Brugada Syndrome (BrS) is an arrhythmogenic disease characterized by ST-segment elevation on ECG, incomplete right bundle-branch block, and increased risk of sudden cardiac death as the result of ventricular fibrillation. BrS is responsible for 4% of all sudden deaths and 20% of sudden deaths among patients with structurally normal hearts.
| Clinical Features | Syncope and cardiac arrest are the most common clinical manifestations of BrS. Some patients with BrS have supraventricular arrhythmias. Most individuals with BrS are asymptomatic. The median age of diagnosis is 45 ± 10 years with a striking 8:1 male-to-female ratio in symptomatic individuals.Cardiac events occur during sleep or at rest. Fever, tricyclic antidepressant use, and cocaine have been identified as specific triggers for events in some patients.
The diagnosis is complicated by the intermittent nature of the electrocardiogram (ECG) pattern. Concealed forms may be unmasked only after performing provocative drug testing with class IC drugs: ajmaline (1mg/kg), flecainide (2mg/kg), or procainamide (15mg/kg) The Brugada ECG pattern, a hallmark of BrS, displays a coved type ST-segment elevation ≥2mm followed by a negative T wave in at least one of the right precordial leads (V1-V3). This pattern, the Type 1 ECG, is observed in the presence or absence of a sodium channel-blocking agent. BrS is diagnosed when a Type I ECG is seen in conjunction with one of the following: Patients with BrS have an increased risk of SCD secondary to VT/VF |
| Incidence | This syndrome is probably underestimated due to the fact that the characteristic ECG-pattern is dynamic and is often concealed. 1:2000 to 1:100,000 Highly prevalent among East Asians |
| Genetics | To date, 17 genes are associated with BrS or BrS ECG phenotype, SCN5A being the major contributor to BrS. |
| Inheritance | Autosomal dominant |
| Disease Pathogenesis | It has been hypothesized that a current-to-load mismatch caused by structural and functional abnormality may explain the ST-segment elevation and susceptibility to arrhythmia. |
| Clinical Utility | Risk stratification- Some asymptomatic BrS patients have an appreciable risk of arrhythmia Genotype-phenotype correlation- A distinct correlation has been observed in individuals with SCN5A mutations Screening family members |
| Indications for Molecular Testing | Genetic testing should be conducted only in patients displaying Type 1 ECG pattern. This may include a cardiac arrest survivor, patients with syncope or asymptomatic individuals.
Mutation-specific genetic testing is recommended for first degree relatives following the identification of the BrS causative mutation in an index case. Spontaneous mutations rarely occur in BrS. Genetic testing is not recommended for those with apparent Type2 or Type 3 ECG pattern. |
| Test Information | Sequence analysis of SCN5A gene. More than 300 mutations in SCN5A are associated with BrS.
Gene exons and intron/exon boundaries are analyzed subsequent to Sanger sequencing. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations. Exonic or whole-gene deletions/duplications will not be detected. Additionally, a negative result does not rule out causal gene mutations as the promoter region and cryptic splicing mutations are not investigated. |
| Clinical Sensitivity | 25% |
| Turnaround Time | 2-4 weeks |
| CPT Codes | Tier 1: 81407 |
Sample and Shipping Information
| Specimen | Whole blood drawn in lavender top (EDTA) tube in a volume of 3-5cc (Adults/Children) and 3 cc (infant) |
| Shipping | Refrigerate sample until time of shipping. Ship sample at room temperature in an insulated container by overnight delivery. |
| Causes for Rejection | Frozen specimen; hemolysis; quantity not sufficient for analysis; improper container. |
References
Nielsen MW, Holst AG, Olesen SP, Olesen MS. The genetic component of Brugada syndrome. Front Physiol. 2013 Jul 15;4:179.
Bayés de Luna A, Brugada J, Baranchuk A, Borggrefe M, Breithardt G, Goldwasser D, Lambiase P, Riera AP, Garcia-Niebla J, Pastore C, Oreto G, McKenna W, Zareba W, Brugada R, Brugada P. Current electrocardiographic criteria for diagnosis of Brugada pattern: a consensus report. J Electrocardiol. 2012 Sep;45(5):433-42.
Gollob MH, Blier L, Brugada R, Champagne J, Chauhan V, Connors S, Gardner M, Green MS, Gow R, Hamilton R, Harris L, Healey JS, Hodgkinson K, Honeywell C, Kantoch M, Kirsh J, Krahn A, Mullen M, Parkash R, Redfearn D, Rutberg J, Sanatani S, Woo A.
Recommendations for the use of genetic testing in the clinical evaluation of inherited cardiac arrhythmias associated with sudden cardiac death: Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position paper. Can J Cardiol. 2011 Mar-Apr;27(2):232-45.
Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP; Heart Rhythm Society (HRS); European Heart Rhythm Association (EHRA). HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Europace. 2011 Aug;13(8):1077-109.
Kapplinger JD, Tester DJ, Alders M, Benito B, Berthet M, Brugada J, Brugada P, Fressart V, Guerchicoff A, Harris-Kerr C, Kamakura S, Kyndt F, Koopmann TT, Miyamoto Y, Pfeiffer R, Pollevick GD, Probst V, Zumhagen S, Vatta M, Towbin JA, Shimizu W, Schulze-Bahr E, Antzelevitch C, Salisbury BA, Guicheney P, Wilde AA, Brugada R, Schott JJ, Ackerman MJ. An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing. Heart Rhythm. 2010 Jan;7(1):33-46
Probst V, Wilde AA, Barc J, Sacher F, Babuty D, Mabo P, Mansourati J, Le Scouarnec S, Kyndt F, Le Caignec C, Guicheney P, Gouas L, Albuisson J, Meregalli PG, Le Marec H, Tan HL, Schott JJ. SCN5A mutations and the role of genetic background in the pathophysiology of Brugada syndrome. Circ Cardiovasc Genet. 2009 Dec;2(6):552-7
Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation. 2005 Feb 8;111(5):659-70.
Resources
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