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The Complex Etiology of Epilepsy: Genetic Analysis and HLA Association in Patients in the Middle East

Abeer Fadda,Mohamed Alsabbagh,Dhanya Vasudeva,Amira Saeed,Sara Aglan Tarek,Satanay Z Hubrack,Ruba Benini,Khaled Zamel,Bernice Lo

Published 2025 in International Journal of Molecular Sciences

ABSTRACT

Epilepsy is one of the most common neurological disorders. Disease etiology and pathogenesis are still not well understood. Genetic mutations are associated with 70% of epilepsies, while 30% are still enigmatic. Attempting to close the knowledge gap, we performed genetic analysis of a cohort of patients from the Middle East and North Africa, both understudied and highly consanguineous populations. Whole exome sequencing (WES) was carried out on 81 patients and their family members at a tertiary center in Qatar. We found damaging mutations in half of the patients: 15 in known epilepsy genes, and 19 in contested or unknown genes. The mutations include single nucleotide polymorphisms (SNVs), frameshifts, copy number variations (CNVs), and loss of homozygosity (LOH). Fifteen of the SNVs are novel, and seventeen are homozygous, reflective of the characteristics of the cohort. In addition, we used the WES data to type HLA alleles for 13 class I and II genes. We show that DRB3*01:01:02G is negatively associated with epilepsy, in contrast to DRB4*01:01:01G, which may be a risk allele. In addition to expanding the knowledge base of genes involved in epilepsy, our findings show that genetic predisposition, inclusive of immune genes, suggests a complex etiology.

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