Arrhythmias & electrophysiology
Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve KCNH2 -LQTS Variant Classification and Cardiac Event Risk Stratification
Authors' conclusion
High-throughput KCNH2 variant MAVE data meaningfully contribute to variant classification at scale, whereas long QT syndrome penetrance estimates and automated patch clamping peak tail current measurements meaningfully contribute to risk stratification of cardiac events in patients with heterozygous KCNH2 missense variants.
Study context
- Population
- Patients heterozygous for KCNH2 missense variants (long QT syndrome)18,796 variants assayed
- Participants
- 1,458 participants
- Comparison
- Sex + QTc vs Penetrance conditioned on multiplexed assay of variant effect (MAVE) vs Patch clamping peak tail current
- Outcome
- Cardiac events
- Follow-up
- 20 years
Methodological detailsmultiplexed assay of variant effect, automated patch clamping, cohort
- Multiplexed assay of variant effect
- Automated patch clamping
- Cohort
Main finding
As reported in the abstract
AUC for 20-year cardiac events
| Group | AUC |
|---|---|
| Sex + QTc | 0.80 [0.76-0.83] |
| Penetrance conditioned on MAVE | 0.86 [0.83-0.89] |
| Patch clamping peak tail current | 0.84 [0.81-0.88] |
AUC
Sex + QTc0.80 [0.76-0.83]
Penetrance conditioned on MAVE0.86 [0.83-0.89]
Patch clamping peak tail current0.84 [0.81-0.88]
Further findings
Correlation of MAVE trafficking scores with patch clamping peak tail currents
- Spearman rank-order ρ (n=433)
- 0.69
MAVE evidence strength (ClinGen calibration)
- Up to pathogenic very strong evidence for severe loss-of-function variants
Original publication
Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve KCNH2 -LQTS Variant Classification and Cardiac Event Risk Stratification. Circulation. Published 24 September 2024. doi:10.
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