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Identification of potential disease-associated variants in idiopathic generalized epilepsy using targeted sequencing

Journal of Human Genetics volume 69, pages 59–67 (2024)Cite this article

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Abstract

Many questions remain regarding the genetics of idiopathic generalized epilepsy (IGE), a subset of genetic generalized epilepsy (GGE). We aimed to identify the candidate coding variants of epilepsy panel genes in a cohort of affected individuals, using variant frequency information from a control cohort of the same region. We performed whole-exome sequencing analysis of 121 individuals and 10 affected relatives, focusing on variants of 950 candidate genes associated with epilepsy according to the Genes4Epilepsy curated panel. We identified 168 candidate variants (CVs) in 137 of 950 candidate genes in 88 of 121 affected individuals with IGE, of which 61 were novel variants. Notably, we identified five CVs in known GGE-associated genes (CHD2, GABRA1, RORB, SCN1A, and SCN1B) in five individuals and CVs shared by affected individuals in each of four family cases for other epilepsy candidate genes. The results of this study demonstrate that IGE is a disease with high heterogeneity and provide IGE-associated CVs whose pathogenicity should be proven by future studies, including advanced functional analysis. The low detection rate of CVs in the GGE-associated genes (4.1%) in this study suggests the current incompleteness of the Genes4Epilepsy panel for the diagnosis of IGE in clinical practice.

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Acknowledgements

We would like to thank all the participants involved in this study. We also thank Dr. Kazuyoshi Hosomichi for his help throughout the study.

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Author notes

  1. Takehiro Sato

    Present address: Department of Human Biology and Anatomy, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

  2. Takayuki Kannon

    Present address: Department of Biomedical Data Science, Fujita Health University School of Medicine, Toyoake, Japan

Authors and Affiliations

  1. Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan

    Regina Gamirova, Takehiro Sato, Takayuki Kannon & Atsushi Tajima

  2. Regulatory Genomics Research Cen­ter, Kazan Federal University, Kazan, Russia

    Elena Shagimardanova

  3. Department of Neurology with Courses in Psychiatry, Clinical Psychology and Medical Genetics, Kazan Federal University, Kazan, Russia

    Rimma Gamirova

  4. Laboratory of Neurocognitive Investigations, Kazan Federal University, Kazan, Russia

    Rimma Gamirova

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Contributions

Conceptualization: ReG, AT and RiG. Investigation: RiG, ES and ReG. Formal analysis: ReG, TS and TK. Funding acquisition: AT. Writing – original draft: ReG and AT. Writing – review and editing: ReG, ES, TS, TK, RiG and AT.

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Correspondence to Rimma Gamirova or Atsushi Tajima.

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The authors declare no competing interests.

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This study was approved by the Local Ethics Committee of Kazan Federal University under the title “Genetics of Epilepsy” (10/06/2019) and by the Human Genome/Gene Analysis Research Ethics Committee of Kanazawa University (protocol code:577; 16/06/2020).

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Gamirova, R., Shagimardanova, E., Sato, T. et al. Identification of potential disease-associated variants in idiopathic generalized epilepsy using targeted sequencing. J Hum Genet 69, 59–67 (2024). https://doi.org/10.1038/s10038-023-01208-3

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