Integrative Analysis of Epilepsy-Associated Genes Reveals Expression-Phenotype Correlations

bioRxiv. 2023 Jun 11;2023.06.09.544142. doi: 10.1101/2023.06.09.544142. Preprint


Epilepsy is a highly prevalent neurological disorder characterized by recurrent seizures. Patients exhibit broad genetic, molecular, and clinical diversity involving mild to severe comorbidities. The factors that contribute to this phenotypic diversity remain unclear. We used publicly available datasets to systematically interrogate the expression pattern of 247 epilepsy-associated genes across human tissues, developmental stages, and central nervous system (CNS) cellular subtypes. We grouped genes based on their curated phenotypes into 3 broad classes: core epilepsy genes (CEG), where seizures are the core syndrome, developmental and epileptic encephalopathy genes (DEEG) that are associated with developmental delay, and seizure-related genes (SRG), which are characterized by developmental delay and gross brain malformations. We find that DEEGs are highly expressed within the CNS, while SRGs are most abundant in non-CNS tissues. DEEGs and CEGs exhibit highly dynamic expression in various brain regions across development, spiking during the prenatal to infancy transition. Lastly, the abundance of CEGs and SRGs is comparable within cellular subtypes in the brain, while the average expression level of DEEGs is significantly higher in GABAergic neurons and non-neuronal cells. Our analysis provides an overview of the expression pattern of epilepsy-associated genes with spatiotemporal resolution and establishes a broad expression-phenotype correlation in epilepsy.

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