Expansion of the Epilepsy Genotype-Phenotype Spectrum: Genetic and Clinical Characterization of 288 Children with Epilepsy in China.

Background: In recent years, advancements in sequencing technology have led to a progressive increase in the proportion of epilepsy cases with genetic etiology, while simultaneously facilitating the ongoing identification of epilepsy-associated genes. To summarize the genotype-phenotype association of epilepsy patients is of great significance for the interpretation of genetic reports, clinical diagnosis and treatment and genetic counseling.

Methods: We reviewed and analyzed the trio-WES/WES results of 886 patients with unexplained epilepsy. Ultimately, 288 epilepsy patients were included in this study. The clinical phenotype, treatment and genotype of the patients were analyzed. The single nucleotide variations in all samples were explained.

Results: Of the original 886 patients with epilepsy with no identified cause, 288 patients were shown to have a genetic abnormality, yielding a WES diagnostic rate of 32.5%. The patients with onset before 2 years of age were more likely to have accompanying developmental delay (p=0.001). A total of 312 pathogenic/likely pathogenic variants involving 125 genes were detected. The most common genes affected were primarily SCN1A. After the pathogenic gene was identified, at least 16.7% more patients were able to use recommended medications. Patients with ion channel gene-related disorders had a significantly higher rate of receiving recommended medications. The CHRNA4, ATP1A2, SPTAN1, KCNMA1, and SCN9A, currently lack reports of incomplete penetrance related to epilepsy and our study suggests the potential for incomplete penetrance in these genes.

Conclusion: This study summarized the clinical characteristics and genetic background of children with epilepsy, expanded the genotype-phenotype spectrum, and provided reference for genetic counseling and clinical diagnosis and treatment.