Genotype-phenotype analysis of pathogenic copy number variations in pediatric epilepsy

To summarize the genotype-phenotype characteristics of pediatric epilepsy with pathogenic copy number variations (CNVs) and explore the potential pathogenic mechanisms of the CNVs, we recruited a cohort of 418 epilepsy patients (age: 0-18 years) from the Children's Hospital of Chongqing Medical University between June 2016 to June 2024. Patients were evaluated using CNV sequencing (CNV-seq). Functional enrichment for dosage-sensitive genes in the CNVs were performed using ClusterProfiler. Protein-protein interaction (PPI) networks for the proteins encoded by these genes were analyzed using the STRING database. We identified 40 patients carrying at least one pathogenic CNVs [detection rate: 9.57 % (40/418)]. A total of 39 microdeletions and five microduplications were identified, ranging in size from 0.11 Mb to 45.53 Mb. The 16p11.2 microdeletion was the most frequently detected (16/418). Thirty patients presented with comorbidities, including 11 with congenital heart disease and 9 exhibiting distinctive facial dysmorphism. Dosage-sensitive genes were significantly enriched in forebrain development, telencephalon development, and the neuronal cell body. Proteins encoded by these dosage-sensitive genes exhibited extensive interaction networks. In conclusion,CNVs are an important cause of pediatric epilepsy and involve dosage-sensitive genes that may cause disease by affecting cortical development and the neuronal cell body. There is a higher probability of identifying a pathogenic CNV when epilepsy is co-morbid with intellectual disability or other systemic diseases.