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. 2022 Mar;91(4):896-902.
doi: 10.1038/s41390-021-01509-3. Epub 2021 Apr 12.

Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

Adam L Numis  1   2 , Gilberto da Gente  3 , Elliott H Sherr  3   4 , Hannah C Glass  3   4   5
Affiliations

Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

Adam L Numis et al. Pediatr Res. 2022 Mar.

Abstract

Background: The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known.

Methods: Case-control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches.

Results: Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy.

Conclusions: In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy.

Impact: We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future 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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
KEGG orthology categorization of pathogenic variants on whole exome.
See this image and copyright information in PMC

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