Transforming refractory epilepsy management: Trio-WES for enhanced genetic diagnosis and prognosis in children

To investigate genetic factors in pediatric refractory epilepsy using trio-whole exome sequencing (trio-WES) and to evaluate the impact of genetic diagnosis on treatment optimization.

Participants diagnosed with refractory epilepsy were recruited between September 2021 and June 2024. Clinical phenotypes were systematically assessed, and trio-WES was performed to facilitate precision medicine approaches.

Pathogenic (P) or likely pathogenic (LP) variants were identified in 42.9% (36/84) of participants. Single-nucleotide variants (SNVs) accounted for a diagnostic yield of 36.9% (31/84), and copy number variations (CNVs) for 7.1% (6/84), with one participant (1.2%, 1/84) harbored both variant types. Key clinical features in the cohort included infantile seizure onset (42.9%), developmental delay (70.2%), facial dysmorphisms (10.7%), and hypotonia (38.1%). Genetic diagnostic yields differed significantly based on age of seizure onset and neurodevelopmental status. A total of 33 P/LP SNVs were identified across 22 genes, among which 27.3% (9/33) were occurred in ion channel genes. Following genetic diagnosis, 19.0% of participants showed a favorable response to targeted therapies, accompanied by a significant reduction in annual medical expenditures for these participants.

Trio-WES is a valuable diagnostic tool for refractory epilepsy, achieving a diagnostic yield of 42.9%. Our findings support the clinical utility of genetic testing in enabling precise diagnosis, guiding therapy selection, improving outcomes, and reducing healthcare costs.