Multimodal KCNQ1 Variant-Effect Maps Define Ion Channel Mechanisms and Disease Risk.

Functional analysis of 13,403 KCNQ1 variants identified 1,757 with strong pathogenic evidence linked to long QT syndrome and arrhythmia risk.

• Why it matters: Accurate interpretation of genetic variants is crucial for risk stratification and personalized treatment in long QT syndrome, but many variants remain of uncertain significance.
• What they did: Researchers created a comprehensive variant library and used four pooled high-throughput assays to measure effects on cell surface abundance and channel function, analyzing over 49,000 functional data points.
• The result: Loss-of-function variants are significantly associated with QT prolongation and long QT syndrome, with most pathogenic variants exhibiting dominant-negative effects linked to higher arrhythmia risk, advancing precision cardiovascular medicine.