Clinical Guidance

Few studies have investigated genotype-phenotype correlations .

SCN5A

• In general, the SCN5A pathogenic variants which cause LQT3 (see Long QT Syndrome) are associated with a gain of function rather than the loss of function associated with Brugada syndrome and progressive conduction system disease; however, pathogenic variants that are associated with both diseases in the same family have been described.

• By restoring (at least partially) sodium current defects, the common SCN5A variant appears to modulate the phenotypic effects of heterozygous SCN5A pathogenic variants such as , which results in clinically significant cardiac conduction disturbances , and , which results in Brugada syndrome .

Source: GeneReviews — "Brugada Syndrome"

Penetrance

SCN5A. Among individuals with an SCN5A pathogenic variant approximately 20%-30% have an EKG diagnostic of Brugada syndrome; and approximately 80% manifest the characteristic EKG changes when challenged with a sodium channel blocker (e.g., ajmaline) .

Source: GeneReviews — "Brugada Syndrome"

Diagnostic Criteria

Brugada syndrome is a channelopathy, caused by genetic changes in transmembrane ion channels that create action potentials, in this case leading to an increased risk of cardiac arrhythmia .

Suggestive Findings

Brugada syndrome should be suspected in individuals with any of the following findings:

• Recurrent syncope

• Ventricular fibrillation

• Self-terminating polymorphic ventricular tachycardia

• Cardiac arrest

• Family history of sudden cardiac death

AND one of the following EKG patterns:

• Type 1 EKG (elevation of the J wave ≥2 mm with a negative T wave and ST segment that is coved type and gradually descending) in more than one right precordial lead (V1-V3)* with or without administration of a sodium channel blocker (e.g., flecainide, pilsicainide, ajmaline, or procainamide)

Source: GeneReviews — "Brugada Syndrome"

Differential Diagnosis

Brugada syndrome should always be considered in the differential diagnosis of the following:

• Sudden cardiac death and syncope in persons with a structurally normal heart

• SIDS. Brugada syndrome does not usually cause problems at such a young age; however, SCN5A pathogenic variants have been described in a few infants with SIDS. SIDS is believed to be etiologically and genetically heterogeneous with an unknown proportion attributed to Brugada syndrome.

• Sick sinus syndrome. Brugada syndrome could be observed in persons with sick sinus syndrome given the defects observed in cardiac conduction .

Other conditions that can be associated with ST segment elevation in right precordial leads include the following (adapted from and with permission).

Source: GeneReviews — "Brugada Syndrome"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Brugada syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Electrocardiogram (EKG)

• Induction with sodium blockers (ajmaline, procainamide, pilsicainide, flecainide) in persons with a type 2 EKG or type 3 EKG and suspicion of the disease

• Electrophysiologic study to assess risk of sudden cardiac death. Although the data are controversial, no other risk stratification parameter is presently available for asymptomatic individuals .

• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse to inform affected individuals and their families about the nature, mode of inheritance, and implications of Brugada syndrome to facilitate medical and personal decision making

Treatment of Manifestations

Brugada syndrome is characterized by the presence of ST segment elevation in leads V1-V3. Implantable cardioverter defibrillators (ICDs) are the only therapy currently known to be effective in persons with Brugada syndrome with syncope or cardiac arrest . See for risk stratification and recommendations of ICD in individuals with Brugada syndrome. Electrical storms respond well to infusion of isoproterenol (1-3 g/min), the first line of therapy before other antiarrhythmics . It is important to:

Source: GeneReviews — "Brugada Syndrome"

Clinical Guidance

The following can unmask the Brugada syndrome EKG :

• Febrile state

• Vagotonic agents

• Alpha-adrenergic agonists

• Beta-adrenergic antagonists

• Tricyclic antidepressants

• First-generation antihistamines (dimenhydrinate)

• Cocaine toxicity

The following should be avoided :

• Class 1C antiarrhythmic drugs including flecainide and propafenone

• Class 1A agents including procainamide and disopyramide

Source: GeneReviews — "Brugada Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Brugada Syndrome"

Surveillance Guidelines

At-risk individuals with a family history of Brugada syndrome or a known pathogenic variant should undergo EKG monitoring every one to two years beginning at birth . The presence of type 1 EKG changes should be further investigated.

Source: GeneReviews — "Brugada Syndrome"