Gain-of-function enhancer variant near KCNB1 causes familial ST-depression syndrome.

Summary

Across 20 families (67 affected individuals), the authors identified a rare noncoding enhancer variant 18 kb downstream of KCNB1 that perfectly co-segregated with autosomal dominant ST-depression. The variant creates a MEF2-binding site, increases transcriptional activity, and regulates KCNB1 as confirmed by dCas9 perturbation and 4C assays, establishing KCNB1’s first implication in human cardiac electrophysiology and arrhythmogenesis.

Key Findings

• Identified a rare noncoding enhancer variant 18 kb downstream of KCNB1 that perfectly co-segregates with FSTD across 20 families with full penetrance.
• The variant creates a de novo MEF2-binding site and enhances transcriptional activity; dCas9 activator/repressor assays implicate KCNB1 as the sole consistently regulated gene.
• Chromosome conformation capture (4C) confirmed physical interaction between the locus and the KCNB1 promoter in cardiomyocytes and human muscle tissue.

Clinical Implications

Genetic testing for noncoding regulatory variants near KCNB1 should be considered in familial ECG syndromes with ST-depression. Mechanistic insights open avenues for precision diagnosis and potential targeted modulation of enhancer–promoter interactions.

Limitations

• Expression analysis in human endocardial tissue did not show differential expression, likely due to tissue heterogeneity.
• Lack of in vivo animal model confirmation of electrophysiologic phenotype.

Future Directions

Develop in vivo models to define KCNB1-driven arrhythmogenesis from enhancer perturbations, and evaluate diagnostic panels capturing regulatory variants in familial ECG syndromes.