Mutation analysis of the SCN5A gene in 147 Brugada syndrome probands

Brugada syndrome (BrS) is a cardiac channelopathy manifesting in apparently structural normal hearts and inherited as an autosomal dominant trait with incomplete penetrance and variable expression. The clinical diagnosis is based on documented ventricular arrhythmias and/or related symptoms, family history and an appearance of the type 1 STsegment ECG elevation of ?2mm in more than one of the V1-V3 precordial leads either spontaneous or induced after sodium-blocker exposure (Brugada et al. 2009). Genetic diagnosis is currently still based on the mutation analysis of the pore-forming alpha-subunit of the sodium channel gene (SCN5A), resulting in a genetic diagnostic yield of approximately 30%.
We performed SCN5A mutation analysis of all 28 exons and flanking intron-exon boundaries in 147 BrS probands of our outclinic patient population. We identified 27 variants possibly associated with cardiac channelopathies, which resulted in a genetic diagnostic yield of 17,4%. Of those 27 identified variants, 18 (66,7%) have already been associated with BrS, 4 (14,8%) are associated with other cardiac arrhythmias and 5 (18,5%) are novel variants, not yet described in literature. With inclusion of the characteristics of the patient's electrocardiogram (ECG), three groups were considered: patients with a baseline BrS type I ECG, a baseline BrS type II ECG and a those with a normal ECG at baseline, but type I or II after injection of a sodium channel blocker (ajmaline). When only taking into account the patients with a baseline type I ECG (8,2%), which is the most convincing diagnostic criterion for BrS, the genetic diagnostic yield increased to 41.6%. Interestingly, this was not observed in patients with a type II ECG (10,8%), in which SCN5A variants seem to be either novel or associated with other arrhythmias. We also identified a substantial number of described SCN5A mutations (> 9%) in BrS patients clinically diagnosed by ajmaline positive testing and a family history of BrS and/or sudden cardiac death (81%), demonstrating the added value of sodium channel blocker-induced ECG testing.
If possible, segregation analysis was performed in the families of the identified SCN5A positive BrS probands to determine genotype-phenotype correlations. In more than 66% of tested families there was an incomplete segregation of the discovered variant. Revision of all ECG data revealed that some ajmaline or baseline ECG negative BrS patients with SCN5A mutations did not meet the stringent diagnostic criteria but demonstrated conduction disease. Given this incomplete variant segregation pattern in some families, studies are on going to better predict in silico the effect of the discovered variants on the protein structure, which might give some more insight into their pathogenic nature and their role in the disease.
These results also urge for the need to revise the clinical diagnostic criteria for BrS, in order to stratify BrS patient groups based on more detailed phenotypic data necessary to discover novel major disease associated genes.