CLINICAL STUDY: GENETICS AND ARRHYTHMIAS
Genotype-phenotype relationship in Brugada syndrome: electrocardiographic features differentiate SCN5A-related patients from non–SCN5A-related patients
Jeroen P. P. Smits, MD*,
Lars Eckardt, MD ,
Vincent Probst, MD ,
Connie R. Bezzina, PhD*,
Jean Jacques Schott, PhD,
Carol Ann Remme, MD*,
Wilhelm Haverkamp, MD,
G.ünter Breithardt, MD,
Denis Escande, MD, PhD,
Eric Schulze-Bahr, MD,
Hervé LeMarec, MD, PhD and
Arthur A. M. Wilde, MD, PhD*,*
* Experimental and Molecular Cardiology Group, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Medizinische Klinik und Poliklinik C (Kardiologie/Angiologie) Universitätsklinikum, Institut f. Arterioskleroseforschung an der Universität Münster, Münster, Germany
INSERM U533, Hôpital Hôtel-Dieu, Nantes, France
Manuscript received January 8, 2002;
revised manuscript received March 26, 2002,
accepted April 17, 2002.
* Reprint requests and correspondence: Dr. Arthur A. M. Wilde, Academic Medical Center, University of Amsterdam, Department of Clinical and Experimental Cardiology, M-0-052, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
M.Kraaijenhof{at}AMC.UVA.NL
OBJECTIVES: We have tested whether a genotype-phenotype relationship exists in Brugada syndrome (BS) by trying to distinguish BS patients with (carriers) and those without (non-carriers) a mutation in the gene encoding the cardiac sodium channel (SCN5A) using clinical parameters.
BACKGROUND: Brugada syndrome is an inherited cardiac disease characterized by a varying degree of ST-segment elevation in the right precordial leads and (non)specific conduction disorders. In a minority of patients, SCN5A mutations can be found. Genetic heterogeneity has been demonstrated, but other causally related genes await identification. If a genotype-phenotype relationship exists, this might facilitate screening.
METHODS: In a multi-center study, we have collected data on demographics, clinical history, family history, electrocardiogram (ECG) parameters, His to ventricle interval (HV), and ECG parameters after pharmacologic challenge with INa blocking drugs for BS patients with (n = 23), or those without (n = 54), an identified SCN5A mutation.
RESULTS: No differences were found in demographics, clinical history, or family history. Carriers had a significantly longer PQ interval on the baseline ECG and a significantly longer HV time. A PQ interval of  210 ms and an HV interval 60 ms seem to be predictive for the presence of an SCN5A mutation. After INa blocking drugs, carriers had significantly longer PQ and QRS intervals and more increase in QRS duration.
CONCLUSIONS: We observed significantly longer conduction intervals on baseline ECG in patients with established SCN5A mutations (PQ and HV interval and, upon class I drugs, more QRS increase). These results concur with the observed loss of function of mutated BS-related sodium channels. Brugada syndrome patients with, and those without, an SCN5A mutation can be differentiated by phenotypical differences.
|
Abbreviations and Acronyms
| | AUC | | area under the curve | | BS | | Brugada syndrome | | ECG | | electrocardiogram/electrocardiographic | | EPS | | electrophysiologic studies | | HR | | heart rate | | HV | | His to ventricle interval | | Na+ | | sodium | | SCN5A | | pore-forming region (alpha-subunit) of the human cardiac sodium channel | | SSCP | | single-strand conformation polymorphism |
|
This article has been cited by other articles:
|
|
|
|
 
A. S. Amin, E. A.A. de Groot, J. M. Ruijter, A. A.M. Wilde, and H. L. Tan
Exercise-Induced ECG Changes in Brugada Syndrome
Circ Arrhythm Electrophysiol,
October 1, 2009;
2(5):
531 - 539.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Veltmann, C. Wolpert, F. Sacher, P. Mabo, R. Schimpf, F. Streitner, J. Brade, F. Kyndt, J. Kuschyk, H. Le Marec, et al.
Response to intravenous ajmaline: a retrospective analysis of 677 ajmaline challenges
Europace,
October 1, 2009;
11(10):
1345 - 1352.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Potet, B. Chagot, M. Anghelescu, P. C. Viswanathan, S. Z. Stepanovic, S. Kupershmidt, W. J. Chazin, and J. R. Balser
Functional Interactions between Distinct Sodium Channel Cytoplasmic Domains through the Action of Calmodulin
J. Biol. Chem.,
March 27, 2009;
284(13):
8846 - 8854.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Chagot, F. Potet, J. R. Balser, and W. J. Chazin
Solution NMR Structure of the C-terminal EF-hand Domain of Human Cardiac Sodium Channel NaV1.5
J. Biol. Chem.,
March 6, 2009;
284(10):
6436 - 6445.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Gaborit, T. Wichter, A. Varro, V. Szuts, G. Lamirault, L. Eckardt, M. Paul, G. Breithardt, E. Schulze-Bahr, D. Escande, et al.
Transcriptional profiling of ion channel genes in Brugada syndrome and other right ventricular arrhythmogenic diseases
Eur. Heart J.,
February 2, 2009;
30(4):
487 - 496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A.M. Wilde and Y. M. Pinto
Cost-Effectiveness of Genotyping in Inherited Arrhythmia Syndromes: Are We Getting Value for the Money?
Circ Arrhythm Electrophysiol,
February 1, 2009;
2(1):
1 - 3.
[Full Text]
[PDF]
|
|
|
|
|
|
|
Yield of genetic screening in inherited cardiac channelopathies: how to prioritize access to genetic testing.
Circ Arrhythm Electrophysiol,
February 1, 2009;
2(1):
6 - 15.
|
|
|
|
|
|
|
B. Benito, A. Sarkozy, L. Mont, S. Henkens, A. Berruezo, D. Tamborero, D. Arzamendi, P. Berne, R. Brugada, P. Brugada, et al.
Gender Differences in Clinical Manifestations of Brugada Syndrome
J. Am. Coll. Cardiol.,
November 4, 2008;
52(19):
1567 - 1573.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Bebarova, T. O'Hara, J. L. M. C. Geelen, R. J. Jongbloed, C. Timmermans, Y. H. Arens, L.-M. Rodriguez, Y. Rudy, and P. G. A. Volders
Subepicardial phase 0 block and discontinuous transmural conduction underlie right precordial ST-segment elevation by a SCN5A loss-of-function mutation
Am J Physiol Heart Circ Physiol,
July 1, 2008;
295(1):
H48 - H58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Francis and C. Antzelevitch
Atrial Fibrillation and Brugada Syndrome
J. Am. Coll. Cardiol.,
March 25, 2008;
51(12):
1149 - 1153.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Casini, H. L. Tan, Z. A. Bhuiyan, C. R. Bezzina, P. Barnett, E. Cerbai, A. Mugelli, A. A.M. Wilde, and M. W. Veldkamp
Characterization of a novel SCN5A mutation associated with Brugada syndrome reveals involvement of DIIIS4-S5 linker in slow inactivation
Cardiovasc Res,
December 1, 2007;
76(3):
418 - 429.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. L. Shang, A. E. Pfahnl, S. Sanyal, Z. Jiao, J. Allen, K. Banach, J. Fahrenbach, D. Weiss, W. R. Taylor, A. M. Zafari, et al.
Human Heart Failure Is Associated With Abnormal C-Terminal Splicing Variants in the Cardiac Sodium Channel
Circ. Res.,
November 26, 2007;
101(11):
1146 - 1154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Paul, J. Gerss, E. Schulze-Bahr, T. Wichter, C. Vahlhaus, A. A.M. Wilde, G. Breithardt, and L. Eckardt
Role of programmed ventricular stimulation in patients with Brugada syndrome: a meta-analysis of worldwide published data
Eur. Heart J.,
September 1, 2007;
28(17):
2126 - 2133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z.-S. Zhang, J. Tranquillo, V. Neplioueva, N. Bursac, and A. O. Grant
Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease
Am J Physiol Heart Circ Physiol,
January 1, 2007;
292(1):
H399 - H407.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Veltmann, R. Schimpf, C. Echternach, L. Eckardt, J. Kuschyk, F. Streitner, S. Spehl, M. Borggrefe, and C. Wolpert
A prospective study on spontaneous fluctuations between diagnostic and non-diagnostic ECGs in Brugada syndrome: implications for correct phenotyping and risk stratification
Eur. Heart J.,
November 1, 2006;
27(21):
2544 - 2552.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A.M. Wilde
Spontaneous electrocardiographic fluctuations in Brugada syndrome: does it matter?
Eur. Heart J.,
November 1, 2006;
27(21):
2493 - 2494.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. R. Cunha and P. J. Mohler
Cardiac ankyrins: Essential components for development and maintenance of excitable membrane domains in heart
Cardiovasc Res,
July 1, 2006;
71(1):
22 - 29.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Aiba, W. Shimizu, I. Hidaka, K. Uemura, T. Noda, C. Zheng, A. Kamiya, M. Inagaki, M. Sugimachi, and K. Sunagawa
Cellular Basis for Trigger and Maintenance of Ventricular Fibrillation in the Brugada Syndrome Model: High-Resolution Optical Mapping Study
J. Am. Coll. Cardiol.,
May 16, 2006;
47(10):
2074 - 2085.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M Sugao, A Fujiki, M Sakabe, K Nishida, T Tsuneda, J Iwamoto, K Mizumaki, and H Inoue
New quantitative methods for evaluation of dynamic changes in QT interval on 24 hour Holter ECG recordings: QT interval in idiopathic ventricular fibrillation and long QT syndrome
Heart,
February 1, 2006;
92(2):
201 - 207.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. R. Bezzina, W. Shimizu, P. Yang, T. T. Koopmann, M. W.T. Tanck, Y. Miyamoto, S. Kamakura, D. M. Roden, and A. A.M. Wilde
Common Sodium Channel Promoter Haplotype in Asian Subjects Underlies Variability in Cardiac Conduction
Circulation,
January 24, 2006;
113(3):
338 - 344.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. O. Verkerk, R. Wilders, E. Schulze-Bahr, L. Beekman, Z. A. Bhuiyan, J. Bertrand, L. Eckardt, D. Lin, M. Borggrefe, G. Breithardt, et al.
Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome
Cardiovasc Res,
December 1, 2005;
68(3):
441 - 453.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Coronel, S. Casini, T. T. Koopmann, F. J.G. Wilms-Schopman, A. O. Verkerk, J. R. de Groot, Z. Bhuiyan, C. R. Bezzina, M. W. Veldkamp, A. C. Linnenbank, et al.
Right Ventricular Fibrosis and Conduction Delay in a Patient With Clinical Signs of Brugada Syndrome: A Combined Electrophysiological, Genetic, Histopathologic, and Computational Study
Circulation,
November 1, 2005;
112(18):
2769 - 2777.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. A.B. van Veen, M. Stein, A. Royer, K. Le Quang, F. Charpentier, W. H. Colledge, C. L.-H. Huang, R. Wilders, A. A. Grace, D. Escande, et al.
Impaired Impulse Propagation in Scn5a-Knockout Mice: Combined Contribution of Excitability, Connexin Expression, and Tissue Architecture in Relation to Aging
Circulation,
September 27, 2005;
112(13):
1927 - 1935.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. R. Bezzina, A. A.M. Wilde, and D. M. Roden
The molecular genetics of arrhythmias
Cardiovasc Res,
August 15, 2005;
67(3):
343 - 346.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. G. Meregalli, A. A.M. Wilde, and H. L. Tan
Pathophysiological mechanisms of Brugada syndrome: Depolarization disorder, repolarization disorder, or more?
Cardiovasc Res,
August 15, 2005;
67(3):
367 - 378.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. I. Keller, J.-S. Rougier, J. P. Kucera, N. Benammar, V. Fressart, P. Guicheney, A. Madle, M. Fromer, J. Schlapfer, and H. Abriel
Brugada syndrome and fever: Genetic and molecular characterization of patients carrying SCN5A mutations
Cardiovasc Res,
August 15, 2005;
67(3):
510 - 519.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T Rossenbacker, E Schollen, C Kuiperi, T J L de Ravel, K Devriendt, G Matthijs, D Collen, H Heidbuchel, and P Carmeliet
Unconventional intronic splice site mutation in SCN5A associates with cardiac sodium channelopathy
J. Med. Genet.,
May 1, 2005;
42(5):
e29 - e29.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Antzelevitch, P. Brugada, M. Borggrefe, J. Brugada, R. Brugada, D. Corrado, I. Gussak, H. LeMarec, K. Nademanee, A. R. Perez Riera, et al.
Brugada Syndrome: Report of the Second Consensus Conference: Endorsed by the Heart Rhythm Society and the European Heart Rhythm Association
Circulation,
February 8, 2005;
111(5):
659 - 670.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Eckardt, V. Probst, J. P.P. Smits, E. S. Bahr, C. Wolpert, R. Schimpf, T. Wichter, P. Boisseau, A. Heinecke, G. Breithardt, et al.
Long-Term Prognosis of Individuals With Right Precordial ST-Segment-Elevation Brugada Syndrome
Circulation,
January 25, 2005;
111(3):
257 - 263.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P.P. Smits, M. W. Veldkamp, and A. A.M. Wilde
Mechanisms of inherited cardiac conduction disease
Europace,
January 1, 2005;
7(2):
122 - 137.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Hong, J. Brugada, A. Oliva, A. Berruezo-Sanchez, D. Potenza, G. D. Pollevick, A. Guerchicoff, K. Matsuo, E. Burashnikov, R. Dumaine, et al.
Value of Electrocardiographic Parameters and Ajmaline Test in the Diagnosis of Brugada Syndrome Caused by SCN5A Mutations
Circulation,
November 9, 2004;
110(19):
3023 - 3027.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Martini, H. L. Tan, R. Tukkie, J. Vleugels, I. K.L.M. de Groot, A. A.M. Wilde, and P. Sogaard
Further Confirmation That a Conduction Disturbance Underlies the Electrocardiographic Pattern of the So-Called Brugada Syndrome * Response
Circulation,
August 3, 2004;
110(5):
e53 - e53.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. H. Thrall
Personalized Medicine
Radiology,
June 1, 2004;
231(3):
613 - 616.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bordachar, S. Reuter, S. Garrigue, X. Cai, M. Hocini, P. Jais, M. Haissaguerre, and J. Clementy
Incidence, clinical implications and prognosis of atrial arrhythmias in brugada syndrome
Eur. Heart J.,
May 2, 2004;
25(10):
879 - 884.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Tukkie, P. Sogaard, J. Vleugels, I. K.L.M. de Groot, A. A.M. Wilde, and H. L. Tan
Delay in Right Ventricular Activation Contributes to Brugada Syndrome
Circulation,
March 16, 2004;
109(10):
1272 - 1277.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. L Tan, C. R Bezzina, J. P.P Smits, A. O Verkerk, and A. A.M Wilde
Genetic control of sodium channel function
Cardiovasc Res,
March 15, 2003;
57(4):
961 - 973.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Probst, F. Kyndt, F. Potet, J.-N. Trochu, G. Mialet, S. Demolombe, J.-J. Schott, I. Baro, D. Escande, and H. Le Marec
Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenegre disease
J. Am. Coll. Cardiol.,
February 19, 2003;
41(4):
643 - 652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Moric, E. Herbert, M. Trusz-Gluza, A. Filipecki, U. Mazurek, and T. Wilczok
The implications of genetic mutations in the sodium channel gene (SCN5A)
Europace,
January 1, 2003;
5(4):
325 - 334.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Antzelevitch, P. Brugada, J. Brugada, R. Brugada, W. Shimizu, I. Gussak, and A.R. Perez Riera
Brugada Syndrome: A Decade of Progress
Circ. Res.,
December 13, 2002;
91(12):
1114 - 1118.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Roden
The problem, challenge and opportunity of genetic heterogeneity in monogenic diseases predisposing to sudden death
J. Am. Coll. Cardiol.,
July 17, 2002;
40(2):
357 - 359.
[Full Text]
[PDF]
|
|
|
|
