robinson JL, et al. Clinical aspects of type-1 long-QT syndrome by location, coding type, and biophysical function of mutations involving the KCNQ1 gene. Circulation. 2007;115:2481–9.

    Article  CAS  Google Scholar 

  8. Shimizu W, Moss AJ, Wilde AA, Towbin JA, Ackerman MJ, January CT, et al. Genotype-phenotype aspects of type 2 long QT syndrome. J Am Coll Cardiol. 2009;54:2052–62.

    Article  CAS  Google Scholar 

  9. Wilde AA, Moss AJ, Kaufman ES, Shimizu W, Peterson DR, Benhorin J, et al. Clinical aspects of type 3 long-QT syndrome: an International Multicenter Study. Circulation. 2016;134:872–82.

    Article  Google Scholar 

  10. Moss AJ, Zareba W, Benhorin J, Locati EH, Hall WJ, Robinson JL, et al. ECG T-wave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation. 1995;92:2929–34.

    Article  CAS  Google Scholar 

  11. Moss AJ, Kass RS. Long QT syndrome: from channels to cardiac arrhythmias. J Clin Invest. 2005;115:2018–24.

    Article  CAS  Google Scholar 

  12. Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell. 2001;105:511–9.

    Article  CAS  Google Scholar 

  13. Splawski I, Timothy KW, Sharpe LM, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell. 2004;119:19–31.

    Article  CAS  Google Scholar 

  14. Medeiros-Domingo A, Kaku T, Tester DJ, et al. SCN4B-encoded sodium channel beta4 subunit in congenital long-QT syndrome. Circulation. 2007;116:134–42.

    Article  Google Scholar 

  15. Schott J-J MP, Gramolini AO. Mutation in the ankyrin-B gene causes Long QT syndrome and sinus node dysfunction. Circulation. 2002;106:II–308.

    Google Scholar 

  16. Mohler PJ, Schott JJ, Gramolini AO, et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature. 2003;421:634–9.

    Article  CAS  Google Scholar 

  17. Vatta M, Ackerman MJ, Ye B, et al. Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation. 2006;114:2104–12.

    Article  CAS  Google Scholar 

  18. Cronk LB, Ye B, Kaku T, et al. Novel mechanism for sudden infant death syndrome: persistent late sodium current secondary to mutations in caveolin-3. Heart Rhythm. 2007;4:161–6.

    Article  Google Scholar 

  19. Anderson CL, Delisle BP, Anson BD, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113:365–73.

    Article  CAS  Google Scholar 

  20. Moss AJ, Robinson JL. Long QT syndrome. Heart Dis Stroke. 1992;1:309–14.

    CAS  PubMed  Google Scholar 

  21. Rautaharju PM, Zhou SH, Wong S, et al. Sex differences in the evolution of the electrocardiographic QT interval with age. Can J Cardiol. 1992;8:690–5.

    CAS  PubMed  Google Scholar 

  22. Vincent GM, Jaiswal D, Timothy KW. Effects of exercise on heart rate, QT, QTc and QT/QS2 in the Romano-Ward inherited long QT syndrome. Am J Cardiol. 1991;68:498–503.

    Article  CAS  Google Scholar 

  23. Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med. 1998;338:1709–14.

    Article  CAS  Google Scholar 

  24. Zhang L, Timothy KW, Vincent GM, et al. Spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation. 2000;102:2849–55.

    Article  CAS  Google Scholar 

  25. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome: an update. Circulation. 1993;88:782–4.

    Article  CAS  Google Scholar 

  26. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J Am Coll Cardiol. 2006;47:764–8.

    Article  Google Scholar 

  27. Krahn AD, Klein GJ, Yee R. Hysteresis of the RT interval with exercise: a new marker for the long-QT syndrome? Circulation. 1997;96:1551–6.

    Article  CAS  Google Scholar 

  28. Takenaka K, Tomohiko A, Shimizu W, et al. Exercise stress test amplifies genotype-phenotype correlation in the LQT1 and LQT2 forms of the long-QT syndrome. Circulation. 2003;107:838–44.

    Article  Google Scholar 

  29. Nemec J, Buncova M, Bulkova V, et al. Heart rate dependence of the QT interval duration: differences among congenital long QT syndrome subtypes. J Cardiovasc Electrophysiol. 2004;15:550–6.

    Article  Google Scholar 

  30. Couderc JP, Vaglio M, Cia X, et al. Impaired T-amplitude adaptation to heart rate characterizes IKr inhibition in the congenital and acquired forms of the long QT syndrome. J Cardiovasc Electrophysiol. 2007;18:1299–305.

    Article  Google Scholar 

  31. Kaufman ES, Priori SG, Napolitano C, et al. Electrocardiographic prediction of abnormal genotype in congenital long QT syndrome: experience in 101 related family members. J Cardiovasc Electrophysiol. 2001;12(4):455–61.

    Article  CAS  Google Scholar 

  32. Antzelevitch C, Shimizu W. Cellular mechanisms underlying the long.QT syndrome. Curr Opin Cardiol. 2002;17:43–51.

    Article  Google Scholar 

  33. Noda T, Takaki H, Kurita T, et al. Gene-specific response of dynamic ventricular repolarization to sympathetic stimulation in LQT1, LQT2 and LQT3 forms of congenital long QT syndrome. Eur Heart J. 2002;23:975–83.

    Article  CAS  Google Scholar 

  34. Ackerman MJ, Khositseth A, Tester DJ, Hejlik J, Shen WK, Porter CJ. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin Proc. 2002;77:413–21.

    Article  CAS  Google Scholar 

  35. Shimizu W, Noda T, Takaki H, et al. Diagnostic value of epinephrine test for genotyping LQT1, LQT2, and LQT3 forms of congenital long QT syndrome. Heart Rhythm. 2004;1:276–83.

    Article  Google Scholar 

  36. Priori SG, Napolitano C, Schwartz PJ, et al. Association of long QT syndrome loci and cardiac events among patients treated with β-blockers. JAMA. 2004;292:1341–4.

    Article  CAS  Google Scholar 

  37. Napolitano C, Priori SG, Schwartz PJ, et al. Genetic testing in the long QT syndrome. Development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005;294:2975–80.

    Article  CAS  Google Scholar 

  38. Taggart NW, Haglund CM, Tester DJ, Ackerman MJ. Diagnostic miscues in congenital long-QT syndrome. Circulation. 2007;115:2613–20.

    Article  Google Scholar 

  39. Tester DJ, Kopplin LJ, Will ML, Ackerman MJ. Spectrum and prevalence of cardiac ryanodine receptor (RyR2) mutations in a cohort of unrelated patients referred explicitly for long QT syndrome genetic testing. Heart Rhythm. 2005;2:1099–105.

    Article  Google Scholar 

  40. Philips KA, Ackerman MJ, Sakiwski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases. Heart Rhythm. 2005;2:1294–300.

    Article  Google Scholar 

  41. Schwartz PJ, Priori SG, Spazzolini C, et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation. 2001;103(1):89–95.

    Article  CAS  Google Scholar 

  42. Ackerman MJ, Tester DJ, Porter CJ. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc. 1999;74(11):1088–94.

    Article  CAS  Google Scholar 

  43. Moss AJ, Robinson JL, Gessman L, et al. Comparison of clinical and genetic variables of cardiac events associated with loud noise versus swimming among subjects with the long QT syndrome. Am J Cardiol. 1999;84(8):876–9.

    Article  CAS  Google Scholar 

  44. Goldenberg I, Thottathil P, Lopes CM, et al. Trigger-specific ion-channel mechanisms, risk factors, and response to therapy in type 1 long QT syndrome. Heart Rhythm. 2012;9(1):49–56.

    Article  Google Scholar 

  45. Kim JA, Lopes CM, Moss AJ, et al. Trigger-specific risk factors and response to therapy in long QT syndrome type 2. Heart Rhythm. 2010;7(12):1797–805.

    Article  Google Scholar 

  46. Locati EH, Zareba W, Moss AJ, et al. Age- and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry. Circulation. 1998;97:2237–44.

    Article  CAS  Google Scholar 

  47. Goldenberg I, Moss AJ, Peterson DR, McNitt S, Zareba W, Andrews ML, et al. Risk factors for aborted cardiac arrest and sudden cardiac death in children with the congenital long-QT syndrome. Circulation. 2008;117:2184–91.

    Article  Google Scholar 

  48. Hobbs JB, Peterson DR, Moss AJ, et al. Risk of aborted cardiac arrest or sudden cardiac death during adolescence in the long-QT syndrome. JAMA. 2006;296:1249–54.

    Article  CAS  Google Scholar 

  49. Sauer AJ, Moss AJ, McNitt S, et al. Long QT syndrome in adults. J Am Coll Cardiol. 2007;49:329–37.

    Article  Google Scholar 

  50. Goldenberg I, Moss AJ, Bradley J, Polonsky S, Peterson DR, McNitt S, et al. Long-QT syndrome after age 40. Circulation. 2008;117:2192–201.

    Article  Google Scholar 

  51. Drici MD, Burklow TR, Haridasse V, Glazer RI, Woosley RL. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation. 1996;94:1471–4.

    Article  CAS  Google Scholar 

  52. Bidoggia H, Maciel JP, Capalozza N, Mosca S, Blaksley EJ, Valverde E, et al. Sex differences on the electrocardiographic pattern of cardiac repolarization: possible role of testosterone. Am Heart J. 2000;140:678–83.

    Article  CAS  Google Scholar 

  53. Liu XK, Katchman A, Drici MD, et al. Gender difference in the cycle length-dependent QT and potassium currents in rabbits. J Pharmacol Exp Ther. 1998;285:672–9.

    CAS  PubMed  Google Scholar 

  54. Seth R, Moss AJ, McNitt S, et al. Long QT syndrome and pregnancy. J Am Col Cardiol. 2007;49:1092–8.

    Article  Google Scholar 

  55. Buber J, Mathew J, Moss AJ, Hall WJ, Barsheshet A, McNitt S, et al. Risk of recurrent cardiac events after onset of menopause in women with congenital long-QT syndrome types 1 and 2. Circulation. 2011;123:2784–91.

    Article  Google Scholar 

  56. Imboden M, Swan H, Denjoy I, Van Langen IM, Latinen-Forsblom PJ, Napolitano C, et al. Female predominance and transmission distortion in the long-QT syndrome. N Engl J Med. 2006;355:2744–5.

    Article  CAS  Google Scholar 

  57. Barsheshet A, Goldenberg I, O-Uchi J, et al. Mutations in cytoplasmic loops of the KCNQ1 channel and the risk of life-threatening events: implications for mutation-specific response to beta-blocker therapy in type 1 long-QT syndrome. Circulation. 2012;125:1988–96.

    Article  CAS  Google Scholar 

  58. Matavel A, Medei E, Lopes CM. PKA and PKC partially rescue long QT type 1 phenotype by restoring channel-PIP(2) interactions. Channels (Austin). 2010;4(1):3–11.

    Article  CAS  Google Scholar 

  59. Costa J, Lopes CM, Barsheshet A, et al. Combined assessment of sex- and mutation-specific information for risk stratification in type 1 long QT syndrome. Heart Rhythm. 2012;9(6):892–8.

    Article  Google Scholar 

  60. Schwartz PJ, Vanoli E, Crotti L, et al. Neural control of heart rate is an arrhythmia risk modifier in long QT syndrome. J Am Coll Cardiol. 2008;51(9):920–9.

    Article  Google Scholar 

  61. Brink PA, Crotti L, Corfield V, et al. Phenotypic variability and unusual clinical severity of congenital long-QT syndrome in a founder population. Circulation. 2005;112(17):2602–10.

    Article  Google Scholar 

  62. Barsheshet A, Peterson DR, Moss AJ, et al. Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome. Heart Rhythm. 2011;8(8):1207–13.

    Article  Google Scholar 

  63. Migdalovich D, Moss AJ, Lopes CM, et al. Mutation and gender-specific risk in type 2 long QT syndrome: implications for risk stratification for life-threatening cardiac events in patients with long QT syndrome. Heart Rhythm. 2011;8(10):1537–43.

    Article  Google Scholar 

  64. Liu JF, Moss AJ, Jons C, et al. Mutation-specific risk in two genetic forms of type 3 long QT syndrome. Am J Cardiol. 2010;105(2):210–3.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Cardiology Division, Clinical Cardiovascular Research Center, University of Rochester Medical Center, Rochester, NY, USA

    Ilan Goldenberg

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  1. Ilan Goldenberg
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Correspondence to Ilan Goldenberg .

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  1. Department of Medicine and Physiology, State University of New York Downstate Medical Center, VA New York Harbor Healthcare Center, Brooklyn, NY, USA

    Nabil El-Sherif

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Goldenberg, I. (2020). Genotype-Phenotype Correlation in Congenital LQTS: Implications for Diagnosis and Risk Stratification. In: El-Sherif, N. (eds) Cardiac Repolarization. Springer, Cham. https://doi.org/10.1007/978-3-030-22672-5_8

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  • DOI: https://doi.org/10.1007/978-3-030-22672-5_8

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