Algorithmic assessment reveals functional implications of GABRD gene variants linked to idiopathic generalized epilepsy

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.

Keywords:

• Variants of uncertain significance
• GABRD
• GABA (A) receptor
• epilepsy
• extrasynaptic

Acknowledgment

The author would like to express gratitude for the time and effort invested by the anonymos Reviewers in evaluating the work and providing constructive feedback.

Disclosure statement

The author declares no conclict of interest.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Notes

1 https://www.ncbi.nlm.nih.gov/gene/2563

2 https://ncbiinsights.ncbi.nlm.nih.gov/2017/05/09/phasing-out-support-for-non-human-genome-org-anism-data-in-dbsnp-and-dbvar/.

3 https://www.ncbi.nlm.nih.gov/snp/.

4 https://www.ncbi.nlm.nih.gov/snp/?term=rs757310515

5 https://www.ncbi.nlm.nih.gov/projects/sviewer/?id=XP_011539496.1&search=XP_011539496.1:p.Arg69Gln&v=1:100&content=5

6 https://www.ncbi.nlm.nih.gov/projects/sviewer/?id=XP_016856425.1&search=XP_016856425.1:p.Arg291Gln&v=1:100&content=5

7 https://www.ncbi.nlm.nih.gov/projects/sviewer/?id=XP_016856425.1&search=XP_016856425.1:p.Arg291Gln&v=1:100&content=5

8 https://www.ncbi.nlm.nih.gov/projects/sviewer/?id=XP_016856425.1&search=XP_016856425.1:p.Arg291Gln&v=1:100&content=5

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.