Arrhythmias & electrophysiology
Multimodal KCNQ1 Variant-Effect Maps Define Ion Channel Mechanisms and Disease Risk
Authors' conclusion
This comprehensive KCNQ1 functional atlas provides novel functional evidence for most KCNQ1 variants of uncertain significance. It also reveals mechanistic principles linking genetic variation to ion channel biology and arrhythmia susceptibility, advancing cardiovascular precision medicine.
Study context
- Population
- Protein-coding variants in the ion channel gene KCNQ1protein-coding variants in KCNQ1
- Participants
- 13,403 participants
- Outcome
- Functional measurements of KCNQ1 variants
Methodological details4 pooled assays followed by high-throughput sequencing, case-control analyses, data from large-scale biobanks
- 4 pooled assays followed by high-throughput sequencing
- Case-control analyses
- Data from large-scale biobanks
Main finding
As reported in the abstract
Functional measurements across the 4 assays
49 305
Observational data: associations, not effects.
Further findings
Pathogenic and benign functional evidence
- Variants with strong pathogenic evidence, of the 13 403 studied variants
- 1757
- Variants with moderate benign evidence, of the 13 403 studied variants
- 6660
QT prolongation and long QT syndrome
- Loss-of-function variants were significantly associated with QT prolongation and long QT syndrome in case-control and biobank analyses
Structural clustering of deleterious variants
- Deleterious variants clustered within distinct structural domains based on their functional classification
Dominant-negative effects and arrhythmia risk
- A majority of pathogenic variants exhibited dominant-negative effects; these variants were linked to a higher risk of arrhythmia diagnoses than were haploinsufficient variants
Original publication
Multimodal KCNQ1 Variant-Effect Maps Define Ion Channel Mechanisms and Disease Risk. Circulation. Published 20 October 2026. doi:10.
Summarised from the published abstract; every number is checked against it