Association of ultra-rare genetic variants with epilepsy

Abstract

Epilepsy represents a wide spectrum of phenotypes with various etiologies and comorbidities. Genetic predisposition to epilepsy is conferred by rare variants and common risk alleles. Ultra-rare variants (URVs) – those not seen in healthy population controls – are thought to underlie a substantial part of the risk mediated by coding variants. In this dissertation, the role of URVs was studied in several cohorts of individuals with common epilepsy syndromes, aiming to identify new genetic etiologies underlying epileptogenesis. Multiple approaches based on whole exome sequencing were utilized, scaling from studies of single families to populations and from genes to gene sets. First, five closely consanguineous Sudanese families, in which multiple siblings (whose parents are cousins) were diagnosed with a genetic epilepsy, were examined to touch upon the role of rare bi-allelic coding variation in familial epilepsies. There was no evidence to support a key role for recessive inheritance in less severe epilepsies. However, the results expanded the phenotypic spectrum of biallelic ultra-rare PRRT2 variants, previously linked to movement disorders, to include mild self-limited epilepsy. Second, sequencing data from individuals diagnosed with genetic generalized epilepsy (GGE; n = 1,928 cases vs. 8,578 ancestry-matched controls of European descent) were analyzed using gene and gene set collapsing approaches to identify key URV associations. Separate analyses of familial GGE (n = 945 cases vs. 8,626 controls) or sporadic GGE (n = 1,005 cases vs. 8,621 controls) were also performed. URVs in GABRG2 showed an association with familial GGE (approaching study-wide significance) but not with sporadic GGE. Additionally, a higher enrichment of URVs affecting genes encoding GABAA receptors and GABAergic pathway genes was seen in familial vs. sporadic GGE. Third, the burden of URVs in a comprehensive range of gene sets was studied in the exomes of individuals diagnosed with GGE (n = 3,064), non-acquired focal epilepsy (NAFE; n = 3,522) or developmental and epileptic encephalopathy (DEE; n = 1,003), compared to 3,962 ancestry-matched controls. In GGE, the burden of URVs in constrained genic regions – those devoid of variations in the general population – was higher in gene sets important for inhibitory signaling vs. in gene sets representative of excitatory signaling. Conversely, there was a relatively higher burden in excitatory vs. inhibitory gene sets in NAFE. In summary, this dissertation presents novel findings pertaining to the role of ultra-rare coding variation in epileptic disorders, providing new insights into the spectrum of key genes and gene sets related to epileptogenesis.