Algorithmic assessment reveals functional implications of GABRD gene variants linked to idiopathic generalized epilepsy.
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| Title: | Algorithmic assessment reveals functional implications of GABRD gene variants linked to idiopathic generalized epilepsy. |
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| Authors: | Arslan, Ayla (AUTHOR) |
| Source: | International Journal of Neuroscience. May2025, Vol. 135 Issue 5, p533-543. 11p. |
| Subjects: | Artificial intelligence, Genetic variation, Protein stability, Databases, Internet servers |
| Abstract: | Objective: The primary objective of this study is to address the challenge posed by the increasing number of variants of unknown clinical significance (VUS) within the GABRD gene, which encodes the δ subunit of γ-Aminobutyric acid type A receptors. The focus is on predicting the most pathogenic GABRD VUS to enhance precision medicine and improve our understanding of relevant pathophysiology. Methods: The study employs a combination of in silico algorithms to analyze 82 variants of unknown clinical significance of GABRD gene sourced from the ClinVar database. Initially, separate algorithms based on sequence homology are utilized to assess this variant set. Subsequently, consensus variants predicted as pathogenic undergo further evaluation through a web server employing an algorithm based on structural homology. The resulting 11 variants are then validated using in silico tools that assess variant effects based on genetic and molecular data. The evaluation includes consideration of disease association and protein stability due to amino acid substitutions. Results: The study identifies specific variants (L111R, R114C, D123N, G150S, and L243P) in the coding region of the GABRD gene, which are predicted as deleterious by multiple algorithms. These variants are evolutionarily conserved, mapped onto the extracellular domain of the δ subunit, and associated with idiopathic generalized epilepsy. Conclusions: The findings suggest structural or functional consequences that lead to pathogenicity, offering valuable insights for wet-lab experimentation. Besides, the findings contribute to the validation of clinically significant genetic variants in the GABRD gene, which is critical for epilepsy precision medicine. [ABSTRACT FROM AUTHOR] |
| Copyright of International Journal of Neuroscience is the property of Taylor & Francis Ltd and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Objective: The primary objective of this study is to address the challenge posed by the increasing number of variants of unknown clinical significance (VUS) within the GABRD gene, which encodes the δ subunit of γ-Aminobutyric acid type A receptors. The focus is on predicting the most pathogenic GABRD VUS to enhance precision medicine and improve our understanding of relevant pathophysiology. Methods: The study employs a combination of in silico algorithms to analyze 82 variants of unknown clinical significance of GABRD gene sourced from the ClinVar database. Initially, separate algorithms based on sequence homology are utilized to assess this variant set. Subsequently, consensus variants predicted as pathogenic undergo further evaluation through a web server employing an algorithm based on structural homology. The resulting 11 variants are then validated using in silico tools that assess variant effects based on genetic and molecular data. The evaluation includes consideration of disease association and protein stability due to amino acid substitutions. Results: The study identifies specific variants (L111R, R114C, D123N, G150S, and L243P) in the coding region of the GABRD gene, which are predicted as deleterious by multiple algorithms. These variants are evolutionarily conserved, mapped onto the extracellular domain of the δ subunit, and associated with idiopathic generalized epilepsy. Conclusions: The findings suggest structural or functional consequences that lead to pathogenicity, offering valuable insights for wet-lab experimentation. Besides, the findings contribute to the validation of clinically significant genetic variants in the GABRD gene, which is critical for epilepsy precision medicine. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00207454 |
| DOI: | 10.1080/00207454.2024.2312987 |
