%0 Journal Article
%T Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome.
%A Zaklyazminskaya E
%A Polyak M
%A Shestak A
%A Sadekova M
%A Komoliatova V
%A Kiseleva I
%A Makarov L
%A Podolyak D
%A Glukhov G
%A Zhang H
%A Abramochkin D
%A Sokolova OS
%J Genes (Basel)
%V 13
%N 4
%D 03 2022 22
%M 35456365
%F 4.141
%R 10.3390/genes13040559
%X 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.
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.
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).
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.