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

Anna G Shestak; Leonid M Makarov; Vera N Komoliatova; Irina V Kolesnikova; Liubov O Skorodumova; Edward V Generozov; Elena V Zaklyazminskaya

doi:10.3389/fgene.2021.722291

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

Front Genet. 2021 Sep 6:12:722291. doi: 10.3389/fgene.2021.722291. eCollection 2021.

Authors

Anna G Shestak¹, Leonid M Makarov², Vera N Komoliatova², Irina V Kolesnikova³, Liubov O Skorodumova³, Edward V Generozov³, Elena V Zaklyazminskaya¹

Affiliations

¹ Russian National Research Center of Surgery Named After B.V. Petrovsky, Moscow, Russia.
² Center for Syncope and Cardiac Arrhythmias in Children and Adolescents of the Federal Medical Biological Agency, Moscow, Russia.
³ Federal Research and Clinical Center of Physical Chemical Medicine of the Federal Medical Biological Agency, Moscow, Russia.

Abstract

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.

Keywords: SCN5A gene; genetic counseling; next generation sequencing; noncanonical transcripts; pathogenicity assessment; whole exome sequencing.