Brugada Syndrome

Actionability Adult Summary Report

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: SCN5A (HGNC:10593)
• Mode(s) of Inheritance: Autosomal Dominant
• Literature Search: 04/10/2015
• Curation Status: Released - Under Revision (1.2.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
SCN5A	N/A ()	601144	Assertion Pending

Actionability Assertion Rationale

• This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Sudden cardiac death / ICD implantation	3	2C	2B	2	9CB

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of Brugada syndrome is difficult to estimate due to the recent identification of the disorder and the difficulty in diagnosis. Available prevalence estimates vary around the world, from 1/700-1/800 in certain endemic areas of Asia to 1/3,300-1/10,000 in Europe and the United States.

Clinical Features (Signs / symptoms)

Brugada syndrome is characterized by a distinctive ECG pattern of sinus tachycardia (ST) segment elevation in the V1-V3 leads (termed "type 1 abnormality") in the absence of gross structural abnormalities. Patients have a high risk for ventricular arrhythmias, which can result in syncope or sudden cardiac death. Clinical presentations may also include sudden infant death syndrome (SIDS) and the sudden unexpected nocturnal death syndrome (SUNDS). Other conduction defects can include first-degree AV block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Electrical storms, multiple episodes of ventricular arrhythmias over a short period of time, are malignant but rare in patients.

Natural History (Important subgroups & survival / recovery)

Brugada syndrome presents primarily during adulthood, with syncope as the most common presenting feature. Age at diagnosis ranges from 2 days to 85 years. The mean age of sudden death is approximately 40 years. Both sexes are at a high risk for ventricular arrhythmias and sudden death, though the vast majority of those affected are male. Patients who have easily induced sustained ventricular arrhythmias, a spontaneous type 1 ECG pattern (compared to pharmacologically-induced), and a history of syncope have a worse prognosis.

Likelihood of Outcome

Mode of Inheritance

Autosomal Dominant

Prevalence of Genetic Variants

Unknown

Pathogenic mutations in SCN5A account for 15-30% of Brugada syndrome cases.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

5-39 %

Among individuals with a pathogenic variant in SCN5A, approximately 20-30% have a type 1 ECG pattern and approximately 80% manifest the characteristic ECG change when challenged with a sodium channel blocker.

Tier 3

5-39 %

The majority of patients remain asymptomatic, while 20-30% experience syncope and 8-12% experience at least one cardiac arrest (potentially leading to sudden death).

Tier 4

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

Information on relative risk was not available.

Expressivity

Information on variable expressivity was not available.

Intervention Effectiveness

Patient Management

An implantable cardioverter defibrillator (ICD) is reasonable for patients with Brugada syndrome, though some guidelines only recommend ICD implantation for those with certain risk factors such as a history of syncope and/or documented ventricular tachycardia that has not resulted in cardiac arrest. ICD should also be considered in patients with a spontaneous type 1 ECG pattern. In the absence of a spontaneous type 1 ECG pattern, an implantable loop recorder (ILR) should be considered. A cohort study of 220 patients with Brugada and a history of syncope reported an appropriate ICD shock rate of 10% over 3 years.

Tier 2

Two additional cohort studies reported appropriate shock rates of 19%, 16%, and 12% for patients with a history of syncope, patients with a type 1 ECG pattern, and asymptomatic patients, respectively.

Tier 5

Treatment of asymptomatic individuals is controversial and recommendations vary, but include observation until the first symptom develops and placement of an ICD in individuals with a family history of sudden cardiac death or when electrophysiological study indicates a likelihood of arrhythmias.

Tier 3

Quinidine is recommended to prevent primary symptoms, and has been shown to restore ST-segment elevation and decrease the incidence of arrhythmias. In one study, of 19 patients treated for 6 to 219 months and followed 0.5 to 22 years, none had an arrhythmic event. In another study, syncope occurred in 2 of 21 patients treated an average of 17 months.

Tier 3

Women experiencing arrhythmic events due to hormone changes during pregnancy can be treated with quinidine to normalize the ECG pattern. In a case study of a young pregnant woman, oral quinidine inhibited the recurrence of ventricular tachyarrhythmia.

Tier 3

Because perioperative pharmacological and physiological changes may precipitate malignant arrhythmias, specific management is required for patients under anesthesia.

Tier 3

Surveillance

To establish extent of disease and individual needs after initial diagnosis, patients are recommended to undergo an ECG, induction with sodium channel blockers among those with a type 2 or type 3 pattern on ECG, electrophysiological study, and medical genetics consultation.

Tier 4

At-risk patients with a family history or a known pathogenic variant should undergo ECG monitoring every one to two years.

Tier 3

Circumstances to Avoid

Patients should avoid certain antiarrhythmic, psychotropic, and anesthetic drugs that can induce cardiac arrhythmias. Other agents to avoid include acetylcholine, alcohol toxicity, cocaine, and ergonovine.

Tier 2

Patients should also avoid or quickly mitigate high fever and electrolyte disturbances.

Tier 3

Nature of Intervention

Nature of Intervention

Identified interventions include the implantation of an ICD, which would involve invasive surgery.

Context: Adult

Chance to Escape Clinical Detection

Brugada syndrome is typically diagnosed with ECG, a screening procedure not typically recommended for asymptomatic adults with apparently low risk of coronary heart disease. It is very likely this disorder could go unrecognized and present in a patient as ventricular arrhythmia and cardiac arrest, resulting in sudden death in 8-12% of affected individuals.

Context: Adult

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			SCN5A			601144

References List

Brugada syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=130

Carey SM, Hocking G. (2011) Brugada syndrome--a review of the implications for the anaesthetist. Anaesthesia and intensive care. 39(4):571-7.

Conte G, Sieira J, Ciconte G, de Asmundis C, Chierchia GB, Baltogiannis G, Di Giovanni G, La Meir M, Wellens F, Czapla J, Wauters K, Levinstein M, Saitoh Y, Irfan G, Julia J, Pappaert G, Brugada P. (2015) Implantable cardioverter-defibrillator therapy in Brugada syndrome: a 20-year single-center experience. Journal of the American College of Cardiology. 65(9):879-88.

Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO, Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NA 3rd, Ferguson TB Jr, Hammill SC, Karasik PE, Link MS, Marine JE, Schoenfeld MH, Shanker AJ, Silka MJ, Stevenson LW, Stevenson WG, Varosy PD. (2013) 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology. 61(3):e6-75.

Implantable cardioverter defibrillators and cardiac resynchronisation therapy for arrhythmias and heart failure. NICE (2014) URL: https://www.nice.org.uk/guidance/ta314

Moya A, Sutton R, Ammirati F, Blanc JJ, Brignole M, Dahm JB, Deharo JC, Gajek J, Gjesdal K, Krahn A, Massin M, Pepi M, Pezawas T, Ruiz Granell R, Sarasin F, Ungar A, van Dijk JG, Walma EP, Wieling W. (2009) Guidelines for the diagnosis and management of syncope (version 2009). European heart journal. 30(21):2631-71.

Postema PG, Wolpert C, Amin AS, Probst V, Borggrefe M, Roden DM, Priori SG, Tan HL, Hiraoka M, Brugada J, Wilde AA. (2009) Drugs and Brugada syndrome patients: review of the literature, recommendations, and an up-to-date website (www.brugadadrugs.org). Heart rhythm : the official journal of the Heart Rhythm Society. 6(9):1335-41.

R Brugada, O Campuzano, P Brugada, J Brugada, K Hong. Brugada Syndrome. (2005) [Updated Apr 10 2014]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1517/

Sacher F, Probst V, Maury P, Babuty D, Mansourati J, Komatsu Y, Marquie C, Rosa A, Diallo A, Cassagneau R, Loizeau C, Martins R, Field ME, Derval N, Miyazaki S, Denis A, Nogami A, Ritter P, Gourraud JB, Ploux S, Rollin A, Zemmoura A, Lamaison D, Bordachar P, Pierre B, Jais P, Pasquie JL, Hocini M, Legal F, Defaye P, Boveda S, Iesaka Y, Mabo P, Haissaguerre M. (2013) Outcome after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: a multicenter study-part 2. Circulation. 128(16):1739-47.