Genes · 2022
Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Zaklyazminskaya Elena, Polyak Margarita, Shestak Anna, Sadekova Mariam, Komoliatova Vera, Kiseleva Irina, Makarov Leonid, Podolyak Dmitriy, Glukhov Grigory, Zhang Han, Abramochkin Denis, Sokolova Olga S
Аннотация
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.
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.