<abstract xmlns="http://www.w3.org/1999/xhtml">

<sec><h3>Background and aim</h3><p>Most of detected variants in cardiogenetic panels are still classified as variants of unknown significance, requiring supplementary analyses for a definite classification. Performing further in-depth studies on such vast number of candidates is unfeasible. We sought to prioritise the novel nonsynonymous missense variants identified in titin gene (TTN) in a cohort of Romanian index cases with hypertrophic cardiomyopathy (HCM).</p></sec>
<sec><h3>Methods</h3><p>45 unrelated probands with HCM were screened by targeted next generation sequencing (NGS) covering all TTN exons. A stepwise strategy was used to select and prioritize the candidate variants for subsequent investigation.</p></sec>
<sec><h3>Results</h3><p>Using rigorous bioinformatic filtering, 7 novel TTN nonsynonymous missense variants were identified and were the subject of <italic>in silico</italic> sequential analysis. 4 of the 7 variants were predicted to be possibly pathogenic by the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm. Of these, three sequence variants (c.30392G>T, c.2518G>T, and c.49G>T) were also predicted to be destabilizing according to the second computational tool (TITINdb) and were designated as likely function-impacting.</p></sec>
<sec><h3>Conclusions</h3><p>Herein we presented our strategy to hand-pick the novel TTN missense variants to be considered for further experimental studies. By applying various <italic>in silico</italic> tools, we restricted the list of sequence variants to be investigated to those most likely to be disease-associated, and thus reducing the need to perform expensive and time-consuming additional studies.</p></sec>
</abstract>

Background and aimMost of detected variants in cardiogenetic panels are still classified as variants of unknown significance, requiring supplementary analyses for a definite classification. Performing further in-depth studies on such vast number of candidates is unfeasible. We sought to prioritise the novel nonsynonymous missense variants identified in titin gene (TTN) in a cohort of Romanian index cases with hypertrophic cardiomyopathy (HCM).
Methods45 unrelated probands with HCM were screened by targeted next generation sequencing (NGS) covering all TTN exons. A stepwise strategy was used to select and prioritize the candidate variants for subsequent investigation.
ResultsUsing rigorous bioinformatic filtering, 7 novel TTN nonsynonymous missense variants were identified and were the subject of in silico sequential analysis. 4 of the 7 variants were predicted to be possibly pathogenic by the Mendelian Clinically Applicable Pathogenicity (M-CAP) algorithm. Of these, three sequence variants (c.30392G>T, c.2518G>T, and c.49G>T) were also predicted to be destabilizing according to the second computational tool (TITINdb) and were designated as likely function-impacting.
ConclusionsHerein we presented our strategy to hand-pick the novel TTN missense variants to be considered for further experimental studies. By applying various in silico tools, we restricted the list of sequence variants to be investigated to those most likely to be disease-associated, and thus reducing the need to perform expensive and time-consuming additional studies.

<italic>In Silico</italic> Analysis of Novel Titin Non-Synonymous Missense Variants Detected by Targeted Next-Generation Sequencing in a Cohort of Romanian Index Patients with Hypertrophic Cardiomyopathy

Department of Cardiology, Emergency Clinical Hospital

„Carol Davila” University of Medicine and Pharmacy

Romanian Journal of Cardiology

This work is licensed under the Creative Commons Attribution 4.0 International License.

 Analysis of Novel Titin Non-Synonymous Missense Variants Detected by Targeted Next-Generation Sequencing in a Cohort of Romanian Index Patients with Hypertrophic Cardiomyopathy

Background and aimMost of detected variants in cardiogenetic panels are still classified as variants of unknown significance, requiring supplementary analyses...

In Silico Analysis of Novel Titin Non-Synonymous Missense Variants Detected by Targeted Next-Generation Sequencing in a Cohort of Romanian Index Patients with Hypertrophic Cardiomyopathy

Article Category: Original Article

Publicado en línea: 05 may 2022

Páginas: 565 - 571

DOI: https://doi.org/10.47803/rjc.2021.31.3.565

Palabras clave
hypertrophic cardiomyopathy, next-generation sequencing, rare genetic variants, analysis, variant prioritization

© 2021 Miruna Mihaela Micheu et al., published by Sciendo

This work is licensed under the Creative Commons Attribution 4.0 International License.

In Silico Analysis of Novel Titin Non-Synonymous Missense Variants Detected by Targeted Next-Generation Sequencing in a Cohort of Romanian Index Patients with Hypertrophic Cardiomyopathy

Article Category: Original Article

Publicado en línea: 05 may 2022

Páginas: 565 - 571

DOI: https://doi.org/10.47803/rjc.2021.31.3.565

Palabras clavehypertrophic cardiomyopathy, next-generation sequencing, rare genetic variants, analysis, variant prioritization

© 2021 Miruna Mihaela Micheu et al., published by Sciendo

This work is licensed under the Creative Commons Attribution 4.0 International License.

Palabras clave
hypertrophic cardiomyopathy, next-generation sequencing, rare genetic variants, analysis, variant prioritization