Arrhythmias & electrophysiology
Gain-of-function enhancer variant near KCNB1 causes familial ST-depression syndrome
Authors' conclusion
A gain-of-function enhancer variant creates a hyperactive regulatory locus that interacts with the KCNB1 promoter and causes FSTD. This is the first time that KCNB1 has been implicated in human cardiac electrophysiology and arrhythmogenesis.
Study context
- Population
- Patients with familial ST-depression syndrome (FSTD)20 families
- Participants
- 67 patients
- Outcome
- Causative variant of FSTD
Methodological detailslinkage analysis, whole-genome sequencing, functional characterization
- Linkage analysis
- Whole-genome sequencing
- Functional characterization
Main finding
As reported in the abstract
- Electrocardiographic (ECG) phenotype inherited autosomal dominantly in all families
- Linkage analysis: single peak on chromosome 20
- Whole-genome sequencing (WGS): single rare non-coding variant 18 kb downstream of KCNB1 on chromosome 20 in all affected individuals
- Perfect co-segregation with ECG phenotype and full penetrance in all families
- Variant creates a MEF2-binding site; variant allele or MEF2 co-expression enhanced transcriptional activity
- dCas9-activator/repressor assays: KCNB1 the only gene consistently regulated by the locus
- 4C in AC16 cells and human muscle tissue confirmed locus–KCNB1 promoter interaction
- No change in gene expression in human endocardial tissue, likely explained by expressional heterogeneity
Original publication
Gain-of-function enhancer variant near KCNB1 causes familial ST-depression syndrome. Eur Heart J. Published 10 April 2025. doi:10.
Composed by AI from the published abstract and checked against it. How Briefs are made →