Brugada syndrome (BrS) is a cardiac arrhythmia syndrome characterized by specific electrocardiographic findings and an increased risk of sudden cardiac death. BrS is believed to
account for approximately 4% of all sudden cardiac deaths and 20% of unexplained deaths among individuals with structurally normal hearts. Men are eight to ten times more likely than women to express the clinical features of BrS, although both sexes can be affected. BrS is characterized by a coved-type ST-segment elevation in the right precordial leads (V1 through V3) on an electrocardiogram (ECG). This finding, known as a type 1 ECG pattern, may occur spontaneously or may be unmasked by administration of a sodium channel blocker. BrS patients may also exhibit other ECG anomalies, including right bundle branch block, polymorphic ventricular tachycardia (VT), ventricular fibrillation (VF), and atrioventricular (AV) block. The clinical manifestations of BrS, which typically manifest in the third to fourth decade of life but may appear as early as infancy, include syncope (fainting), palpitations, shortness of breath, and cardiac arrest. However, sudden cardiac death, which often occurs during sleep or at rest, is the first sign of BrS in some patients. A
clinical diagnosis of BrS is established in patients with a type 1 ECG pattern in the presence or absence of a sodium channel blocker, along with at least one of the following: VF, polymorphic VT, a family history of sudden cardiac death (at < 45 years of age), a family history of coved-type ECGs, electrophysiological inducibility of VT, syncope, or nocturnal agonal respiration (irregular gasping breaths during sleep). BrS is a genetically heterogeneous condition caused by sequence variants in one of several different genes. All are inherited in an autosomal dominant manner and exhibit incomplete penetrance and variable expressivity. The most common cause of BrS appears to be loss-of-function variants in the gene encoding the alpha subunit of the cardiac sodium channel, SCN5A, which may be found in approximately 20% to 30% of clinically diagnosed BrS patients. Interestingly, gain-of-function variants in the same gene lead to a different cardiac arrhythmia condition, long QT syndrome (LQTS) type 3. Moreover, it has been found that specific SCN5A gene variants may lead to different phenotypes (BrS, LQTS, or isolated cardiac conduction disease) depending on the person carrying the alteration. Other genes linked to BrS include those encoding the glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), the alpha and beta subunits of the L-type calcium channel (CACNA1C and CACNB2), the beta subunits of the type 1 and 3 sodium channels (SCN1B and SCN3B), and the potassium channel beta subunit (KCNE3). However, the proportion of BrS patients carrying sequence variants in these genes appears to be relatively small.