Genetic background of Brugada syndrome is more complex than what we would like it to be!

Brugada syndrome (BrS) has been named after the description of the disease made by the Brugada brothers in 1992. BrS is clinically characterized by arrhythmic events, in particular ventricular fibrillation, resulting in syncope and sudden cardiac arrest mainly in middle-aged men. The ECG shows a peculiar down-sloping elevation of the ST segment in the right pre-cordial ECG leads with inversion of T-waves. Since 1998, a genetic component to BrS has been demonstrated. Over the past years, at least 20 genes have been proposed either to cause BrS or to be BrS-susceptibility genes. For several years, SCN5A, which encodes the ‘cardiac sodium channel’ Nav1.5, was presented as a gene ‘causing’ BrS in 20% of the patients; however, this concept had to be revised due to recent findings. First, in some families where the probands were found to carry SCN5A rare variants, other family membersdiagnosed with BrS did not carry the supposedly pathogenic variant. Second, a recent genome-wide association study (GWAS) led to the concept that BrS could no longer be considered a monogenic disease and it suggested a key role for the three genes: SCN10A, SCN5A, and HEY2. Patients who accumulated more than four of the risk alleles in these genes had an odds ratio of .20 to have BrS. The two genes SCN5A and SCN10A, which encode two different voltage-gated sodium channels, were also implicated in other GWAS studies in physiological cardiac conduction, assessed as ECG parameters. These findings motivated several groups to investigate the, thus far, unknown role of the SCN10A gene product, the sodium channel Nav1.8, in cardiac electrical activity as this channel was only thought to be important in the sensory nervous system. As it sometimes happens in science, this has led to controversial results. The first unresolved question is the location of expression of Nav1.8 in cardiac tissues. Two hypotheses are currently debated. On the one hand, expression of Nav1.8 is proposed by one research group to be specific to intracardiac neurons, while on the other hand, expression in cardiac myocytes of the myocardium and of the conductionpathway was suggested byanother group. The secondpoint of disagreement is the role of genetic variants that were found in the gene SCN10A in patients with cardiac arrhythmias, in particular BrS. Upon investigation of a population of 150 BrS probands and family members, a recent study by Hu et al. came to the conclusion that SCN10A genetic variants may cause BrS in 16.7% of these probands, thus putting SCN10A as a major susceptibility gene of BrS. In the current issue of Cardiovascular Research, Dr E.R. Behr presents a multi-centre collaborative study, involving 156 SCN5A mutation negative BrS probands where 7 candidate genes, including SCN10A, were sequenced. Contrary to the previous study by Hu et al., while most of the rare genetic variants were found in SCN10A, no statistical association with these SCN10Avariants and BrS was observed. However, many of these variants showed functional alterations, such as reduction in Nav1.8-mediated sodium current when studied by patch clamping. Behr et al. did not investigate the functional consequences of the co-expression of the Nav1.8 with the Nav1.5 channel in the same cells as done by Hu et al. Their rationale not to study it is based on the evidence that these two channels are not co-expressed in cardiomyocytes. This question of co-expression still remains unsolved, but one can nevertheless note that proteomic studies performed using mouse cardiac tissue only revealed significant amounts of Nav1.5 and Nav1.4 peptides and none from Nav1.8. These observations by Behr et al. suggest that, while these rare Nav1.8 variants and their functional effects are consistent with the observed role of this channel in cardiac conduction, they are not directly involved in the pathogenesis of BrS. The authors of the present study thus concluded that ‘rare variation in SCN10, particularly in SCN5A mutation negative cases, is unlikely to cause BrS’. Behr et al. discuss the possible origins of this discrepancy and propose that their studied BrS population is more focused (enriched), and that a more stringent ‘mutation’ definition had been used. They also mention that by looking at larger control variant databases, only 2% of the SCN10A variants reported by Hu et al. should be classified as ‘rare’. Here, one should also mention the recent study by Le Scouarnec et al. from the Institut du Thorax in Nantes, where the burden of rare coding variants in 20 BrS genes was estimated. Using a ‘burden test’ for the exonic sequences of these genes from 167 BrS probands, a significant enrichment in rare variants [with a