Environmental and treatment-related factors associated with developmental outcomes in genetic epilepsies.
OBJECTIVE The mechanistic effects of genetic variants underlying genetic neurodevelopmental disorders (NDDs) are widely studied, but the contribution of external factors remains largely unexplored. METHODS In this cross-sectional study using the Simons Searchlight population dataset, we examined caregiver-reported environmental exposures and functional outcomes from 970 individuals with (67%) and without (33%) epilepsy across 93 NDDs. The primary outcome was adaptive function (Vineland-3) at last follow-up, with quality of life (Quality of Life Inventory-Disability) and autism symptoms (Social Communication Questionnaire-Lifetime) as secondary analyses. RESULTS Compared to individuals with NDDs without epilepsy, individuals with epilepsy had lower adaptive function (p < .001). On multivariable regression analysis, we found positive associations between socioeconomic factors and quality of life (parents' highest educational status: β = .014, p = .013; annual household income: β = .007, p = .021) and negative associations between treatment-related factors and adaptive function (treatment with sodium channel blockers: β = -.087, p = 2.44 × 10-5; hospitalizations: β = -.055, p = 3.65 × 10-7). These associations were mediated by epilepsy duration, etiology, and polytherapy. Results were consistent across sensitivity analyses but were not observed in individuals without epilepsy, suggesting epilepsy-specific effects. Together, environmental exposures explained more variance in developmental outcomes than genetic etiology alone (additional R2 = 19.6%, p = .003). Importantly, the additional variance explained by environmental exposures was different across genes, ranging from ~15% (SCN2A, SLC6A1) to >30% (16p11.2 deletion), suggesting gene-specific vulnerability. Overall, ~60% of variance in developmental outcomes remained unexplained, motivating further studies on genome and exposome influences. SIGNIFICANCE Our findings highlight genetic NDDs as genome-informed yet exposure-sensitive disorders. We found several external factors that both represent markers of epilepsy severity and may support early, genetically informed seizure management and careful stewardship of treatment exposures. Prospective, controlled studies are needed to disentangle the developmental effects of the underlying disease from treatment-related factors.