Anđelković M1*, Klaassen K1, Skakić A1, Marjanovic I1, Kravljanac R2,3, Đorđević M2,3, Vučetić Tadić B2,3, Kecman B2, Pavlović S1, Stojiljković M1
1 Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Serbia;
2 Mother and Child Healthcare Institute „dr Vukan Cupic“, School of Medicine, University of Belgrade, Serbia;
3 Faculty of Medicine, University of Belgrade, Belgrade, Serbia
marina.andjelkovic [at] imgge.bg.ac.rs
Abstract
Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled identification of disease-causing genes and variants in epilepsies.
In our study, 55 children with epilepsy of unknown etiology were analyzed combining clinical-exome (CES) and whole-exome sequencing (WES). Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction.
Molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in 5 unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes: ASH1L, CSNK2B RHOBTB2 and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, identification of variants in ALDH7A1, KCNQ2, PNPO, SCN1A and SCN2A gene directed therapy decision of 11 children from our study, including four children who all carry novel SCN1A genetic variants.
Our study emphasizes the importance of NGS in diagnosing childhood epilepsy. With an increasing number of genes associated with epilepsy, comprehensive analysis using CES and WES is crucial for high diagnostic success. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target.
Keywords: childhood epilepsy, monogenic disease, CES, WES, novel genetic variants
Acknowledgement: This work was supported by Ministry of Science, Technological Development and Innovations Republic of Serbia [Number: 451-03-47/2023-01/ 200042].