Epilepsy is a complex neurological disease that involves a huge genetic component that is not fully understood. This study provides a current list of all genes that have some association with epilepsy by grouping each gene on their specific association level. This study identified a total of 2,536 genes that have some level of association with epilepsy compared to a study by Zheng MW, et al. [1] who identified a total of 1506 genes to be associated with epilepsy back in 2023 (published in 2024). This study provides mode/s of inheritance details for each gene, phenotypic details of each gene (Supplementary Table S1) and an overall classification. With this information, researchers are able to gain an insight on an up-to-date catalogue of epilepsy associated genes in which to base their future studies on. Recognition of the genes associated with epilepsy will benefit future screening strategies and aid in the discovery of the precise clinical molecular diagnosis and how we manage epilepsy.

Neurological diseases are inherently complex due to the intricate anatomy and function of the nervous system, the presence of multiple causal and contributing factors, diverse symptoms and diagnostic challenges. Many of these diseases are heritable, meaning that genetic factors play a large role in their development, expression and progression. Epilepsy is the second most prevalent chronic neurological disease with thousands of associated genes contributing to its diverse clinical manifestations, with new genetic links to different types of epilepsy uncovered every year [2]. Advances in next-generation sequencing technologies and bioinformatics have accelerated the discovery of new epilepsy associated genes and our understanding of the disease. Many papers have previously analysed the total number of genes that are associated with epilepsy. In 2017, Wang et al. [3] identified 977 genes that were associated with epilepsy based on clinical-genetic evidence. In 2024, Zhang MW, et al. [1] almost doubled this number identifying 1506 genes that were associated with epilepsy based on the same clinical-genetic evidence. Over the past several years a significant number of epilepsy associated genes has been identified. Many novel genes have been introduced and many are no longer considered to be associated with epilepsy. With an ever changing and evolving list of epilepsy associated genes, studies need to be continuously updated to aid epilepsy research. Many previous papers have focussed on providing a list of genes that can be potentially useful in clinical genetic diagnosis and precise treatment of epilepsy. To update the current list of epilepsy associated genes we utilised three major databases, this includes the Online Mendelian Inheritance in Man (OMIM) database, PubMed and ClinGen. The purpose of this study is to group together all genes potentially associated with epilepsy to specifically aid genetics research in the field of epilepsy.

To update the list of genes associated with epilepsy, a systematic study was conducted based on data from several online databases until November 2025. After obtaining and filtering through the list of genes identified from the OMIM, ClinGen and PubMed database, genes were grouped into three categories: “Epilepsy genes” (Table 1), “Epilepsy associated genes” (Table 2) or “Predicted epilepsy associated genes” (Table 3) based on independent criteria for each database. Requirements for each category can be found in Supplementary Table S1. A table was produced for each category showcasing the current list of genes associated with epilepsy as well as the mode of inheritance and phenotype. Another table (Table 4) was created to summarise all epilepsy genes that were identified in all databases that includes each genes phenotype/s and mode/s of inheritance. The phenotypes found in Table 4 were database derived and formatted and confirmed manually.

Genes were first searched in the OMIM database ¹ using the following terms: epilepsy, epilepsies, epileptic, convulsion, convulsions, seizure, seizures. The OMIM database utilises a phenotype map key to further characterise each gene. We took advantage of this key to categorise genes into their respective categories. The phenotype map key is comprised of four types, this includes [2] there is a gene-disease relationship, however the underlying genetic defect is unknown according to the University of California Santa Cruz (UCSC) genome browser [3]; the gene has been included through linkage analysis (mapping studies), however a specific gene mutation has yet to be identified [1]; the molecular basis of the disorder is known and a mutation has been identified [4]; the disorder is a contiguous gene deletion or duplication syndrome (multiple genes are deleted or duplicated) according to the UCSC genome browser. Genes from the OMIM database were categorised as “Epilepsy genes” if they had a phenotype map key of 1 and the phenotype included at least one of the key words that was originally searched. Genes were categorised as “Epilepsy associated genes” if the phenotype map key was 1,3 and/or 4 and the phenotype did not include one of the epilepsy key words. Finally, genes were grouped into the “Predicted epilepsy associated genes” category if the phenotype map key was 2 or blank and the phenotype did not include one of the epilepsy key words.

ClinGen ² was the second database utilised where we included all genes in the gene-disease validity section. Genes were grouped into the three categories based on their classification and phenotype. Classifications included disputed, limited, moderate and definitive. Genes were immediately excluded if their classification was disputed. Only genes with one of the epilepsy key words as previously mentioned were included. Genes were added to the current “Epilepsy genes” list if they were classified as definitive, genes were added to “Epilepsy associated genes” if they were classified as moderate and genes were added to “Predicted epilepsy associated genes if they were classified as limited.

The final database utilised was PubMed ³ where we followed a similar procedure as the OMIM database. Genes were added to the list based on if the key words were included in its respective phenotype. Only genes found in homo sapiens were recorded for this study. Genes that did not included one or more of the epilepsy key words were assigned to the Epilepsy associated genes group. We understand that the PubMed database is a literature database rather than a curated gene-disease resource. To resolve this, genes found only within the PubMed database, the highest level of classification they received was “Epilepsy associated genes.” Priority was given to the other databases OMIM and ClinGen as they are curated gene-disease resources. To resolve conflicting classifications across the three databases, a predefined hierarchical evidence framework was applied. Gene categories were ranking according to confidence level where the highest confidence classification was “Epilepsy genes” and the lowest was “Predicted epilepsy associated genes”. When a gene was assigned to multiple categories across different databases, the highest confidence classification was retained as the final group. This approach ensured consistent prioritisation based on evidence strength rather than source frequency.

The present study filtered through a list of 3686 epilepsy-associated genes from OMIM, 1977 epilepsy-associated genes from PubMed and 3334 genes from ClinGen and grouped the genes according to their potential associated with epilepsy and the mode of inheritance. These genes included 238 epilepsy genes, 1317 epilepsy associated genes, and 981 predicted epilepsy associated genes, which were recruited from OMIM, and genes were added from ClinGen and PubMed accordingly. The distribution of these genes between the databases is illustrated in Figure 1A and the distribution of the modes of inheritance is illustrated in Figure 1B. Therefore, based on the criteria of this study, a total of 2536 genes currently have some association with epilepsy.

The aim of the present study was to provide a list of the current genes that are or have a predicted association with epilepsy. Previously, a study by Zhang MW, et al. [1] identified 1440 epilepsy associated genes based on OMIM, PubMed and the human genome mutation database (HGMD). The epilepsy keywords that were searched within each database remain the same between this study and the one performed by Zhang MW, et al. The current study identified a list of 2,536 epilepsy associated genes based on experimental and clinical evidence as provided by the three databases: OMIM, ClinGen and PubMed. This was done by evaluating gene-disease associations that involved multiple aspects of evidence and characteristics. The wide acceptance of genes from these three databases allowed for the incorporation of more potentially disease-associated genes, giving researchers a broader catalogue of genes to study. To aid in this endeavour, genes were categorised into three categories based on the level of currently known association to epilepsy.

This study identified 238 genes (Table 1) that are classified as epilepsy genes, which is more than that of Zhang MW, et al. [1] who classified 168 genes as epilepsy genes. It is important to note that the comparison of results made between this study and the study by Zhang MW, et al. [1] used different parameters and databases. Most of the epilepsy genes identified in this study had a phenotype of encephalopathy (43.7%) which is to be expected when looking at a list of genes with the strongest link to epilepsy.

This study identified 1317 genes (Table 2) that are classified as epilepsy associated genes, which is more than that of Zhang MW, et al. [1] who classified 364 neurodevelopment-associated epilepsy genes. Most of these genes had a phenotype of mitochondrial dysfunction (8.9%) and neurodevelopmental dysfunction (6.8%). This category produced the largest list of genes which also produced the largest variation in phenotypes. This explains the lower distribution percentages of each phenotype listed.

This study identified 981 genes (Table 3) that are classified as predicted epilepsy associated genes, which is more than that of Zhang MW, et al. [1] who classified 974 genes as epilepsy-related genes. Most of these genes had an unknown phenotype (16.6%) but were still classified into potential epilepsy associated genes by the databases looked at in this study.

Finally, we provided a list of 86 genes (Table 4) that are categorised as epilepsy genes and were identified in all databases. Summarised phenotypes have been included for each of these genes. Some of the least published genes from this list include FRRS1L, NECAP1, NSRP1, QARS1 and VARS1. The ferric chelate reductase 1 like protein (FRRS1L) is a protein coding gene that encodes an important receptor protein in the brain and modulates glutamate signalling. Loss of the FRRS1L gene has shown to disrupt synaptic AMPA receptor function resulting in neurodevelopmental, motor and cognitive abnormalities [5]. Variants in this gene have caused epileptic encephalopathy with hyperkinetic movements [6] and epileptic-dyskinetic encephalopathy [7]. NECAP endocyctosis associated 1 (NECAP1) is a coding gene that produces a protein that localises to clathrin-coated vesicles, where it binds components of the adapter protein complexes and aids in endocytosis. This gene has been linked to early onset epileptic encephalopathy through next-generation sequencing [8]. However, the genetic aetiology of NECAP1 remains to be fully understood. NSRP1 is involved in developmental process and regulation of alternative mRNA splicing, via spliceosome. This gene has been associated with breast cancer [9], spastic cerebral palsy and epilepsy [10]. These papers are both recent and introductory into the investigation of connecting this gene to an association with a disease phenotype. QARS1 is involved with dendritic and axonal development. This gene has been associated with epileptic encephalopathy [11, 12] and breast cancer [13]. Finally, VARS1 shares similar functions with QARS1 in which they both encode tRNA synthetases but effect different tRNA functions. VARS1 has been associated with improving melanoma immunotherapy efficacy [14], hepatocellular carcinoma [15] and neurodevelopment disorder [16].

This study has several limitations that should be taken into consideration. To generate this list, all genes were included from all three databases whether they showed a direct link to epilepsy or not. Such genes, for example, that did not have an established phenotype were grouped into the predicted epilepsy associated genes category. These genes have been underlined within Table 3 and makeup approximately 16% of the genes in the Predicted associated epilepsy gene category. Comparisons were made throughout the paper with a previous paper by Zheng MW, et al. [1] and it should be noted that our paper used different parameters and databases to this paper. This comparison is to show a general trend of how our understanding of epilepsy associated genes are progressing. Finally, it should be noted that there may be potential biases in such data produced from all three databases.

In conclusion, the present study updates the list of epilepsy associated genes based on currently available genetic databases, to provide a catalogue of genetic information in the hopes to better understand the aetiology of epilepsy and possibly other neurodevelopmental diseases. This list showcases a range of inheritance modes and phenotypes of the most common genes to aid in this endeavour.