Multiplexed Assays of Variant Effect and Automated Patch Clamping Improve <i>KCNH2</i>-LQTS Variant Classification and Cardiac Event Risk Stratification.

ABSTRACT:

Background

Long QT syndrome is a lethal arrhythmia syndrome, frequently caused by rare loss-of-function variants in the potassium channel encoded by KCNH2. Variant classification is difficult, often because of lack of functional data. Moreover, variant-based risk stratification is also complicated by heterogenous clinical data and incomplete penetrance. Here we sought to test whether variant-specific information, primarily from high-throughput functional assays, could improve both classification and cardiac event risk stratification in a large, harmonized cohort of KCNH2 missense variant heterozygotes.

Methods

We quantified cell-surface trafficking of 18 796 variants in KCNH2 using a multiplexed assay of variant effect (MAVE). We recorded KCNH2 cu

SUBMITTER: O'Neill MJ 

PROVIDER: S-EPMC11611689 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature