Genomic factors in epilepsy etiological structure and diagnostics

Knowledge of genetic epilepsy structure is crucial in clinical practice for proper choice of genetic testing methods and algorithms, and in science for determination of functions and molecular pathways of epilepsy-associated genes, study of ictogenesis/ epileptogenesis mechanisms, and eventually, search for novel treatments of epilepsy. We comprised the most extensive to our knowledge database of genes and monogenic disorders associated with epilepsy or seizures, EpiGene (version 3.0, 985 genes), performed characterization of these genes, analysis of genetic/ clinical structure and diagnostic possibilities of these diseases, constructed a list of 97 diseases that have specific treatments. Next, we created additional tools for genomic diagnostics and identification of candidate genes, including virtual gene panel for next-generation sequencing, genomaps of epilepsy- or seizure-associated genes and a composite gene functional variation intolerance score - Tscore. These tools were applied to genomic testing of 309 patients with epilepsy or seizures. Application of a comprehensive diagnostic exome sequencing method and virtual gene panel to testing of 87 patients allowed us to achieve a high diagnostic yield (49%) and to identify novel candidate genes for monogenic epilepsies. Composite functional variation intolerance score Tscore was more sensitive in the identification of known AD and X-linked epilepsy genes and in the differentiation between AD and AR genes. Application of Tscore for the analysis of copy number variation identified in 222 patients allowed us to comprise a list of candidate genes for the observed phenotypes