Abstract

A genetic etiology is determined in more than 30% of all diagnosed cases of epilepsy with onset at the pediatric age. About 210 single disease-causing genes and 400 chromosomal imbalances are associated with epilepsy, and a presumed pathogenic role has been suggested for about 7000 different genes. Genetic epilepsies can be divided, according to the main correlated epileptogenic mechanisms, into the following groups: a) channelopathies, b) transportopathies, c) disorders of the intermediate metabolism, d) disorders of the neuronal cellular cycle and signaling, e) disorders of synaptic vesicles trafficking and release, f) disorders involving neuronal structural proteins, g) disorders of synaptic secreted proteins and h) chromosomopathies and pathogenic copy number variants. A careful diagnostic work-up should be focused on the exclusion of acquired causes of seizures, the analysis of family history, the definition of seizure semiology and epileptic syndromes, and the characterization of associated neurological and non-neurological manifestations. Traditional genetic techniques (karyotype, array CGH, and Sanger sequencing) remain useful for known epilepsy phenotypes (e.g. Dravet syndrome) and for various syndromes including neurodevelopmental impairment. Next-generation sequencing (NGS) includes different techniques (targeted gene panels and whole genome sequencing) that allow a simultaneous sequencing of exons belonging to a selected group of genes organized in panels or to the whole exome or genome. Advantages of NGS include: a) the identification of new disease-causing genes associated with epilepsy, b) an expansion of the known phenotypes associated with previously discovered disease-causing genes, c) an improvement of genetic counseling, d) a reduction of the times for the diagnosis, and e) a reduction of economic costs.