The aim. To evaluate diagnostic efficiency and clinical utility of exome sequencing in patients with epilepsy or seizures in clinical practice.
Methods. Diagnostic exome sequencing including evaluation of mitochondrial DNA variants and copy number variation was applied to 87 patients with epilepsy or seizures during a period of 30 months. Two-stage exome data filtration, analysis and interpretation was performed: the first stage included filtration with a comprehensive gene panel that was comprised of 862 genes associated with monogenic diseases involving epilepsy or seizures based on EpiGene database. The second stage included analysis of non-filtrated exome variants.
Results. 47 pathogenic, likely-pathogenic and variants of unknown clinical significance were identified. In 43 patients, genetic diagnosis was confirmed with a diagnostic efficiency of 49%. Three novel genes were associated with monogenic epilepsies (SOX5, SCN3A and UBA5). Eleven patients were diagnosed with inborn errors of metabolism (11/47, 23%). Majority of diagnosed diseases were just recently described or ultra-rare. The phenotypes of patients included a vast diversity of symptoms and many patients presented with non-specific, overlapping symptoms or incomplete range of phenotypic features, mostly due to young age. Clinical utility of diagnostic exome sequencing was especially high in patients with diseases that have specific treatments (12/47, 26% of patients with established diagnosis, 11/87, 13% of all patients).
Conclusions. By applying a comprehensive diagnostic exome sequencing method that takes into account genetic and clinical heterogeneity of monogenic diseases involving epilepsy or seizures and various types of molecular pathology, and a two-stage exome data analysis including filtration with a comprehensive gene panel, a high diagnostic efficiency was achieved and novel monogenic epilepsy-associated genes were identified.
