Abstracts

Rationale: Finding a treatable cause of epilepsy is the foundation of precision medicine, which offers customized treatment for patients with epilepsy (PWE) and to improve long-term outcome.  It has been recognized that genetic factors play an important role in epilepsy etiology. The utility of genetic testing in adult PWE with DRE remained less explored, especially the discovery of VUS leaves the clinicians with practice challenging. We aimed to identify possible genetic causes of DRE in adult PWE.

Methods: We performed a retrospective analysis of all adult PWE with DRE who received genetic testing through our comprehensive epilepsy program from 2016 to 2021. The genetic testing results (Epilepsy Comprehensive NGS panel) were reviewed by epileptologists, medical geneticists. Results classified as pathogenic or likely pathogenic (P/LP) and VUS were studied along with the clinical data (seizure history, EEG, and brain imaging). VUS was further investigated as a “candidate variants” if there was reported associated clinical rationale and strong prediction of protein malfunction. To identify potential regulators and downstream targets/pathways of the VUS genes, we performed the gene co-expression network analysis using the published expression profiles derived from human epileptic hippocampus tissues.

Results: A total of 30 DRE patients were identified and were sub-grouped as childhood-onset (C) or adult-onset seizures (A). The detection of P/LP mutations was considerably higher in the group C, 8 of the 10 patients with intellectual disability (ID), 5 of the 8 patients without ID discovered P/LP mutation. Whereas only 3 patients in the A group (12 patients) were found with P/LP mutations (Table 1). Over 80 VUS genes were identified in our studies. Notably most of the VUS genes were reported association with epilepsy syndrome or conditions with increased risk of seizures. However, the discovered variants in our cohort were mostly not reported in the Human Gene Mutation Database (HGMD). Applying Alphafold AI and deep learning, it revealed if VUS likely impacts the protein structure which may attribute the VUS gene protein function. Accordingly, such analysis increased the confidence of reclassifying VUS, and associating with the patient phenotype. The reclassified candidate VUS were noted to likely affect potential neurobiological mechanisms of epilepsy, regulating (1) synaptic function; (2) ion channel; (3) cell growth, proliferation, and migration; and (4) chromatin remodeling (Table 2). Gene co-expression network analysis revealed potential regulating pathway in susceptibility of increased seizure risk.  Relating to genetic test and analysis results, about 55% of patients from our cohort received actionable intervene, such as anti-seizure medication recommendations, recommendation of metabolic treatment, recommendation of possible surgical indications, extending genetic counseling/testing to family members.

Conclusions: For PWE with adult-onset seizures and DRE, the genetic test and co-expression network analysis can help clinicians to further explore the etiology and to improve the understanding of the disease and may provide valuable information for potential precision management.

Funding: None