Neonatal-onset genetic epilepsies: Insights from a large multicentre cohort

Neonatal-onset genetic epilepsies are clinically heterogeneous and are increasingly diagnosed through genomic testing. We aimed to describe the phenotypes and neurodevelopmental outcomes of infants with neonatal-onset genetic epilepsy from eighteen tertiary centres and to explore subgroup differences across functional gene categories.

This retrospective multicentre study included 144 infants with seizure onset within the neonatal period and a genetically supported etiology. Clinical, electroencephalographic, neuroimaging, and genetic data were obtained from participating centres and re-evaluated. Functional gene categories were predefined, and comparative analyses were performed. A sensitivity analysis was conducted in the pathogenic/likely pathogenic subset.

We identified 107 variants across 76 genes; whole-exome sequencing was the most common diagnostic method (64.6%). Variants mapped most frequently to genes related to cell metabolism/functioning/signalling (58.3%), followed by ion channels/neurotransmitter receptors (29.2%) and synaptic vesicle docking/release (12.5%). Mean postnatal age at seizure onset was 11.9 ± 12.4 days (range 1-45), and median follow-up was 24 months (range 3-84). Across functional gene groups, seizure onset occurred earliest in the ion channel/neurotransmitter receptor group (p = 0.038), and dysmorphic features were more frequent in the cell metabolism/functioning/signalling group (p = 0.002). These findings remained consistent in sensitivity analyses restricted to pathogenic/likely pathogenic cases (onset: p = 0.046; dysmorphia: p = 0.007). Comparative analyses showed no significant differences between VUS and pathogenic/likely pathogenic groups in evaluated clinical and outcome variables.

This large multicentre cohort delineates the phenotypic and molecular spectrum of neonatal-onset genetic epilepsies and highlights patterns across functional gene groups that warrant validation in prospective studies.