Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome
Background: The <i>KCNJ2</i> 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...
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MDPI AG
2022-03-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/13/4/559 |
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| author | Elena Zaklyazminskaya Margarita Polyak Anna Shestak Mariam Sadekova Vera Komoliatova Irina Kiseleva Leonid Makarov Dmitriy Podolyak Grigory Glukhov Han Zhang Denis Abramochkin Olga S. Sokolova |
| author_facet | Elena Zaklyazminskaya Margarita Polyak Anna Shestak Mariam Sadekova Vera Komoliatova Irina Kiseleva Leonid Makarov Dmitriy Podolyak Grigory Glukhov Han Zhang Denis Abramochkin Olga S. Sokolova |
| author_sort | Elena Zaklyazminskaya |
| collection | DOAJ |
| description | Background: The <i>KCNJ2</i> 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 <i>KCNJ2</i> 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. |
| first_indexed | 2024-03-09T10:36:32Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-09T10:36:32Z |
| publishDate | 2022-03-01 |
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| record_format | Article |
| series | Genes |
| spelling | doaj.art-b8bd61c017f640fcba3173b710a1fdf92023-12-01T20:56:14ZengMDPI AGGenes2073-44252022-03-0113455910.3390/genes13040559Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT SyndromeElena Zaklyazminskaya0Margarita Polyak1Anna Shestak2Mariam Sadekova3Vera Komoliatova4Irina Kiseleva5Leonid Makarov6Dmitriy Podolyak7Grigory Glukhov8Han Zhang9Denis Abramochkin10Olga S. Sokolova11Medical Genetics Laboratory, B.V. Petrovsky National Research Center of Surgery, 119991 Moscow, RussiaMedical Genetics Laboratory, B.V. Petrovsky National Research Center of Surgery, 119991 Moscow, RussiaMedical Genetics Laboratory, B.V. Petrovsky National Research Center of Surgery, 119991 Moscow, RussiaMedical Genetics Laboratory, B.V. Petrovsky National Research Center of Surgery, 119991 Moscow, RussiaCenter for Syncope and Cardiac Arrhythmias in Children and Adolescents, Federal Medical Biological Agency, 115481 Moscow, RussiaCenter for Syncope and Cardiac Arrhythmias in Children and Adolescents, Federal Medical Biological Agency, 115481 Moscow, RussiaCenter for Syncope and Cardiac Arrhythmias in Children and Adolescents, Federal Medical Biological Agency, 115481 Moscow, RussiaMedical Genetics Laboratory, B.V. Petrovsky National Research Center of Surgery, 119991 Moscow, RussiaFaculty of Biology, Shenzhen MSU-BIT University, Shenzhen 517182, ChinaFaculty of Biology, Shenzhen MSU-BIT University, Shenzhen 517182, ChinaFaculty of Biology, Lomonosov Moscow State University, 119234 Moscow, RussiaFaculty of Biology, Shenzhen MSU-BIT University, Shenzhen 517182, ChinaBackground: The <i>KCNJ2</i> 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 <i>KCNJ2</i> 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.https://www.mdpi.com/2073-4425/13/4/559primary arrhythmiaLong QT syndromeLQT7Andersen-Tawil syndromeKir2.1<i>KCNJ2</i> |
| spellingShingle | Elena Zaklyazminskaya Margarita Polyak Anna Shestak Mariam Sadekova Vera Komoliatova Irina Kiseleva Leonid Makarov Dmitriy Podolyak Grigory Glukhov Han Zhang Denis Abramochkin Olga S. Sokolova Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome Genes primary arrhythmia Long QT syndrome LQT7 Andersen-Tawil syndrome Kir2.1 <i>KCNJ2</i> |
| title | Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome |
| title_full | Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome |
| title_fullStr | Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome |
| title_full_unstemmed | Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome |
| title_short | Variable Clinical Appearance of the Kir2.1 Rare Variants in Russian Patients with Long QT Syndrome |
| title_sort | variable clinical appearance of the kir2 1 rare variants in russian patients with long qt syndrome |
| topic | primary arrhythmia Long QT syndrome LQT7 Andersen-Tawil syndrome Kir2.1 <i>KCNJ2</i> |
| url | https://www.mdpi.com/2073-4425/13/4/559 |
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