Role of SCN5A coding and non-coding sequences in Brugada syndrome onset: What's behind the scenes?

Abstract

BackgroundBrugada syndrome (BrS) is a rare inherited cardiac arrhythmia associated with a high risk of sudden cardiac death (SCD) due to ventricular fibrillation (VF). BrS is characterized by coved-type ST-segment elevation in the right precordial leads (V1-V3). Mutations in SCN5A gene coding for the α-subunit of the NaV1.5 cardiac sodium channel are identified in 15–30% of BrS cases. Genetic testing of BrS patients generally involves sequencing of the protein-coding portions and flanking intronic regions of SCN5A. This excludes the 5′UTR and 3′UTR from the routine genetic testing.MethodsWe here screened the coding sequence, the flanking intronic regions as well as the 5′ and 3′UTR regions of SCN5A gene and further five candidate genes (GPD1L, SCN1B, KCNE3, SCN4B, and MOG1) in a Tunisian family diagnosed with BrS.ResultsA new SCN5A-Q1000K mutation was identified along with two common polymorphisms (H558R and D1819). Multiple genetic variants were identified on the SCN5A 3′UTR, one of which is predicted to create additional microRNA binding site for miR-1270. Additionally, we identified the hsa-miR-219a-rs107822. No relevant coding sequence variant was identified in the remaining studied candidate genes.ConclusionsThe absence of genotype-phenotype concordance within all the identified genetic variants in this family gives extra evidences about the complexity of the disease and suggests that the occurrence and prognosis of BrS is most likely controlled by a combination of multiple genetic factors, rather than a single variant. Most SCN5A variants were localized in non-coding regions hypothesizing an impact on the miRNA-target complementarities.

Post-mortem genetic investigation of cardiac disease–associated genes in sudden infant death syndrome (SIDS) cases

“…The twin brother of the deceased infant exhibited no pathological cardiac symptoms. Abnormalities in the gene SCN5A are mainly associated with BrS and LQTS [ 21 ]. The detected variant is located at the transition site of the sodium channel in the fourth segment of the third domain close to the cytoplasm and has not been described in the literature and functional studies so far.…”

The many (sur)faces of B cells

“…Daimi et al. elegantly manage to make both elements meet in their present study about the genetic elements underlying a cardiac disorder [16].…”

MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel

“…SCN5A alterations, either up-or downregulation, are known to cause arrhythmias, and SCN5A is downregulated in ischemic cardiomyopathy (27)(28)(29). Nevertheless, the mechanisms whereby ischemia causes a reduction in SCN5A have not been fully explored but include mRNA destabilization (9,27).…”