IndraLab

"In another recent study, Park et al demonstrated that within a multigenerational BrS/overlapping phenotype pedigree harboring the truncating Q646RfsX5-SCN5A mutation, those individuals, who also harbored a 2-SNP minor haplotype (rs41310749 and rs41310239) in the SCN5A promoter on both the mutant and normal SCN5A alleles (i.e. homozygous for the minor alleles), had a severe arrhythmia phenotype (defined as suffering from syncope, OHCA, or SCD) in comparison to the mild arrhythmia phenotype (defined as no cardiac events) displayed by those Q646RfsX5-positive individuals who only inherited the 2-SNP haplotype on their mutant SCN5A allele.[ xref ] Interestingly, in comparison to the wild-type 2-SNP SCN5A promoter haplotype, previous in vitro studies conducted in a variety of cell types displayed a trend towards reduced promoter activity associated with the minor 2-SNP SCN5A promoter haplotype.[ xref ] As such, Park et al hypothesized that the modest reduction in both mutant and normal SCN5A expression associated with the minor 2-SNP promoter haplotype functioned in an additive manner to aggravate the underlying arrhythmia phenotype associated with the Q646RfsX5 loss-of-function mutation.[ xref ]"