Brugada syndrome

Last update: December 3, 2018

CPVT - Catecholaminergic polymorphic ventricular tachycardiaRecommended panel testing at Breda Genetics for this condition:

Brugada syndrome (CACNA1C, CACNB2, GPD1L, HCN4, KCNE3, SCN1B,SCN3B, SCN5A)

Summary

Ion channelopathies are diseases caused by dysfunctional ion channels that may lead to sudden death. These diseases can be either acquired or inherited. The main phenotypes of Brugada syndrome in patients carrying these heritable arrhythmia syndromes are congenital long QT syndromeBrugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. In the recent years, tremendous progress has been made in the  diagnosis, etiopathogenesis, and treatment of these diseases.

Detailed clinical description

Brugada syndrome is a dynamic disease, influenced by ethnicity, gender, genotype, autonomic tone, regionally abnormal myocardium, and varied physiologic and pharmacologic stimuli. Initially attributed to loss of sodium channel function, Brugada syndrome has also been attributed to loss of calcium channel function. Thus, the disease is not only a sodium channelopathy, but rather related to an imbalance between inward and outward currents during phase 1 of the action potential.

The hallmark electrocardiogram (ECG) feature is a type-1 pattern of a coved ST-segment elevation ≥2 mm followed by a negative T-wave, present in greater than 1 right precordial lead (V1-V3), occurring either spontaneously or provoked with a sodium channel antagonist. However, Brugada syndrome patients are only 25% likely to present a type 1 ECG. Patients may show also type 2 or type 3 ECG, but may also show normal ECG. Spatiotemporal characteristics of surface ECG recordings enable a robust identification of Brugada syndrome even without the presence of a type 1 ECG. Despite this, the diagnosis of Brugada syndrome based on the ECG is hampered by the dynamic nature of its ECG manifestations. Programmed ventricular stimulation (PVS)  – or programmed electrical stimulation (PES) – has been reported to be a useful tool for risk stratification, and to identify those at higher risk of sudden death. However, this recommendation is controversial. In fact, PVS-induced arrhythmias are associated with future ventricular arrhythmia risk. Induction with fewer extrastimuli is associated with higher risk. Clinical risk factors are important determinants of arrhythmia risk, and lack of induction does not necessarily portend low ventricular arrhythmia risk particularly in patients with high-risk clinical features.

Clinical presentation of Brugada syndrome in female is less severe than in men, with more asymptomatic carriers and less spontaneous type 1 ECG. The prognosis is more favourable, with an event rate of 0.7% year. However, women with sudden cardiac death (SCD) or previous sinus node dysfunction are at higher risk of arrhythmic events.

Specialized inherited arrhythmia clinics were founded to optimize management and prevention of SCD in the population. In general, longitudinal care in a specialized inherited arrhythmia clinic is associated with a low incidence of SCD and a low rate of primary implantable cardioverter-defibrillator utilization in patients with inherited arrhythmia syndromes.

Molecular diagnosis

Heredity of Brugada syndrome is autosomal dominant. Pathogenic mutations have been thus far identified in the following genes: CACNA1C, CACNB2, GPD1L, HCN4, KCNE3, SCN1B, SCN3B, and SCN5A. Despite earlier reports, mutations in the SCN10A gene have been excluded to have a primary role in the etiopathogenesis of arrhythmic phenotypes. The CC genotype of the common single-nucleotide polymorphism rs9388451, localised downstream from the HEY2 gene, has been found to possibly be a favorable prognostic marker for Brugada syndrome,  acting protectively to prevent ventricular fibrillation, presumably by regulating the repolarization current.

The clinical interpretation of variants identified in these genes can be particularly difficult, also because of the frequent occurrence of private mutations (mutations found in one family). Among laboratories experienced in genetic testing for cardiac arrhythmias, there can be frequently low concordance in designating variant significance. In unselected population, it may happen that putative pathogenic genetic variants are not associated with an abnormal phenotype. Therefore, these findings raise questions about the implications of notifying incidental genetic findings to patients, especially when these undergo the “whole approach” testing (whole exome sequencing, whole genome sequencing).

Recommended panel testing at Breda genetics for this condition:

Brugada syndrome (CACNA1C, CACNB2, GPD1L, HCN4, KCNE3, SCN1B,SCN3B, SCN5A)

References:

Inherited ion channel diseases: a brief review. Lieve KV, Wilde AA. Europace. 2015 Oct;17 Suppl 2:ii1-6. PMID: 26842110

Spatiotemporal Characteristics of QRS Complexes Enable the Diagnosis of Brugada Syndrome Regardless of the Appearance of a Type 1 ECG. Guillem MS, Climent AM, Millet J, Berne P, Ramos R, Brugada J, Brugada R. J Cardiovasc Electrophysiol. 2016 May;27(5):563-70. PMID: 26799774

Programmed Ventricular Stimulation for Risk Stratification in the Brugada Syndrome: A Pooled Analysis. Sroubek J, Probst V, Mazzanti A, Delise P, Hevia JC, Ohkubo K, Zorzi A, Champagne J, Kostopoulou A, Yin X, Napolitano C, Milan DJ, Wilde A, Sacher F, Borggrefe M, Ellinor PT, Theodorakis G, Nault I, Corrado D, Watanabe I, Antzelevitch C, Allocca G, Priori SG, Lubitz SA. Circulation. 2016 Feb 16;133(7):622-30. PMID: 26797467

Even a Pooled Analysis Does Not Resolve the Debate of Electrophysiology Testing in Brugada Syndrome. Daoud EG. Circulation. 2016 Feb 16;133(7):619-21. PMID: 26797466

Diagnosis of Brugada’s syndrome after subarachnoid injection of prilocaine. Oliván B, Arbeláez A, de Miguel M, Pelavski A. Rev Esp Anestesiol Reanim. 2016 Oct;63(8):483-6. PMID: 26778671

Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. Van Driest SL, Wells QS, Stallings S, Bush WS, Gordon A, Nickerson DA, Kim JH, Crosslin DR, Jarvik GP, Carrell DS, Ralston JD, Larson EB, Bielinski SJ, Olson JE, Ye Z, Kullo IJ, Abul-Husn NS, Scott SA, Bottinger E, Almoguera B, Connolly J, Chiavacci R, Hakonarson H, Rasmussen-Torvik LJ, Pan V, Persell SD, Smith M, Chisholm RL, Kitchner TE, He MM, Brilliant MH, Wallace JR, Doheny KF, Shoemaker MB, Li R, Manolio TA, Callis TE, Macaya D, Williams MS, Carey D, Kapplinger JD, Ackerman MJ, Ritchie MD, Denny JC, Roden DM. JAMA. 2016 Jan 5;315(1):47-57. PMID: 26746457

Patient Outcomes From a Specialized Inherited Arrhythmia Clinic. Adler A, Sadek MM, Chan AY, Dell E, Rutberg J, Davis D, Green MS, Spears DA, Gollob MH. Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003440.  PMID: 26743238

Absence of a Primary Role for SCN10A Mutations in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. Te Riele AS, James CA, Murray B, Tichnell C, Amat-Alarcon N, Burks K, Tandri H, Calkins H, Polydefkis M, Judge DP. J Cardiovasc Transl Res. 2016 Feb;9(1):87-9. PMID: 26733327

Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current. Nakano Y, Ochi H, Onohara Y, Toshishige M, Tokuyama T, Matsumura H, Kawazoe H, Tomomori S, Sairaku A, Watanabe Y, Ikenaga H, Motoda C, Suenari K, Hayashida Y, Miki D, Oda N, Kishimoto S, Oda N, Yoshida Y, Tashiro S, Chayama K, Kihara Y. Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003436. PMID: 26729854

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