Abstract
IntroductionIdiopathic focal epilepsy (IFE) is a group of self-limited epilepsies. The etiology for the majority of the patients with IFE remains elusive. We thus screened disease-causing variants in the patients with IFE.MethodsWhole-exome sequencing was performed in a cohort of 323 patients with IFE. Protein modeling was performed to predict the effects of missense variants. The genotype–phenotype correlation of the newly defined causative gene was analyzed.ResultsFour novel heterozygous variants in PGM3, including two de novo variants, were identified in four unrelated individuals with IFE. The variants included one truncating variant (c.1432C > T/p.Q478X) and three missense variants (c.478C > T/p.P160S, c.1239C > G/p.N413K, and c.1659T > A/p.N553K), which had no allele frequency in the gnomAD database. The missense variants were predicted to be damaging and affect hydrogen bonds with surrounding amino acids. Mutations Q478X, P160S, and N413K were associated with benign childhood epilepsy with centrotemporal electroencephalograph (EEG) spikes. P160S and N413K were located in the inner side of the enzyme active center. Mutation N553K was associated with benign occipital epilepsy with incomplete penetrance, located in the C-terminal of Domain 4. Further analysis demonstrated that previously reported biallelic PGM3 mutations were associated with severe immunodeficiency and/or congenital disorder of glycosylation, commonly accompanied by neurodevelopmental abnormalities, while monoallelic mutations were associated with milder symptoms like IFE.ConclusionThe genetic and molecular evidence from the present study implies that the PGM3 variants identified in IFE patients lead to defects of the PGM3 gene, suggesting that the PGM3 gene is potentially associated with epilepsy. The genotype–phenotype relationship of PGM3 mutations suggested a quantitative correlation between genetic impairment and phenotypic severity, which helps explain the mild symptoms and incomplete penetrance in individuals with IFE.
Highlights
Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies
Eligible subjects had a clinical diagnosis of IFE according to the International League Against Epilepsy (ILAE-1989, 2006, and 2017) (Commission on Classification and Terminology of the International League Against Epilepsy, 1989; Engel, 2006; Scheffer et al, 2017) after appropriate investigations, including long-term video electroencephalography (VEEG), brain MRI, cognitive and behavioral evaluation, and neurometabolic testing
The amino acid sequence alignment showed that residues P160 and N413 were highly conserved across vertebrates
Summary
Idiopathic focal epilepsy (IFE) is a group of self-limited epilepsies. The etiology for the majority of the patients with IFE remains elusive. Idiopathic focal epilepsy (IFE), named as localizationrelated idiopathic epilepsy (G40.0 in ICD-10 2016, WHO), is a common group of self-limited childhood-onset epilepsies. It contains two major subtypes, i.e., benign childhood epilepsy with centrotemporal electroencephalograph (EEG) spikes (BECTS, OMIM# 117100) and benign occipital epilepsy (BOE, OMIM# 132090). BECTS is affecting 0.2% of the population (Strug et al, 2009), while the prevalence of BOE is unknown but is considered to affect around 6% of children aged 1–15 years (Weir et al, 2018) Both BECTS and BOE are generally regarded as autosomal dominant inheritance with age-dependent penetrance, rare causative genes are identified in the patients. The etiology for majority of patients with IFE remains unknown
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