Congenital long QT syndromes: Clinical features, molecular genetics and genetic testing

Expert Review of Molecular Diagnostics

Volumn 6, Issue 3, 2006, Pages 365-374

  Ching, Chi Keong ^b   Tan, Ene Choo ^a,c  

^a KK WOMEN'S AND CHILDREN'S HOSPITAL   (Singapore)

^b DEPARTMENT OF CARDIOLOGY   (Singapore)

^c NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

Cardiac arrhythmia; Channelopathy; Genetic testing; Mutation; QT interval; Sudden cardiac death

Indexed keywords

ION CHANNEL; POTASSIUM CHANNEL HERG; POTASSIUM CHANNEL KCNQ1;

AUTOSOMAL DOMINANT INHERITANCE; AUTOSOMAL RECESSIVE INHERITANCE; CLINICAL FEATURE; CONGENITAL DEAFNESS; ELECTROCARDIOGRAM; GENE MUTATION; GENETIC DISORDER; HEART DEATH; HEART VENTRICLE TACHYCARDIA; LONG QT SYNDROME; MOLECULAR GENETICS; ONSET AGE; REVIEW; SYNCOPE; TORSADE DES POINTES; DIAGNOSTIC PROCEDURE; DOMINANT GENE; GENETIC PREDISPOSITION; GENETIC PROCEDURES; GENETIC SCREENING; GENETICS; HETEROZYGOTE; HOMOZYGOTE; HUMAN; METHODOLOGY; MOLECULAR BIOLOGY; MUTATION; RECESSIVE GENE;

ETHER-A-GO-GO POTASSIUM CHANNELS; GENES, DOMINANT; GENES, RECESSIVE; GENETIC PREDISPOSITION TO DISEASE; GENETIC SCREENING; GENETIC TECHNIQUES; HETEROZYGOTE; HOMOZYGOTE; HUMANS; LONG QT SYNDROME; MOLECULAR BIOLOGY; MOLECULAR DIAGNOSTIC TECHNIQUES; MUTATION;

EID: 33745949703     PISSN: 14737159     EISSN: 17448352     Source Type: Journal    
DOI: 10.1586/14737159.6.3.365     Document Type: Review

References (109)

1. Myerburg RJ, Castellanos A. Cardiac arrest and sudden cardiac death. In: Heart Disease: A Textbook of Cardiovascular Medicine. Sixth Edition. Braunwald E (Ed.) WB Saunders, PA, USA, 890-931 (2001).
2. Bachman JW, McDonald GS, O'Brien PC. A study of out-of-hospital cardiac arrests in northeastern Minnesota. JAMA 256, 477-483 (1986).
3. Becker LB, Smith DW, Rhodes KV. Incidence of cardiac arrest: a neglected factor in evaluating survival rates. Ann. Emerg. Med. 22, 86-91 (1993).
4. Priori SG, Aliot E, Zipes DP et al. Task force on sudden cardiac death of the European Society of Cardiology. Eur. Heart J. 22, 1374-1450 (2001).
5. Sen-Chowdhry S, McKenna WJ. Sudden cardiac death in the young: a strategy for prevention by targeted evaluation. Cardiology 105, 196-206 (2006).
6. Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am. Heart J. 54, 59-68 (1957).
7. Romano C, Gemme G, Pongiglione R. Aritmie cardiache rare dell'eta' pediatrica. Clin. Pediatr. 45, 656-683 (1963).
8. Ward OC. A new familial cardiac syndrome in children. J. Ir. Med. Assoc. 54, 103-106 (1964).
9. Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr. Scand. 60, 559-564 (1971).
10. Moss AJ, Schwartz PJ, Crampton RS et al. The long QT syndrome: prospective longitudinal study of 328 families. Circulation 84, 1136-1144 (1991).
11. Zipes DP. The long QT interval syndrome. A Rosetta stone for sympathetic related ventricular tachyarrhythmias. Circulation 84, 1414-1419 (1991).
12. Ackermman MJ. Cardiac channelopathies: it's in the genes. Nature Med. 10, 463-464 (2004).
13. Wilde AA, Jongbloed RJ, Doevendans PA. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1-related patients (LQTS1). J. Am. Coll. Cardiol. 33, 327-332 (1999).
14. 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. 84, 876-879 (1999).
15. Schwartz PJ, Priori SG, Spazzolini C et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 103, 89-95 (2001).
16. Khositseth A, Tester DJ, Will ML, Bell CM, Ackerman MJ. Identification of a common genetic substrate underlying postpartum cardiac events in congenital long QT syndrome. Heart Rhythm. 1, 60-64 (2004).
17. Roden DM, Spooner PM. Inherited long QT syndromes: a paradigm for understanding arrhythmogenesis. J. Cardiovasc. Electrophysiol. 10, 1664-1683 (1999).
18. Zareba W, Moss AJ, Schwartz PJ et al. Influence of genotype on the clinical course of the long QT syndrome. N. Engl. J. Med. 339, 960-965 (1998).
19. Khan IA. Clinical and therapeutic aspects of congenital and acquired long QT syndrome. Am. J. Med. 112, 58-66 (2002).
20. Priori SG, Schwartz PJ, Napolitano C et al. Risk stratification in the long-QT syndrome. N. Engl. J. Med. 348, 1866-1874 (2003). • Correlated mutations with clinical manifestations.
21. Schwartz PJ, Zaza A, Locati E, Moss AJ. Stress and sudden death. The case of the long QT syndrome. Circulation 83(Suppl. II), 71-80 (1991).
22. Vincent GM, Timothy KW, Leppert M, Keating M. The spectrum of symptoms and QT intervals in carriers of the gene for the long QT syndrome. N. Engl. J. Med. 327, 846-852 (1992).
23. Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome: an update. Circulation 88, 782-784 (1993).
24. Moss AJ, Zareba W, Benhorin J et al. ECG Twave patterns in genetically distinct forms of the hereditary long QT syndrome. Circulation 92, 2929-2934 (1995).
25. Zhang L, Timothy KW, Vincent GM et al. A spectrum of ST-T-wave patterns and repolarization parameters in congenital long-QT syndrome: ECG findings identify genotypes. Circulation 102, 2849-2855 (2000).
26. Schwartz PJ, Malliani A. Electrical alteration of the T wave: clinical and experimental evidence of its relationship with the sympathetic nervous system and with the long QT syndrome. Am. Heart J. 89, 45-50 (1975).
27. Shimizu W, Noda T, Takaki H et al. Epinephrine unmasks latent mutation carriers with LQT1 form of congenital long QT syndrome. J. Am. Coll. Cardiol. 41, 633-642 (2003).
28. Ackerman MJ, Khositseth A, Tester DJ et al. Epinephrine-induced QT interval prolongation: a gene-specific paradoxical response in congenital long QT syndrome. Mayo Clin. Proc. 77, 413-421 (2002).
29. 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 1, 276-283 (2004).
30. Vyas H, Hejlik J, Ackerman MJ. Epinephrine QT stress testing in the evaluation of congenital long-QT syndrome: diagnostic accuracy of the paradoxical QT response. Circulation 113, 1385-1392 (2006).
31. Bhandari AK, Shapiro WA, Morady F, Shen EN, Mason J, Scheinman MM. Electrophysiologic testing in patients with the long QT syndrome. Circulation 71, 63-71 (1985).
32. Moss AJ, Schwartz PJ, Crampton RS et al. The long QT syndrome: prospective longitudinal study of 328 families. Circulation 84, 1136-1144 (1991).
33. Ackerman MJ. The long QT syndrome: ion channel diseases of the heart. Mayo Clin. Proc. 73, 250-269 (1998).
34. Fraser GR, Froggatt P, Murphy T. Genetical aspects of the cardioauditory syndrome of Jervell and Lange-Nielsen (congenital deafness and electrocardiographic abnormalities). Ann. Hum. Genet. 28, 133-157 (1964).
35. Keating M, Atkinson D, Dunn C, Timothy K, Vincent GM, Leppert M. Linkage of a cardiac arrhythmia, the long QT syndrome, and the Harvey Ras-1 gene. Science 252, 704-706 (1991).
36. Keating M, Dunn C, Atkinson D, Timothy K, Vincent GM, Leppert M. Consistent linkage of the long-QT syndrome to the Harvey Ras-1 locus on chromosome 11. Am. J. Hum. Genet. 49, 1335-1339 (1991).
37. Wang Q Curran ME, Splawski I et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nature Genet. 12, 17-23 (1996).
38. Sarkozy A, Brugada P. Sudden cardiac death and inherited arrhythmia syndromes. J. Cardiovasc. Electrophysiol. 16(Suppl. 1), S8-S20 (2005).
39. Hong K, Piper DR, Diaz-Valdecantos A et al. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc. Res. 68, 433-440 (2005).
40. sK associated with both Jervell and Lange- Nielsen and Romano-Ward forms of Long-QT syndrome. Circulation 97, 142-146 (1998).
41. Neyroud N, Tesson F, Denjoy I et al. A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nature Genet. 15, 186-189 (1997).
42. Splawski I, Timothy KW, Vincent GM, Atkinson DL, Keating MT. Molecular basis of the long-QT syndrome associated with deafness. N. Engl. J. Med. 336, 1562-1567 (1997).
43. Chen Q, Zhang D, Gingell RL et al. Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome. Circulation 99, 1344-1347 (1999).
44. Wang Z, Li H, Moss AJ et al. Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Mol. Genet. Metab. 75, 308-316 (2002).
45. Ning L, Moss AJ, Zareba W et al. Novel compound heterozygous mutations in the KCNQ1 gene associated with autosomal recessive long QT syndrome (Jervell and Lange-Nielsen syndrome). Ann. Noninvasive Electrocardiol. 8, 246-250 (2003).
46. Tyson J, Tranebjaerg L, McEntagart M et al. Mutational spectrum in the cardioauditory syndrome of Jervell and Lange-Nielsen. Hum. Genet. 107, 499-503 (2000).
47. Wang Q, Curran ME, Splawski I et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmia. Nature Genet. 12, 17-23 (1996).
48. Jiang C, Atkinson D, Towbin JA et al. Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nature Genet. 8, 141-147 (1994).
49. Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc. Natl Acad. Sci. USA 91, 3438-3442 (1994).
50. Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80, 795-803 (1995).
51. Kr potassium channel. Cell 81, 299-307 (1995).
52. Gong Q, Keeny DR, Robinson JC, Zhou Z. Defective assembly and trafficking of mutant HERG channels with C-terminal truncations in long QT syndrome. J. Mol. Cell Cardiol. 37, 1225-1233 (2004).
53. Zhang L, Vincent GM, Barelle M et al. An intronic mutation causes long QT syndrome. J. Am. Coll. Cardiol. 44, 1283-1291 (2004).
54. Koopmann TT, Alders M, Jongbloed RJ et al. Long QT syndrome caused by a large duplication in the KCNH2 (HERG) gene undetectable by current polymerase chain reaction-based exon-scanning methodologies. Heart Rhythm 3, 52-55 (2006).
55. Berthet M, Denjoy I, Donger C et al. C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence. Circulation 99, 1464-1470 (1999).
56. Brugada R, Hong K, Dumaine R et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 109, 30-35 (2004).
57. Tester DJ, Will ML, Haglund CM, Ackerman MJ. Compendium of cardiac channel mutations in 541 consecutive unrelated patients referred for long QT syndrome genetic testing. Heart Rhythm 2, 507-517 (2005). • Compilation of mutations detected in a large cohort for long QT syndrome genetic testing.
58. 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 294, 2975-2980 (2005). • Report on genetic screening in a large cohort and recommendations for genotyping.
59. Chen Q, Kirsch GE, Zhang D et al. Genetic basis and molecular mechanism for idiopathic ventricular fibrillation. Nature 392, 293-296 (1998).
60. Baroudi G, Napolitano C, Priori SG, Del Bufalo A, Chahine M. Loss of function associated with novel mutations of the SCN5A gene in patients with Brugada syndrome. Can. J. Cardiol. 20, 425-430 (2004).
61. Hong K, Guerchicoff A, Pollevick GD et al. Cryptic 5′ splice site activation in SCN5A associated with Brugada syndrome. J. Mol. Cell. Cardiol. 38, 555-560 (2005).
62. Grant AO. Electrophysiological basis and genetics of Brugada syndrome. J. Cardiovasc. Electrophysiol. 16(Suppl 1), S3-S7 (2005).
63. Verkerk AO, Wilders R, Schulze-Bahr E et al. Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome. Cardiovasc. Res. 68, 441-453 (2005).
64. Mohler PJ, Schott JJ, Gramolini AO et al. Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421, 634-639 (2003).
65. Mohler PJ, Splawski I, Napolitano C et al. A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Natl Acad. Sci. USA 101, 9137-9142 (2004).
66. Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81, 299-307 (1995).
67. Ks cardiac potassium current. Nature 384, 78-80 (1996).
68. Kr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97, 175-187 (1999).
69. Zhang M, Jiang M, Tseng GN. minK-related peptide 1 associates with Kv4.2 and modulates its gating function: potential role as β subunit of cardiac transient outward channel? Circ. Res. 88, 1012-1019 (2001).
70. Firouzi M, Groenewegen WA. Gene polymorphisms and cardiac arrhythmias. Europace 5, 235-242 (2003).
71. Ai T, Fujiwara Y, Tsuji K et al. Novel KCNJ2 mutation in familial periodic paralysis with ventricular dysrhythmia. Circulation 105, 2592-2594 (2002).
72. 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 105, 511-519 (2001).
73. Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, Benson DW. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am. J. Hum. Genet. 71, 663-668 (2002).
74. Tristani-Firouzi M, Jensen JL, Donaldson MR et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J. Clin. Invest. 110, 381-388 (2002).
75. Donaldson MR, Jensen JL, Tristani-Firouzi M et al. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 60, 1811-1816 (2003).
76. Hosaka Y, Hanawa H, Washizuka T et al. Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen's syndrome. J. Mol. Cell. Cardiol. 35, 409-415 (2003).
77. Zhang L, Benson DW, Tristani-Firouzi M et al. Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation 111, 2720-2726 (2005).
78. Priori SG, Pandit SV, Rivolta I et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ. Res. 96, 800-807 (2005).
79. Splawski I, Timothy KW, Sharpe LM et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19-31 (2004).
80. Splawski I, Timothy KW, Decher N et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc. Natl Acad. Sci. USA 102, 8089-8096 (2005).
81. 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 2, 1099-1105 (2005).
82. Bezzina CR, Verkerk AO, Busjahn A et al. A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization. Cardiovasc. Res. 5, 27-36 (2003).
83. Pietila E, Fodstad H, Niskasaari E et al. Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women. J. Am. Coll. Cardiol. 4, 511-514 (2002).
84. Gouas L, Nicaud V, Berthet M et al. Association of KCNQ1, KCNE1, KCNH2 and SCN5A polymorphisms with QTc interval length in a healthy population. Eur. J. Hum. Genet. 13, 1213-1222 (2005).
85. Crotti L, Lundquist AL, Insolia R et al. KCNH2-K897T is a genetic modifier of latent congenital long-QT syndrome. Circulation 112, 1251-1258 (2005).
86. Marian AJ, Brugada R, Roberts R. Cardiovascular diseases due to genetic abnormalities. In: Hurst's the Heart. 11th Edition. Fuster V, Alexander RW, O'Rourke RA (Eds), McGraw-Hill, NY, USA (2004).
87. Tester DJ, Will ML, Haglund, Ackerman MJ. Effect of clinical phenotype on yield of long QT syndrome genetic testing. J. Am. Coll. Cardiol. 47, 764-768 (2006). • Recommendation on the use of clinical phenotypes to improve the yield of genetic testing.
88. Wilde AAM, Roden DM. Predicting the long QT genotype from clinical data. Circulation 102, 2796-2798 (2000).
89. Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: a HuGE review. Genet. Med. 8, 143-155 (2006). •• Latest review summarizing genetic and electrophysiology findings.
90. Lupoglazoff JM, Denjoy I, Berhet M et al. Notched T waves on Holter recordings enhance detection of patients with LQT2 (HERG) mutations. Circulation 103, 1095-1101 (2001).
91. Van Langen IM, Birnie E, Alders M, Jongbloed RJ, Le Marec H, Wilde AA. The use of genotype-phenotype correlations in mutation analysis for the long QT syndrome. J. Med. Genet. 40, 141-145 (2003).
92. Phillips KA, Ackerman MJ, Sakowski J, Berul CI. Cost-effectiveness analysis of genetic testing for familial long QT syndrome in symptomatic index cases. Heart Rhythm 2, 1294-1300 (2005).
93. Ackerman MJ, Siu BL, Sturner WQ. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 286, 2264-2269 (2001).
94. Maron BJ, Clark CE, Goldstein RE et al. Potential role of QT interval prolongation in sudden infant death syndrome. Circulation 54, 423-430 (1976).
95. Ackerman MJ, Tester DJ, Jones GS, Will ML, Burrow CR, Curran ME. 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, 1479-1487 (2003).
96. Tester DJ, McCormack J, Ackerman MJ. Prenatal molecular genetic diagnosis of congenital long QT syndrome by strategic genotyping. Am. J. Cardiol. 93, 788-791 (2004).
97. Sharma D, Glatter KA, Timofeyev V et al. Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2: implications for genetic testing. J. Mol. Cell. Cardiol. 37, 79-89 (2004).
98. Shimizu W. The long QT syndrome: therapeutic implications of a genetic diagnosis. Cardiovasc. Res. 67, 347-356 (2005).
99. Priori SG, Napolitano C, Schwartz PJ et al. Association of long QT syndrome loci and cardiac events among patients treated with β-blockers. JAMA 292, 1341-1344 (2004).
100. Shimizu W, Aiba T, Antzelevitch C. Specific therapy based on the genotype and cellular mechanism in inherited cardiac arrhythmias. Long QT syndrome and Brugada syndrome. Curr. Pharm. Des. 11, 1561-1572 (2005).
101. Chiang CE, Roden DM. The long QT syndromes: genetic basis and clinical implications. J. Am. Coll. Cardiol. 36, 1-12 (2000).
102. Garson A, Dick M, Fournier A et al. The long QT syndrome in children: an international study of 287 patients. Circulation 87, 1866-1872 (1993).
103. Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation 109, 1834-1841 (2004).
104. Moss AJ, Schwartz PJ. 25th anniversary of the International Long-QT Syndrome Registry: an ongoing quest to uncover the secrets of long-QT syndrome. Circulation 111, 1199-1201 (2005).
105. Vincent GM. The long-QT syndrome - bedside to bench to bedside. N. Engl. J. Med. 348, 1837-1838 (2003).
106. Moss AJ. Long QT syndrome. JAMA 289, 2041-2044 (2003). •• Good introduction on the clinical features of long QT syndrome.
107. Hendricks KSWH, Grosfeld SJM, van Tintelen JP et al. Can parents adjust to the idea that their child is at risk for a sudden death?: psychological impact of risk for long QT syndrome. Am. J. Med. Genet. 138A, 107-112 (2005).
108. Vincent GM. Gene Reviews: Romano-Ward syndrome www.genetests.org
109. Gene Connection For The Heart http://pc4.fsm.it:81/cardmoc