REVIEW ARTICLES
The long QT syndromes: genetic basis and clinical implications
Chern-En Chiang, MD, PhD* and
Dan M. Roden, MD, FACC
* Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan
Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
Manuscript received October 28, 1999;
revised manuscript received January 18, 2000,
accepted March 27, 2000.
Reprint requests and correspondence: Chern-En Chiang, Division of Cardiology, Veterans General Hospital-Taipei, 201, Sec 2, Shih-Pai Road, Taipei, Taiwan
cechiang{at}vghtpe.gov.tw
It is becoming clear that mutations in the KVLQT1, human "ether-a-go-go" related gene, cardiac voltage-dependent sodium channel gene, minK and MiRP1 genes, respectively, are responsible for the LQT1, LQT2, LQT3, LQT5 and LQT6 variants of the Romano-Ward syndrome, characterized by autosomal dominant transmission and no deafness. The much rarer Jervell-Lange-Nielsen syndrome (with marked QT prolongation and sensorineural deafness) arises when a child inherits mutant KVLQT1 or minK alleles from both parents. In addition, some families are not linked to the known genetic loci. Cardiac voltage-dependent sodium channel gene encodes the cardiac sodium channel, and long QT syndrome (LQTS) mutations prolong action potentials by increasing inward plateau sodium current. The other mutations cause a decrease in net repolarizing current by reducing potassium currents through "dominant negative" or "loss of function" mechanisms. Polymorphic ventricular tachycardia (torsade de pointes) is thought to be initiated by early after- depolarizations in the Purkinje system and maintained by reentry in the myocardium. Clinical presentations vary with the specific gene affected and the specific mutation. Nevertheless, patients with identical mutations can also present differently, and some patients with LQTS mutations may have no manifest baseline phenotype. The question of whether the latter situation is one of high risk for administration of QT prolonging drugs or during myocardial ischemia is under active investigation. More generally, the identification of LQTS genes has provided tremendous new insights for our understanding of normal cardiac electrophysiology and its perturbation in a wide range of conditions associated with sudden death. It seems likely that the approach of applying information from the genetics of uncommon congenital syndromes to the study of common acquired diseases will be an increasingly important one in the next millennium.
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Abbreviations and Acronyms
| | ECG | = electrocardiogram | | HERG | = human "ether-a-go-go" related gene | | IKr | = rapidly activating component of delayed rectifier potassium current | | IKs | = slowly activating component of delayed rectifier potassium current | | JLN | = Jervell-Lange-Nielsen | | LQTS | = long QT syndrome | | MiRP1 | = minK related peptide 1 | | QTc | = corrected QT interval | | RW | = Romano-Ward | | SCN5A | = cardiac voltage-dependent sodium channel gene |
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Y. Rudy, M. J. Ackerman, D. M. Bers, C. E. Clancy, S. R. Houser, B. London, A. D. McCulloch, D. A. Przywara, R. L. Rasmusson, R. J. Solaro, et al.
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|
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G. C. L. Bett and R. L. Rasmusson
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586(4):
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|
|
|
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I. R. Boulet, A. J. Labro, A. L. Raes, and D. J. Snyders
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585(2):
325 - 337.
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|
|
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S. Giunti, G. Bruno, E. Lillaz, G. Gruden, V. Lolli, N. Chaturvedi, J. H. Fuller, M. Veglio, P. Cavallo-Perin, and The EURODIAB IDDM Complications Study Group
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|
|
|
|
|
|
|
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291(1):
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|
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P. K. Sura
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70(3):
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|
|
|
|
|
|
|
M C S Hall and D M Todd
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|
|
|
|
|
|
|
E. S. Kaufman
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December 21, 2005;
294(23):
3027 - 3028.
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|
|
|
|
|
|
|
A. D. Krahn, M. Gollob, R. Yee, L. J. Gula, A. C. Skanes, B. D. Walker, and G. J. Klein
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112(15):
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|
|
|
|
|
|
|
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67(3):
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|
|
|
|
|
|
|
P. Miranda, T. Giraldez, P. de la Pena, D. G Manso, C. Alonso-Ron, D. Gomez-Varela, P. Dominguez, and F. Barros
Specificity of TRH receptor coupling to G-proteins for regulation of ERG K+ channels in GH3 rat anterior pituitary cells
J. Physiol.,
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566(3):
717 - 736.
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|
|
|
|
|
|
|
T. Chen, M. Inoue, and M. F. Sheets
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June 1, 2005;
288(6):
H2666 - H2676.
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|
|
|
|
|
|
|
P. Zimetbaum and M. E. Josephson
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141(9):
720 - 726.
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|
|
|
|
|
|
|
Md. S. Amran, K. Hashimoto, and N. Homma
Effects of Sodium-Calcium Exchange Inhibitors, KB-R7943 and SEA0400, on Aconitine-Induced Arrhythmias in Guinea Pigs in Vivo, in Vitro, and in Computer Simulation Studies
J. Pharmacol. Exp. Ther.,
July 1, 2004;
310(1):
83 - 89.
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|
|
|
|
|
|
|
P. J. Mohler, I. Splawski, C. Napolitano, G. Bottelli, L. Sharpe, K. Timothy, S. G. Priori, M. T. Keating, and V. Bennett
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June 15, 2004;
101(24):
9137 - 9142.
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|
|
|
|
|
|
|
A. Krumerman, X. Gao, J.-S. Bian, Y. F. Melman, A. Kagan, and T. V. McDonald
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286(6):
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|
|
|
|
|
|
|
R. Owczuk, M. A. Wujtewicz, W. Sawicka, M. Wujtewicz, and M. Swierblewski
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92(5):
658 - 661.
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|
|
|
|
|
|
|
S. P. Etheridge, S. J. Compton, M. Tristani-Firouzi, and J. W. Mason
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42(10):
1777 - 1782.
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|
|
|
|
|
|
|
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J. Biol. Chem.,
October 24, 2003;
278(43):
42136 - 42148.
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[Full Text]
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|
|
|
|
|
|
|
T. Tosaka, M. C. Casimiro, Q. Rong, S. Tella, M. Oh, A. N. Katchman, J. C. Pezzullo, K. Pfeifer, and S. N. Ebert
Nicotine Induces a Long QT Phenotype in Kcnq1-Deficient Mouse Hearts
J. Pharmacol. Exp. Ther.,
September 1, 2003;
306(3):
980 - 987.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C Savoye, D Klug, I Denjoy, P.V Ennezat, T Le Tourneau, P Guicheney, and S Kacet
Tissue Doppler echocardiography in patients with long QT syndrome
Eur J Echocardiogr,
September 1, 2003;
4(3):
209 - 213.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-X. Yan, R. S. Lankipalli, J. F. Burke, S. Musco, and P. R. Kowey
Ventricular repolarization components on the electrocardiogram: Cellular basis and clinical significance
J. Am. Coll. Cardiol.,
August 6, 2003;
42(3):
401 - 409.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Al-Khatib, N. M. A. LaPointe, J. M. Kramer, and R. M. Califf
What Clinicians Should Know About the QT Interval
JAMA,
April 23, 2003;
289(16):
2120 - 2127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Gomez-Varela, T. Giraldez, P. d. la Pena, S. G Dupuy, D. Garcia-Manso, and F. Barros
Protein kinase C is necessary for recovery from the thyrotropin-releasing hormone-induced r-ERG current reduction in GH3 rat anterior pituitary cells
J. Physiol.,
March 15, 2003;
547(3):
913 - 929.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.A. Groenewegen, C. R. Bezzina, J.P. van Tintelen, T. M. Hoorntje, M. M.A.M. Mannens, A. A.M. Wilde, Habo.J. Jongsma, and M. B. Rook
A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics
Cardiovasc Res,
March 15, 2003;
57(4):
1072 - 1078.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Goldschlager, A. E. Epstein, B. P. Grubb, B. Olshansky, E. Prystowsky, W. C. Roberts, M. M. Scheinman, and for the Practice Guidelines Subcommittee, North Am
Etiologic Considerations in the Patient With Syncope and an Apparently Normal Heart
Arch Intern Med,
January 27, 2003;
163(2):
151 - 162.
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. T. Yetman, R. A. Bornemeier, and B. W. McCrindle
Long-term outcome in patients with Marfan syndrome: is aortic dissection the only cause of sudden death?
J. Am. Coll. Cardiol.,
January 15, 2003;
41(2):
329 - 332.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Chen and M. F. Sheets
Enhancement of closed-state inactivation in long QT syndrome sodium channel mutation Delta KPQ
Am J Physiol Heart Circ Physiol,
September 1, 2002;
283(3):
H966 - H975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C.-E. Chiang, H.-N. Luk, T.-M. Wang, and P. Y.-A. Ding
Prolongation of cardiac repolarization by arsenic trioxide
Blood,
August 28, 2002;
100(6):
2249 - 2252.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Xu, J. J. Salata, J. Wang, Y. Wu, G.-X. Yan, T. Liu, R. A. Marinchak, and P. R. Kowey
Increasing IKs corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy
Am J Physiol Heart Circ Physiol,
August 1, 2002;
283(2):
H664 - H670.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-X. Yan, S. J. Rials, Y. Wu, T. Liu, X. Xu, R. A. Marinchak, and P. R. Kowey
Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization
Am J Physiol Heart Circ Physiol,
November 1, 2001;
281(5):
H1968 - H1975.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Wedekind, J. P.P. Smits, E. Schulze-Bahr, R. Arnold, M. W. Veldkamp, T. Bajanowski, M. Borggrefe, B. Brinkmann, I. Warnecke, H. Funke, et al.
De Novo Mutation in the SCN5A Gene Associated With Early Onset of Sudden Infant Death
Circulation,
September 4, 2001;
104(10):
1158 - 1164.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Brunner, W. Guo, G. F. Mitchell, P. D. Buckett, J. M. Nerbonne, and G. Koren
Characterization of mice with a combined suppression of Ito and IK,slow
Am J Physiol Heart Circ Physiol,
September 1, 2001;
281(3):
H1201 - H1209.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G.-X. Yan, Y. Wu, T. Liu, J. Wang, R. A. Marinchak, and P. R. Kowey
Phase 2 Early Afterdepolarization as a Trigger of Polymorphic Ventricular Tachycardia in Acquired Long-QT Syndrome : Direct Evidence From Intracellular Recordings in the Intact Left Ventricular Wall
Circulation,
June 12, 2001;
103(23):
2851 - 2856.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Laitinen, K. M. Brown, K. Piippo, H. Swan, J. M. Devaney, B. Brahmbhatt, E. A. Donarum, M. Marino, N. Tiso, M. Viitasalo, et al.
Mutations of the Cardiac Ryanodine Receptor (RyR2) Gene in Familial Polymorphic Ventricular Tachycardia
Circulation,
January 30, 2001;
103(4):
485 - 490.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
