Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome

Abstract

Background: The KCNJ2 gene encodes inward rectifier Kir2.1 channels, maintaining resting potential and cell excitability. Presumably, clinical phenotypes of mutation carriers correlate with ion permeability defects. Loss-of-function mutations lead to QTc prolongation with variable dysmorphic features, whereas gain-of-function mutations cause short QT syndrome and/or atrial fibrillation. Methods: We screened 210 probands with Long QT syndrome for mutations in the KCNJ2 gene. The electrophysiological study was performed for the p.Val93Ile variant in the transfected CHO-K1 cells. Results: We found three rare genetic variants, p.Arg67Trp, p.Val93Ile, and p.R218Q, in three unrelated LQTS probands. Probands with p.Arg67Trp and p.R218Q had a phenotype typical for Andersen-Tawil (ATS), and the p.Val93Ile carrier had lone QTc prolongation. Variant p.Val93Ile was initially described as a gain-of-function pathogenic mutation causing familial atrial fibrillation. We validated electrophysiological features of this variant in CHO-K1 cells, but no family members of these patients had atrial fibrillation. Using ACMG (2015) criteria, we re-assessed this variant as a variant of unknown significance (class III). Conclusions: LQT7 is a rare form of LQTS in Russia, and accounts for 1% of the LQTS cohort. Variant p.Val93Ile leads to a gain-of-function effect in the different cell lines, but its clinical appearance is not so consistent. The clinical significance of this variant might be overestimated.

In silico models of the macromolecular NaV1.5-KIR2.1 complex

“…Mutation V93I is associated with familial atrial fibrillation and can lead to increased channel activity ( Xia et al, 2005 ). In vitro analysis of channel function revealed a gain-of-function for this variant ( Xia et al, 2005 ; Zaklyazminskaya et al, 2022 ). A study of Russian patients with this variant revealed a surprising phenotype without any signs of ATS1 or mild but evident QTc prolongation ( Zaklyazminskaya et al, 2022 ).…”

“…In vitro analysis of channel function revealed a gain-of-function for this variant ( Xia et al, 2005 ; Zaklyazminskaya et al, 2022 ). A study of Russian patients with this variant revealed a surprising phenotype without any signs of ATS1 or mild but evident QTc prolongation ( Zaklyazminskaya et al, 2022 ). Thus, the clinical significance of this variant remains unclear; however, it is classified as a potential proarrhythmogenic risk factor.…”