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: 10/10/2019
• Curation Status: Released (2.0.3)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
SCN5A	Brugada syndrome 1 (0011001)	601144	Strong Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Sudden cardiac death / Avoidance of drugs with sodium channel blocking properties and high fever	3	2C	2B	3	10CB

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 electrocardiographic (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 (VA), which can result in syncope or sudden cardiac death (SCD). 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 atrioventricular (AV) block, intraventricular conduction delay, right bundle branch block, and sick sinus syndrome. Electrical storms, multiple episodes of VA over a short period of time, are malignant but rare in patients. Symptoms include nocturnal agonal respiration, palpitations and chest discomfort, which often occur during rest, sleep, during a febrile state, or with vagotonic conditions, but rarely during exercise.

Natural History (Important subgroups & survival / recovery)

Brugada syndrome presents primarily during adulthood, with syncope as the most common presenting feature. Age at diagnosis may range from infancy to late adulthood. The mean age of SCD is approximately 40 years. Both sexes are at a high risk for VA and SCD, though the vast majority of those affected are male. Patients who have easily induced sustained VA, 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

The population prevalence of pathogenic variants associated with Brugada syndrome was not available. However, it is estimated that 15-30% of Brugada syndrome cases can be attributed to pathogenic variants in SCN5A. (Tier 3)

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

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

An implantable cardioverter defibrillator (ICD) is reasonable for patients with Brugada syndrome with certain risk factors such as a history of arrhythmic syncope and/or spontaneous type 1 ECG pattern, and/or documented ventricular tachycardia (VT) and/or are survivors of aborted cardiac arrest. One guideline recommends considering ICD implantation in those with Brugada syndrome who develop ventricular fibrillation (VF) during programmed ventricular stimulation (PVS) with two or three extrastimuli at two sites.

Tier 1

ICD implantation has been shown to reduce mortality in symptomatic patients with Brugada syndrome. A systematic review reports that in patients with Brugada syndrome (who had already survived a sudden cardiac arrest event) randomized to ICD therapy, there was a nine-fold lower risk of mortality compared with people randomized to medical therapy (0% with ICD versus 18% with medical therapy; RR 0.11, 95% CI 0.01 to 0.83; 2 trials, 86 participants). A meta-analysis of 1539 patients with Brugada syndrome reported that during a mean follow-up of 4.9 years, 229 patients (18%) experienced appropriate ICD intervention. The appropriate ICD intervention rate was 3.1 per 100 person years.

Tier 1

The following studies have been performed in clinically affected individuals. There is conflicting evidence regarding risk stratification based on electrophysiological study (EPS). A multicenter prospective study investigated risk stratification in individuals (N = 320) with type 1 ECG pattern for primary prevention of SCD and no previous cardiac arrest or documented VT/VF. EPS with PVS was performed in 245 patients and ICD placement occurred in 110. During follow-up (median = 40 months) major arrhythmic events occurred in 14% of patients with positive EPS, 0% patients with negative EPS, and 5.3% patients without EPS.

Tier 1

However, another study evaluated a Brugada syndrome registry of 1029 consecutive patients with type 1 ECG pattern at baseline or after drug challenge. Cardiac event rate per year was 7.7% in patients with aborted SCD, 1.9% in patients with syncope, and 0.5% in asymptomatic patients (median follow-up = 31.9 months), suggesting symptoms and spontaneous type 1 ECG were predictive of arrhythmatic events. Though not specifically noted in the recommendation for ICD placement, studies have assessed additional risk factors such as QRS fragmentation and SCN5A pathogenic variant status. A prospective study (N = 308) assessed predictors of arrhythmic events in patients with Brugada syndrome without history of VT/VF during a median follow-up of 34 months and found that arrhythmia inducibility was not a predictor while history of syncope, spontaneous type 1 ECG, ventricular refractory period <200 ms, and QRS fragmentation were significant predictors. In a large case series of patients with Brugada syndrome who experienced an arrhythmic event, SCN5A pathogenic variants were found in 30% of the cohort. Higher SCN5A pathogenic variant rates were observed in females in all age groups.

Tier 5

A meta-analysis of 1780 patients with Brugada syndrome found that the presence of SCN5A pathogenic variants was associated with elevated risk of major arrhythmic events in both Asian (OR = 1.82, 95% CI 1.07-3.11; P=0.03) and white (OR 2.24, 95% CI 1.02-4.90; P=0.04) populations.

Tier 1

Observation without therapy is recommended in asymptomatic patients with only inducible type 1 ECG pattern. Implantation of an ICD in an asymptomatic patient without a spontaneous type 1 ECG pattern has not been shown to confer any benefit.

Tier 1

Women experiencing arrhythmic events due to hormone changes during pregnancy can be treated with quinidine to normalize the ECG pattern.

Tier 3

Because perioperative pharmacological and physiological changes may precipitate syncope or sudden death, specific management is required for patients under anesthesia.

Tier 3

Surveillance

Individuals with a known pathogenic variant in should undergo ECG monitoring every one to two years beginning at birth.

Tier 3

Circumstances to Avoid

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

Tier 2

One retrospective study evaluated 74 adult cases of drug-induced type 1 Brugada pattern on ECG from noncardiac drugs (including psychotropic and anesthetic drugs); 77% were males, drug toxicity was involved in 46%, and mortality was 13%. These 74 patients more frequently had abnormal ECG in the absence of drugs than the ECG of controls (56% vs 33%, p=0.04). Fever was present in 10 cases (13.5%); 3 of these 10 febrile patients developed VF

Tier 2

Patients should also avoid or quickly mitigate high fever with antipyretic drugs.

Tier 2

One retrospective multicenter study evaluated fever related arrhythmic events in patients with Brugada syndrome (defined as a typical type 1 ECG either spontaneously or after IV administration of a sodium channel blocking drug). In 35 of 588 patients (6%) the arrhythmic event occurred during a febrile illness; 80% were male, 80% presented with aborted cardiac arrest and 17% with arrhythmic storm. An SCN5A pathogenic variant was found in 12 of 28 (43%) who underwent genetic testing. The highest proportion of fever-related arrhythmic events were observed in the pediatric population (age <16 years), with a disproportionately higher event rate in the very young (age 0-5 years; 65%).

Tier 5

Nature of Intervention

Nature of Intervention

Identified interventions include the implantation of an ICD, which would involve invasive surgery and device management, potentially starting at a young age; those who are young will require multiple device replacements during their lifetime. In the pediatric patients, ICD implantation is more challenging and complications are more frequent due to the increased heart rates and activity of the population. Inappropriate ICD shocks and device complications can be minimized by optimal device programming and appropriate lead selection. A meta-analysis of 1037 Brugada syndrome patients from 17 studies reported that 21 (3.9% rate per year [95% CI 3.0-4.8]) experienced inappropriate shocks, and 21 (3.4% rate per year [95% CI 2.5-4.3]) experienced complications. In addition, the use of ICD therapy carries a risk for psychological consequences due to the fear of being shocked, particularly among patients who have experienced a shock.

Context: Adult Pediatric

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, which may result in sudden death.

Context: Adult Pediatric

Tier 3

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			SCN5A			601144	0011001	0015263

References List

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