Long QT syndrome type 1: clinical and functional characterization of KCNQ1 variant c.1111G > C.

BACKGROUND: Congenital long QT syndrome is a clinical disorder of genetic origin characterized by delayed repolarization of the myocardium, electrocardiographic QT prolongation, and increased risk of syncope, and sudden cardiac death due to polymorphic ventricular tachycardia. KCNQ1-related congenital long QT syndrome (LQT1) is the most prevalent of the long QT syndrome genetic subgroups and is typically caused by pathogenic missense or protein-truncating gene variants. Phenotypic features, computational analysis, and electrophysiological characterization of the variant are essential steps in assessing the pathogenicity of DNA variants and contribute to the future management of patients. METHODS: We report the results of the clinical evaluation of five Lithuanian families with a rare pathogenic heterozygous KCNQ1 variant c.1111G > C [p.(Ala371Pro)], including computational Kv7.1 protein structure analysis, molecular dynamics simulations, and electrophysiological characterization of the affected Kv7.1 channel. RESULTS: The individuals with the pathogenic variant (n = 9) exhibited phenotypic LQTS features during an exercise stress test (mean QTc during peak exercise was 497 ± 26 ms; mean QTc during the 4th minute of the recovery – 485 ± 22 ms) despite the low penetrance in the resting 12-lead ECG (mean QTc 423 ± 37 ms) or their symptomatic status. The sudden cardiac deaths of two females at the age of 34 years were reported in these families. Molecular dynamics simulations showed that the change p.Ala371Pro might disrupt the structure of the helix A in the Kv7.1 protein. Functional evaluation revealed that the pathogenic variant reduced the conductance of the channel by 46%, while the voltage dependence of activation was not affected. CONCLUSIONS: This is the first functional description of the KCNQ1 variant c.1111G > C that causes LQT1 phenotypic features. The variant is highly suggestive of the risk of disease-related cardiac events, particularly under adrenergic urge.