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

Abstract

Loss-of-function variants in KCNQ1 are the primary cause of congenital Long QT Syndrome (LQTS), characterized by QT prolongation and increased risk of fatal arrhythmias. The surge in genetic testing continues to uncover vast numbers of variants of uncertain significance in Mendelian disease genes, including KCNQ1. Using four multiplexed assays, we mapped the functional landscape of KCNQ1, identifying trafficking, gating, and dominant negative variants. We provide functional evidence for 13,403 variants, including 1,757 with strong pathogenic and 6,660 with moderate benign evidence. Structure-function analyses revealed variant enrichment in regions regulating trafficking, multimerization, ubiquitylation, and channel gating. Loss-of-function variants showed a risk ratio of 263 (95% CI 241-286) in an LQTS cohort and were significantly associated with QTc prolongation and LQTS diagnoses in biobank participants. By characterizing the functional impact of nearly all KCNQ1 variants, we provide critical insights into arrhythmia mechanisms and open new avenues for precision medicine in LQTS. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/25341924v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@1a8f100org.highwire.dtl.DTLVardef@6664fcorg.highwire.dtl.DTLVardef@700edcorg.highwire.dtl.DTLVardef@dfa65c_HPS_FORMAT_FIGEXP M_FIG C_FIG