Epilepsy is a chronic neurological disorder characterized by an increased predisposition for epileptic seizures (Annegers et al., 1982; Bromfield et al., 2006). It is one of the most common neurological disorders affecting approximately 0.6–0.8% of the general population (Forsgren et al., 2005) resulting in about 50–100 million affected, and 2–4 million new cases diagnosed each year worldwide (Pitkänen et al., 2016). Genetic abnormalities reportedly cause or influence more than 70% of epileptic conditions (Dunn et al., 2018). In the last decade, a growing list of autoimmune diseases has also been implicated in the etiology of epileptic seizures with accumulating evidence to support the role of autoimmune-mediated factors in patients with refractory seizures (Fang et al., 2017). Even after a thorough diagnostic evaluation, a large proportion of patients have epilepsy of an unknown etiology(Berg et al., 1999; Sillanpää, 2000). However, 4–78% of selected patients with initially unknown etiology have genetic variants of probable or definitive etiologic significance (Sánchez Fernández et al., 2019).
The discovery of epilepsy genes came initially through delineation of mutations present in several affected individuals. To this date, there are approximately 165 epilepsy genes in the OMIM, 425 validated genes in the Genomics England panel, about 300 in commercial testing panels (Invitae for example), and as many as 977 in some reports (Sharma et al., 2020). The heterogeneity of the phenotype and pleiotropism of the affected genes make it difficult to define a distinct set of epilepsy genes. Consequently, different inheritance models are proposed to explain the heritability of epilepsy, from full-penetrant monogenic to additive polygenic, where every gene involved acts as a risk factor. Several big initiatives were launched to discover and assess the contribution of genes in epileptogenesis, such as Epi4K, now unified with other consortia to form the Epi25K consortium, the Epilepsy Phenome/Genome Project, Epicure, EuroEPINOMICS, CoGIE, EpiPGX and ILAE Consortium. With thousands of samples, these consortia were able to use non-Mendelian analysis methods: GWAS, genetic burden, or risk scores, enabling the discovery of more risk genes.
Epilepsy classification has been fraught with complexity and often controversy since its inception in 1969 by the ILAE. The latest classification in 2017 uses 5 dimensions: seizure type, epilepsy type, etiology and comorbidity (Rosenow et al., 2020), thereby enabling enhanced precision of diagnosis as well as classification at multiple levels (Sharma et al., 2020). However, this advancement did not come without a price; straightforward comparison of genetic studies using different classification schemas became complicated, adding yet another hurdle to epilepsy genetic research.
In addition to genetic etiology, the immune system is a well-established but not fully understood player. Autoimmune epilepsies are classified as a distinct group in the latest ILAE classification. Evidence for neuroinflammation as a trigger to epileptogenesis, but also as a response to epileptic activity, has been reported (Langenbruch et al., 2020; Leal et al., 2017; Owens et al., 2019; Vezzani et al., 2011), and associations with specific mutations in immune genes, including HLA, have been found (Benedek et al., 2020; Chaves et al., 2020). The difficulty of obtaining brain tissue limits our understanding of the extent of the immune system’s involvement in the different types of epilepsies.
To bridge some of the knowledge gaps in the etiology of epilepsy, we turned to a cohort from the MENA region. Patients from this region are generally under-represented in epilepsy studies but are also progenies of higher consanguinity marriages, creating a high potential for novel genetic discoveries. We examined the genetics of a cohort of 67 pediatric epilepsy patients and their families looking for potential disease-linked mutations in the exonic regions of genes, including 13 HLA genes. We have a genetic yield close to 22% for known epilepsy genes, and we put forward a candidate list of 20 genes. We show that genes linked to focal or generalized epilepsies are biologically connected, suggesting common pathways of pathogenesis for the two types. Our HLA analysis reveals that class II HLA genes may influence the disease status, in particular DRB4*03:01N, a null allele, plays a strong protective role. The presence of HLA risk alleles in subjects with clear genetic etiology suggests that the lines between genetic and immune epilepsies may be less defined than previously thought.