Whole-genome sequencing implicates rare, low-frequency and structural non-coding variation at the SCN5A locus in Brugada syndrome

Rare and structural non-coding variants at the SCN5A locus altering cardiac cis-regulatory elements

Using WGS of 752 European-ancestry Brugada syndrome (BrS) cases and 1,827 controls, the authors explore rare non-coding variation at the SCN5A locus. Sliding-window and cis-regulatory-element aggregate testing implicate three conserved CREs, including a 178 bp enhancer in intron 17 of SCN5A that replicated in an independent cohort. A low-frequency variant in an intron 1 CRE, Bonferroni-significant and five-fold case-enriched, was associated with slower cardiac conduction in the UK Biobank. Structural analyses identified a 10.5 kb deletion upstream of SCN5A reducing sodium current in an hiPSC-CM model, and a case-enriched retrotransposon insertion.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An ambitious preprint extending BrS genetic architecture beyond the coding sequence, with hiPSC-CM functional validation and replication, potentially explaining part of the residual GWAS signal. Pending peer review, but the locus-targeted WGS approach is methodologically exemplary. Diagnostic impact will depend on integrating these regulatory regions into routine interpretation.

Analysis by Dr Thibaut Benquey