Cargando…

Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation

Primary cardiac channelopathies are a group of diseases wherein the role of DNA testing in aiding diagnosis and treatment-based decision-making is gaining increasing attention. However, in some cases, evaluating the pathogenicity of new variants is still challenging. We report an accurate multistage...

Descripción completa

Detalles Bibliográficos
Autores principales: Shestak, Anna G., Makarov, Leonid M., Komoliatova, Vera N., Kolesnikova, Irina V., Skorodumova, Liubov O., Generozov, Edward V., Zaklyazminskaya, Elena V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450431/
https://www.ncbi.nlm.nih.gov/pubmed/34552620
http://dx.doi.org/10.3389/fgene.2021.722291
_version_ 1784569645629440000
author Shestak, Anna G.
Makarov, Leonid M.
Komoliatova, Vera N.
Kolesnikova, Irina V.
Skorodumova, Liubov O.
Generozov, Edward V.
Zaklyazminskaya, Elena V.
author_facet Shestak, Anna G.
Makarov, Leonid M.
Komoliatova, Vera N.
Kolesnikova, Irina V.
Skorodumova, Liubov O.
Generozov, Edward V.
Zaklyazminskaya, Elena V.
author_sort Shestak, Anna G.
collection PubMed
description Primary cardiac channelopathies are a group of diseases wherein the role of DNA testing in aiding diagnosis and treatment-based decision-making is gaining increasing attention. However, in some cases, evaluating the pathogenicity of new variants is still challenging. We report an accurate multistage assessment of a rare genetic variant in the SCN5A gene using next-generation sequencing (NGS) techniques and Sanger sequencing. Female sportsman (14 years old) underwent genetic counseling and DNA testing due to QT interval prolongation registered during ECG Holter monitoring. Genetic testing of the proband was performed in two independent laboratories. Primary DNA testing was performed by WES using the Ion Proton(TM) System. Target panel sequencing of 11 genes was performed using PGM Ion Torrent. Search for variants in non-canonical and canonical exons 6 was performed by Sanger sequencing. The cascade familial screening and control re-sequencing were provided for proband with identified genetic variant p.S216L (g.38655290G>A, NM_198056.2:c.647C>T, and rs41276525) in the canonical exon 6 of the SCN5A gene after receiving data from another laboratory. Control Sanger and NGS sequencing revealed the absence p.S216L in the canonical exon 6 and confirmed the presence of p.S216L (g.38655522G>A, c.647C>T, and rs201002736) in the non-canonical exon 6 of the SCN5A gene. The identified variant was re-interpreted. The non-canonical transcripts of the exon 6 of the SCN5A gene is poorly represented in cardiac tissue (gnomAD). The detected variant was found in proband’s healthy mother. The correct interpretation of genetic data requires close cooperation between clinicians and researchers. It can help to avoid financial costs and stress for proband’s and families.
format Online
Article
Text
id pubmed-8450431
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-84504312021-09-21 Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation Shestak, Anna G. Makarov, Leonid M. Komoliatova, Vera N. Kolesnikova, Irina V. Skorodumova, Liubov O. Generozov, Edward V. Zaklyazminskaya, Elena V. Front Genet Genetics Primary cardiac channelopathies are a group of diseases wherein the role of DNA testing in aiding diagnosis and treatment-based decision-making is gaining increasing attention. However, in some cases, evaluating the pathogenicity of new variants is still challenging. We report an accurate multistage assessment of a rare genetic variant in the SCN5A gene using next-generation sequencing (NGS) techniques and Sanger sequencing. Female sportsman (14 years old) underwent genetic counseling and DNA testing due to QT interval prolongation registered during ECG Holter monitoring. Genetic testing of the proband was performed in two independent laboratories. Primary DNA testing was performed by WES using the Ion Proton(TM) System. Target panel sequencing of 11 genes was performed using PGM Ion Torrent. Search for variants in non-canonical and canonical exons 6 was performed by Sanger sequencing. The cascade familial screening and control re-sequencing were provided for proband with identified genetic variant p.S216L (g.38655290G>A, NM_198056.2:c.647C>T, and rs41276525) in the canonical exon 6 of the SCN5A gene after receiving data from another laboratory. Control Sanger and NGS sequencing revealed the absence p.S216L in the canonical exon 6 and confirmed the presence of p.S216L (g.38655522G>A, c.647C>T, and rs201002736) in the non-canonical exon 6 of the SCN5A gene. The identified variant was re-interpreted. The non-canonical transcripts of the exon 6 of the SCN5A gene is poorly represented in cardiac tissue (gnomAD). The detected variant was found in proband’s healthy mother. The correct interpretation of genetic data requires close cooperation between clinicians and researchers. It can help to avoid financial costs and stress for proband’s and families. Frontiers Media S.A. 2021-09-06 /pmc/articles/PMC8450431/ /pubmed/34552620 http://dx.doi.org/10.3389/fgene.2021.722291 Text en Copyright © 2021 Shestak, Makarov, Komoliatova, Kolesnikova, Skorodumova, Generozov and Zaklyazminskaya. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Shestak, Anna G.
Makarov, Leonid M.
Komoliatova, Vera N.
Kolesnikova, Irina V.
Skorodumova, Liubov O.
Generozov, Edward V.
Zaklyazminskaya, Elena V.
Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation
title Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation
title_full Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation
title_fullStr Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation
title_full_unstemmed Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation
title_short Coexistence of Two Rare Genetic Variants in Canonical and Non-canonical Exons of SCN5A: A Potential Source of Misinterpretation
title_sort coexistence of two rare genetic variants in canonical and non-canonical exons of scn5a: a potential source of misinterpretation
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450431/
https://www.ncbi.nlm.nih.gov/pubmed/34552620
http://dx.doi.org/10.3389/fgene.2021.722291
work_keys_str_mv AT shestakannag coexistenceoftworaregeneticvariantsincanonicalandnoncanonicalexonsofscn5aapotentialsourceofmisinterpretation
AT makarovleonidm coexistenceoftworaregeneticvariantsincanonicalandnoncanonicalexonsofscn5aapotentialsourceofmisinterpretation
AT komoliatovaveran coexistenceoftworaregeneticvariantsincanonicalandnoncanonicalexonsofscn5aapotentialsourceofmisinterpretation
AT kolesnikovairinav coexistenceoftworaregeneticvariantsincanonicalandnoncanonicalexonsofscn5aapotentialsourceofmisinterpretation
AT skorodumovaliubovo coexistenceoftworaregeneticvariantsincanonicalandnoncanonicalexonsofscn5aapotentialsourceofmisinterpretation
AT generozovedwardv coexistenceoftworaregeneticvariantsincanonicalandnoncanonicalexonsofscn5aapotentialsourceofmisinterpretation
AT zaklyazminskayaelenav coexistenceoftworaregeneticvariantsincanonicalandnoncanonicalexonsofscn5aapotentialsourceofmisinterpretation