Environmental modifiers of developmental outcomes in genetic epilepsy

Genetic neurodevelopmental disorders (NDDs) with epilepsy are genome-defined yet exposure-sensitive. While the mechanistic effects of genetic variants underlying these disorders are widely studied to understand clinical heterogeneity among patients, the contribution of external environmental factors remains largely unexplored. 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), with quality of life (QI-Disability) and autism symptoms (SCQ Lifetime) as secondary analyses. Compared to individuals with NDD without epilepsy, individuals with epilepsy were more likely to be admitted for inpatient or intensive care and more likely to receive treatment with sodium channel blockers; however other exposures were similar across groups. While quality of life was similar, those with epilepsy had lower adaptive function (p < 0.001). On multivariable regression analysis, we found positive associations between socioeconomic factors and quality of life (parents highest educational status: {beta} = 0.014, 95% CI: [0.003, 0.025], p = 0.013) and annual household income: {beta} = 0.007, 95% CI: [0.001, 0.014], p = 0.021) and negative associations between treatment-related factors and adaptive function (treatment with sodium channel blockers: {beta} = -0.087, 95% CI: [-0.127, -0.047], p = 2.44x10-5; hospitalisations: {beta} = - 0.055, 95% CI: [-0.076, -0.034], p = 3.65x10-7), among others. These associations were mediated by epilepsy duration and severity, burden of polytherapy, and the underlying genetic aetiology, suggesting that genetics-informed care and early seizure control may facilitate better developmental outcomes. Results were consistent across subgroups and sensitivity analyses but were not observed in comparison groups of 322 and 1,276 individuals without epilepsy, suggesting gene-, disease-, or treatment-specific effects in epilepsy. Together, environmental exposures explained significantly more variance in developmental outcomes than genetic aetiology alone (additional R2 = 19.6%, p = 0.003). Importantly, the additional variance explained by environmental exposures was different across genes and ranged from [~]15% (SCN2A, SLC6A1) to >30% (16p11.2 deletion), suggesting gene-specific vulnerability to external factors. Overall, 38-58% of variance in developmental outcomes remained unexplained, supporting further data collection and the identification of additional genome and exposome influences. Collectively, these findings reframe genetic NDDs as genome-informed yet exposure-sensitive disorders and point to early, genetically informed seizure management and careful stewardship of treatment exposures as immediate levers to improve developmental trajectories.