Mapping the Functional Landscape of KCNQ1 to Define Ion Channel Mechanisms and Arrhythmia Risk

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Loss-of-function variants in KCNQ1 are a primary cause of congenital Long QT Syndrome (LQTS).
• Genetic testing reveals numerous variants of uncertain significance in KCNQ1, complicating diagnosis and treatment.
• Understanding KCNQ1 variant function is critical for managing LQTS and associated fatal arrhythmias.

Purpose of the Study:

• To functionally characterize a comprehensive set of KCNQ1 variants.
• To identify specific variants affecting KCNQ1 trafficking, gating, and function.
• To provide evidence for variant pathogenicity or benignity to aid clinical interpretation.

Main Methods:

• Utilized four multiplexed assays to assess KCNQ1 variant function.
• Performed structure-function analyses to pinpoint variant impact on protein regions.
• Analyzed genotype-phenotype correlations in LQTS cohorts and biobank participants.

Main Results:

• Functionally characterized 13,403 KCNQ1 variants, providing evidence for 1,757 pathogenic and 6,660 benign variants.
• Identified variant enrichment in critical functional regions including trafficking, multimerization, ubiquitylation, and gating.
• Demonstrated a significant association between loss-of-function KCNQ1 variants, QTc prolongation, and LQTS diagnoses.

Conclusions:

• Comprehensive functional mapping of KCNQ1 variants offers critical insights into arrhythmia mechanisms.
• This study provides a foundation for improved genetic variant interpretation in LQTS.
• Characterization of KCNQ1 variants opens new avenues for precision medicine approaches in managing LQTS.