Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome
Brugada syndrome (BrS) is an inherited cardiac arrhythmia characterized by ST-elevation, negative T-wave, and a high risk of sudden cardiac death (SCD) due to ventricular tachycardia. It is associated with mutations in over 20 genes but only SCN5A is recommended for routine genetic screening. This s...
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.984299/full |
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| author | Elena Zaklyazminskaya Elena Zaklyazminskaya Anna Shestak Dmitry Podolyak Vera Komoliatova Leonid Makarov Anna Novitskaya Amiran Revishvili |
| author_facet | Elena Zaklyazminskaya Elena Zaklyazminskaya Anna Shestak Dmitry Podolyak Vera Komoliatova Leonid Makarov Anna Novitskaya Amiran Revishvili |
| author_sort | Elena Zaklyazminskaya |
| collection | DOAJ |
| description | Brugada syndrome (BrS) is an inherited cardiac arrhythmia characterized by ST-elevation, negative T-wave, and a high risk of sudden cardiac death (SCD) due to ventricular tachycardia. It is associated with mutations in over 20 genes but only SCN5A is recommended for routine genetic screening. This study was performed to estimate diagnostic yield and pathogenicity assessment of rare genetic variants in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome (BrS). Targeted genes panel sequencing of the five genes were screened using IonTorrent PGM with following Sanger confirmation. Detailed clinical evaluation of 75 unrelated BrS probands with a deep phenotyping of SCN5A (+) probands was performed. Twelve rare genetic variants (six missense, six truncating) were initially identified and classified as disease-causing. Reassessment of the clinical significance in the light of the current guidelines revealed: 2 Pathogenic (P) variants; 8 Likely Pathogenic (LP); two missense variants (p.G274S and p. S1778H) were re-classified later as a variant of uncertain significance (VUS). Unique VUS (p.Arg100Ser) was detected in the SCN4B gene. Lone Brugada-pattern was observed in 46% probands; 54% patients had concomitant arrhythmias. PR interval, the only electrocardiography parameter correlating with SCN5A-mutation, was longer (207 ± 24 ms) than normal in SCN5A (+) probands. SCD cases were registered in 31 families. Depression was the only recurring extra-cardiac complaint in SCN5A (+) probands; it was self-reported in five SCN5A (+) probands, and co-segregated with Brugada pattern in 2 families. After variants reassessment, the ratio of SCN5A (+) probands with Brugada syndrome accounts for 13% in Russian cohort. |
| first_indexed | 2024-12-10T18:28:04Z |
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| id | doaj.art-d7defbcd692b496f9e9f540512ebc7a8 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-10T18:28:04Z |
| publishDate | 2022-08-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-d7defbcd692b496f9e9f540512ebc7a82022-12-22T01:38:02ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-08-011310.3389/fphar.2022.984299984299Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndromeElena Zaklyazminskaya0Elena Zaklyazminskaya1Anna Shestak2Dmitry Podolyak3Vera Komoliatova4Leonid Makarov5Anna Novitskaya6Amiran Revishvili7Petrovsky National Research Centre of Surgery, Moscow, RussiaBochkov Research Centre for Medical Genetics, Moscow, RussiaPetrovsky National Research Centre of Surgery, Moscow, RussiaPetrovsky National Research Centre of Surgery, Moscow, RussiaCentre of Syncope and Cardiac Arrhythmias in Children and Adolescents, Moscow, RussiaCentre of Syncope and Cardiac Arrhythmias in Children and Adolescents, Moscow, RussiaSechenov First Medical State University, Moscow, RussiaVishnevsky Institute of Surgery, Moscow, RussiaBrugada syndrome (BrS) is an inherited cardiac arrhythmia characterized by ST-elevation, negative T-wave, and a high risk of sudden cardiac death (SCD) due to ventricular tachycardia. It is associated with mutations in over 20 genes but only SCN5A is recommended for routine genetic screening. This study was performed to estimate diagnostic yield and pathogenicity assessment of rare genetic variants in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome (BrS). Targeted genes panel sequencing of the five genes were screened using IonTorrent PGM with following Sanger confirmation. Detailed clinical evaluation of 75 unrelated BrS probands with a deep phenotyping of SCN5A (+) probands was performed. Twelve rare genetic variants (six missense, six truncating) were initially identified and classified as disease-causing. Reassessment of the clinical significance in the light of the current guidelines revealed: 2 Pathogenic (P) variants; 8 Likely Pathogenic (LP); two missense variants (p.G274S and p. S1778H) were re-classified later as a variant of uncertain significance (VUS). Unique VUS (p.Arg100Ser) was detected in the SCN4B gene. Lone Brugada-pattern was observed in 46% probands; 54% patients had concomitant arrhythmias. PR interval, the only electrocardiography parameter correlating with SCN5A-mutation, was longer (207 ± 24 ms) than normal in SCN5A (+) probands. SCD cases were registered in 31 families. Depression was the only recurring extra-cardiac complaint in SCN5A (+) probands; it was self-reported in five SCN5A (+) probands, and co-segregated with Brugada pattern in 2 families. After variants reassessment, the ratio of SCN5A (+) probands with Brugada syndrome accounts for 13% in Russian cohort.https://www.frontiersin.org/articles/10.3389/fphar.2022.984299/fullSCN5ANav1.5 channelBrugada syndrome comorbidityBrugada syndromecardiac channelopathy |
| spellingShingle | Elena Zaklyazminskaya Elena Zaklyazminskaya Anna Shestak Dmitry Podolyak Vera Komoliatova Leonid Makarov Anna Novitskaya Amiran Revishvili Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome Frontiers in Pharmacology SCN5A Nav1.5 channel Brugada syndrome comorbidity Brugada syndrome cardiac channelopathy |
| title | Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome |
| title_full | Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome |
| title_fullStr | Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome |
| title_full_unstemmed | Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome |
| title_short | Diagnostic yield and variant reassessment in the genes encoding Nav1.5 channel in Russian patients with Brugada syndrome |
| title_sort | diagnostic yield and variant reassessment in the genes encoding nav1 5 channel in russian patients with brugada syndrome |
| topic | SCN5A Nav1.5 channel Brugada syndrome comorbidity Brugada syndrome cardiac channelopathy |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.984299/full |
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