Assistant Professor of Neurology & Pediatrics University of California, San Francisco San Francisco, California
Rationale: Whole exome sequencing (WES) with targeted gene analysis has been important for establishing diagnosis and prognosis of severe early-onset epileptic encephalopathies, but the contribution of pathogenic gene variants to epileptogenesis after acute symptomatic neonatal seizures is not known. Here, we aim to evaluate the association of WES results with the development of epilepsy after acute symptomatic neonatal seizures. Methods: We performed a case-control study of 20 trios in children with a history of acute symptomatic neonatal seizures: ten with and ten without post-neonatal epilepsy. Medical records were abstracted for clinical, electroencephalography, and imaging variables. We performed WES to identify pathogenic de novo, transmitted, and non-transmitted variants from genes with known association with epilepsy and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis using genes associated with coronary artery disease (CAD). We then analyzed pathogenic variants throughout the exome to evaluate for differential enrichment of functional properties using Kyoto Encyclopedia of Genes and Genomes (KEGG) searches. Results: Among 200 known genes associated with epilepsy, we identified 35 variants in 30 genes. Nine (26%) of 35 variants were classified as pathogenic in six children with post-neonatal epilepsy and in two children without subsequent epilepsy (Table 1, OR 6.0, 95% CI 0.6-80, p=0.07). There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy genes. Similarly, there was no difference in the number of children with pathogenic variants in CAD genes between groups. On WES, seventeen pathogenic de novo variants were found in genes without a known association with epilepsy. Children who developed post-neonatal epilepsy had a relative enrichment in variants associated with the nervous system, including synaptic transmission and those without epilepsy had a relative enrichment of variants in cell death pathways (Figure 1). Conclusions: In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of pathogenic variants on WES with targeted epilepsy gene analysis compared to those patients without subsequent epilepsy. Larger studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis. Funding: Please list any funding that was received in support of this abstract.: Marcus Program Seeding Bold Ideas Award. Click here to view image/table
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