Genetic epilepsy and role of mutation variants in 27 epileptic children: results from a “single tertiary centre” and literature review
Authors: Pavone Piero , Avola Ottavia , Oliva Claudia , Di Nora Alessandra , Timpanaro Tiziana , Nannola Chiara , Greco Filippo , Falsaperla Raffaele , Polizzi Agata 
Published: September 2024

<sec><title>Aim and scope</title><p>The wide use of next-generation sequencing has allowed professionals to reach relevant progress in the medical field including diagnoses, prognoses, and genetic counselling and to help in recognizing the pathogenic mechanisms which underlie several epileptic disorders. Genetic epilepsy refers to a disorder in which genetic mutations are recognized as the primary cause of epileptic seizures in the patients. Various types of epilepsy have been highlighted alongside a clear etiologic relationship with genetic mutations; however, for a select number of patients, some doubts remain on the role played by the variant mutations, as well as the adverse pathologic events which may interfere with the clinical manifestations. In this study, twenty-seven children affected by epileptic seizures are reported, with the aim to describe the clinical and neurological involvement presented by the children according to the genes and variant mutations, and to compare the neurological signs observed in these children with those reported in children with similar genetic mutations. Additionally, the roles played by single or associated variants on the clinical expression of the affected children are discussed.</p></sec><sec><title>Material and methods</title><p>A retrospective observational study was conducted on the gene mutations observed in 27 children affected by a clinical history and diagnosis of epilepsy, alongside an electroencephalographic analysis performed with the Pediatric Department of the University-Hospital S. Marco during the years ranging from January 2020 to January 2022. A genetic analysis was performed using an array comparative genomic hybridization (array CGH), a gene panel for epilepsy, Whole Exome Sequencing (WES), and a single nucleotide polymorphism (SNP) array.</p></sec><sec><title>Results</title><p>Nineteen children showed a single nucleotide variant, eight children carried two or more gene mutations in different genes, and one child was not reported. In this study, we identified a total of thirty-six gene mutations, where seventeen were de novo mutations, and twenty-two had either a maternal or paternal inheritance. The genes in which one or more allelic variants were found included <italic>GRIN2A</italic>, <italic>GABRA1</italic>, <italic>SCN2A1</italic>, <italic>KCNT1</italic>, <italic>PCDH19</italic>, <italic>SCN8A</italic>, <italic>KCNK4</italic>, <italic>SLC2A1</italic>, <italic>DNM1</italic>, <italic>ARID1B</italic>, <italic>WWOX</italic>, <italic>GABRG2</italic>, and others.</p></sec><sec><title>Conclusions</title><p>Genetic analyses are recognized to have a central role in the diagnostic process of children with epileptic seizures, alongside their family history, and clinical, neuroradiologic, and neurophysiologic examinations. The gene mutation anomalies reported in this study may be useful to be included in the wide field of factors related to epileptic seizures in children. The roles played by single or associated variant mutations in the clinical expression of the affected epileptic children remain difficult to be defined. Moreover, other factors such as pre-, peri-, and post-natal adverse events may negatively interfere with the severity of the clinical manifestations.</p></sec>