Brugada Syndrome

Genetics

BrS is a hereditary disease with an autosomal dominant pattern of transmission. To date, nearly 300 pathogenic variants in 19 genes have been published ( Table 95.2 ). The first gene associated with BrS was SCN5A, which encodes the α-subunit of the cardiac sodium channel. The SCN5A gene is related to the sodium current responsible for phase 0 of the cardiac action potential. Mutations in SCN5A result in loss of function of the sodium channel. A mutation in the SCN5A gene, classified as BrS type I, is found in 35% to 45% of individuals with BrS. An individual diagnosed with BrS and concomitant conduction system disease had a large-scale deletion of the SCN5A gene. This copy number variation (CNV) is the only rearrangement identified as a cause of the disease to date. A recent study described a comprehensive genetic evaluation of main BrS susceptibility genes and CNV in a Spanish BrS cohort. Selga et al. report that the mean pathogenic variation discovery yield is higher than that described for other European BrS cohorts (32.7% vs. 20%–25%, respectively) and is even higher for patients in the age range of 30 to 50 years.

Other genes probably related to BrS include the sodium channel β-1 subunit ( SCN1B ), sodium channel β-2 subunit ( SCN2B ), and sodium channel β-3 subunit ( SCN3B ), which modify the function of the channel (increasing or decreasing I _Na ). Also, the SCN10A gene (neuronal sodium channel Na _V 1.8) has been shown to modulate SCN5A expression and the electrical function of the heart. Another gene reported as responsible for BrS was GPD1-L. Mutations in GPD1-L reduce both the surface membrane expression and inward sodium current. Kattygnarath et al. published a study supporting that RANGRF can impair the trafficking of Na _V 1.5 to the membrane, leading to I _Na reduction and clinical manifestation of BrS. In 2012 Ishikawa et al. reported pathogenic variations in the sarcolemmal membrane–associated protein ( SLMAP ) gene, a gene of unknown function that is found at T-tubules and the sarcoplasmic reticulum. SLMAP causes BrS by modulating the intracellular trafficking of the Na _V 1.5 channel. Pathogenic variations in the plakophilin-2 ( PKP2 ) gene were reported to be associated with BrS. ^, PKP2 is the primary gene responsible for arrhythmogenic RV cardiomyopathy (ARVC), a desmosomal disease characterized by fibrofatty replacement of myocardium, leading to SCD in young men, mainly during exercise. Correlation between the loss of expression of PKP2 and reduced I _Na has been identified in BrS patients. Apart from sodium channels, several potassium channels have also been related to BrS. The first one described was KCNE3, which codifies the MiRP2 protein (the β-subunit that regulates the potassium channel I _to ) and modulates some potassium currents in the heart. Another gene associated with BrS is KCNJ8, also previously related to early repolarization syndrome (ERS). KCNJ8 was described as a novel J wave syndrome susceptibility gene and a marker gain-of-function in the cardiac K _(ATP) K _ir 6.1 channel. In 2011 Giudicessi et al. provided the first molecular and functional evidence implicating novel KCND3 gain-of-function mutations (K _ir 4.3 protein) in the pathogenesis and phenotypic expression of BrS, with enhanced I _to current gradient within the RV where KCND3 gene expression is the highest. Furthermore, in 2011, novel variants in KCNE5 appeared to cause gain-of-function effects on I _to . The KCNE5 gene is located in the X chromosome and encodes an auxiliary β-subunit for K channels. Similar is the role of sulfonylurea receptor subunit 2A (SUR2A), encoded by the ATP-binding cassette, subfamily C member 9 ( ABCC9 ) gene. Gain-of-function pathogenic variants in ABCC9 induce changes in adenosine triphosphate (ATP)-sensitive potassium (K-ATP) channels, and, when coupled with loss-of-function pathogenic variants in SCN5A, these pathogenic variants may underlie the severe arrhythmic phenotype of BrS. BrS was also associated with HCN4, which codes for the HCN4 channel or If channel (hyperpolarization-activated cyclic nucleotide-gated potassium channel 4). Its mutations also predispose to inherited sick sinus syndrome (SSS) and long QT syndrome associated with bradycardia. Calcium channel abnormalities have also been associated with BrS. Mutations in the CACNA1C gene are responsible for a defective unit of the L-type calcium channel. Mutation of the CACNB2B gene leads to a defect in the L-type calcium channel. Both induce a loss of channel function. In 2010 the CACNA2D1 gene was reported to be responsible for BrS. The α ₂ /δ-subunit of voltage-dependent calcium channels regulates current density and the activation/inactivation kinetics of the calcium channel. Finally, pathogenic variations have also been reported in the transient receptor potential melastatin protein number 4 ( TRPM4 ) gene, a calcium-activated nonselective cation channel that is a member of a large family of transient receptor potential genes. This gene is involved in conduction blocks, and the consequences of pathogenic variations are diverse. Thus reduction or increase in TRPM4 channel function may reduce the availability of the sodium channel and lead to BrS.

Genetic and Environmental Modulators

Several genetic and environmental modulators of the phenotype have been described. It is well known that environment may play a role in the predisposition to arrhythmias in patients with BrS. The identification of several triggering factors of the Brugada ECG pattern and of SCD, such as fever, cocaine, electrolyte disturbances, class I antiarrhythmic drugs (AADs), and a number of other noncardiac medications, has prompted the need to adopt preventive measures in patients with the diagnostic ECG pattern. In addition, the incomplete penetrance of the disease, as well as the variable expressivity, has brought into question the role of additional genetic factors in the final phenotype. Single nucleotide polymorphisms (SNPs) became one of the first players to be studied in defining this variability. The SCN5A polymorphism p.H558R is present in 20% of the population. This polymorphism has been shown to partially restore the sodium current impaired by mutations in SCN5A. Thus this common variant is a genetic modulator of BrS among carriers of an SCN5A mutation, in whom the presence of the less common allele makes BrS less severe. Genetic variants in the SCN5A promoter region may also play a pathophysiologic role in BrS. A haplotype of six polymorphisms in the SCN5A promoter has been identified and functionally linked to a reduced expression of the sodium current in the Japanese population. Other studies have shown the role of double mutants in causing a more severe phenotype. ^, The role of genetic mutation in risk stratification remains to be clearly defined. Recent data proposed the type of genetic mutation as a tool for risk stratification in BrS. In this study, patients and relatives with a truncated protein had a more severe phenotype and more severe conduction disorders. This is the proof of concept that some of the mutations appear to confer a worse prognosis, but the use of these data in the clinical setting is not yet sufficient to make clinical decisions.

Early Repolarization Syndrome

ERS is a common ECG variant characterized by J-point elevation, ST segment elevation with upper concavity, and prominent T waves in at least two contiguous leads. ERS and BrS share cellular, ionic, and ECG similarities (appearance of J waves), representing parts of a phenotypic spectrum called J wave syndromes, although the degree to which ERS and BrS may overlap remains undetermined. In the last 5 years, reports have been published on patients with BrS and ERS. ERS has been linked to mutations in CACNA1C, CACNB2, CACNA2D1, and KCNJ8.

Lev-Lenègre Syndrome

Lev-Lenègre syndrome (also called progressive cardiac conduction disease [PCCD]) is a rare entity characterized by disruption of the cardiac conduction system with syncope and even SCD. The presence of PCCD in BrS families is not uncommon because they both result from a reduction in the sodium current, and it has been described as a different expression of the same genetic phenotype. The first mutations associated with PCCD were described in the gene SCN5A ^, and in its β1-subunit.

Sick Sinus Syndrome

SSS is characterized by persistent inappropriate sinus bradycardia, sinus arrest, atrial standstill, and tachycardia-bradycardia syndrome, all of which are associated with dysfunction of the sinoatrial node (SAN). Patients may exhibit varied symptoms, including syncope and even SCD. The course of SSS can be intermittent and unpredictable and is related to the severity of the underlying heart disease. So far, both autosomal recessive and dominant forms have been described. In 2003 the association between SCN5A mutations and congenital SSS was reported. In 2005 a novel SCN5A mutation was identified in patients presenting with both SSS and BrS, showing that in the same family, both diseases may be related to the expression of a loss-of-function mutation in I _Na . SSS has a very negative impact in the prognosis of patients with BrS, particularly children.

Atrial Fibrillation

Atrial fibrillation (AF) is the most common atrial arrhythmia found in BrS. It is of extreme clinical importance to realize that AF can be the first manifestation of BrS. AF also has a very negative effect on the prognosis of BrS and is associated with a high incidence of embolic events. Administration of some AADs in these cases can lead to VF and sudden death. BrS should be excluded by drug challenge in young individuals with atrial flutter or AF and a normal heart and normal ECG. Approximately 15% to 20% of patients with BrS develop supraventricular arrhythmias. Some studies have reported prolongation of His atrial and His ventricular (HV) interval; these changes occur principally in patients with SCN5A mutations and are consistent with a decreased excitability in the conduction system secondary to the loss of function of sodium channel activity.