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

KCNQ1

KCNQ1 loss-of-function variants affecting cell surface abundance and channel function, with a dominant-negative effect for most pathogenic variants

The authors built a nearly comprehensive library of 13,403 coding variants in KCNQ1, the leading genetic cause of congenital long QT syndrome, and used 4 pooled assays followed by high-throughput sequencing to measure their effect on cell surface abundance and channel function, both alone and in the heterozygous state. In total, 49,305 functional measurements were generated: 1757 variants showed strong pathogenic evidence and 6660 moderate benign evidence. In case-control analyses and large biobank data, loss-of-function variants were significantly associated with QT prolongation and long QT syndrome. Most pathogenic variants had a dominant-negative effect, associated with a higher risk of arrhythmia diagnoses than haploinsufficient variants, and classes of deleterious variants clustered in distinct structural domains.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This kind of comprehensive functional map concretely changes interpretation: for most KCNQ1 variants of uncertain significance, graded functional evidence becomes available without individual testing. The distinction between dominant-negative and haploinsufficient effects adds an element of arrhythmic risk stratification that will need prospective confirmation. It remains to be seen what evidence strength expert panels will grant these measurements within ACMG criteria.

Analysis by Dr Thibaut Benquey