The complex etiology of Epilepsy: Genetic analysis and HLA association in patients in the Middle East

Abstract Epilepsy is one of the most common neurological disorders. The cost to the health system and the impact on quality of life for patients with intractable epilepsies and associated comorbidities is significant. Disease etiology and pathogenesis are still not well understood. Genetic mutations have been shown to be associated with 70% of epilepsies, with the majority being non-monogenic, and the remaining 30% enigmatic. This knowledge gap necessitates further research. The goal of this study is to partially bridge this gap through the genetic analysis of a cohort of patients with epilepsy from an understudied and highly consanguineous population, primarily of ethnicities from the Middle East and North Africa region. Whole exome sequencing was carried out in 81 patients with epilepsy and their family members at a tertiary center in Qatar. We used the data to identify pathogenic variants and type HLA alleles for 13 class I & II genes. We associated the resulting alleles with disease status, using controls of a closely related ethnicity. The genetic yield was approximately 22% for known epilepsy genes. We also suggest a list of 20 genes that could be culprits. Analysis of the biological pathways in which these genes are involved show that focal and generalized epilepsy genes are highly interwound. HLA analysis revealed that class II HLA genes are associated with disease status, particularly DRB4*03:01N, which plays a strong protective role. Our findings suggest that an immune etiology may contribute to the disease together with a genetic culprit, emphasizing the complexity of the etiology of the disease.