Does genetic diagnosis influence long-term seizure and developmental outcomes in childhood developmental and...

To evaluate long-term seizure and developmental outcomes of childhood-onset developmental and epileptic encephalopathies (DEE) of presumed genetic etiology and to determine whether genetic diagnosis influences the electroclinical trajectory.

We conducted a cohort study on children with seizure onset before 12 years diagnosed with DEE who underwent next-generation sequencing (NGS) and had ≥1 year of follow-up. Outcomes compared included seizure freedom, seizure reduction and developmental status at last follow-up between children with pathogenic/likely pathogenic variants and those with negative genetic test results. Clinical predictors of drug-resistant epilepsy (DRE) and adverse developmental outcome were assessed using multivariate logistic regression.

Among 255 children (median follow-up 5 years), a genetic diagnosis was made in 111 (43.5%). Positive genetic results were significantly associated with younger age at seizure onset (p < 0.001) and lower likelihood of independent ambulation (p = 0.008). Seizure freedom was achieved in 40.4% overall and was not deteremined by genetic test status. On multivariate analysis, predictors of DRE were initial delayed development (Odds ratio-OR 1.87; 95%; p = 0.021) and negative family history of seizures (OR-0.55; p = 0.029). Predictors of adverse developmental outcome were psychomotor delay prior to seizure onset (OR-2.91; p < 0.001), early age of onset of epilepsy (OR-2.15; p = 0.015) and regression of milestones (OR4.13; p < 0.001). Genetic test positivity did not emerge as an independent predictor of seizure freedom or developmental outcome. Syndrome-specific analyses revealed higher possibility of DRE in genetically confirmed Dravet syndrome.

In our large longitudinal cohort, genetic diagnosis was associated with earlier epilepsy onset and functional impairment but did not independently predict long-term seizure or developmental outcomes. Prior neurodevelopmental status and epilepsy-onset timing remain the strongest determinants of prognosis, underscoring the need to integrate genetic testing with early clinical recognition, aggressive seizure management and timely developmental interventions.