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

Abstract Objectives 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 variants have been shown to be associated with 70% of epilepsies, 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. Methods Whole exome sequencing was carried out in 67 patients and their family members at a tertiary center in Qatar. The focus was on identifying deleterious genetic variants associated with epilepsy. Additionally, we performed in silico typing for 13 class I & II HLA genes and performed association analysis with disease status. Results Approximately 30% of cases were resolved through genetic analysis, revealing deleterious variants within 15 genes of established relevance to epilepsy and 5 others with weaker ties to the condition. These variants include single nucleotide variations (SNVs), small insertion/deletions (indels), copy number variations (CNVs) and loss of heterozygosity (LOH). Around 40% of the SNVs and indels are novel. The mode of inheritance is roughly evenly distributed between autosomal dominant and autosomal recessive, with two cases of X-linked recessive and one case of X-linked inheritance. Furthermore, we identified positive associations between epilepsy and alleles DRB1*07:01:01G and DRB4*01:01:01G , while allele DRB3*01:01:02G exhibited a negative association. Significance Collectively, these findings delineate novel variants and a multifaceted genetic etiology in epilepsy pathogenesis, encompassing both immune and non-immune genes.