Exploring the genetic etiology of drug-resistant epilepsy: incorporation of exome sequencing into practice

Background By affecting about 50 million people worldwide, epilepsy is considered a global concern in neurology. Intolerable enough, up to 1/4 of all patients do not respond to antiepileptic drugs and have recurring seizures. Therefore, revealing the underlying etiology is quite demanding in a clinical context to improve diagnosis and disease management. Methods Initially, 85 patients suspected of epilepsy underwent thorough clinical and paraclinical evaluation and 24 individuals with drug-resistant epilepsy entered the study. Using whole-exome sequencing, the genetic etiology of drug-resistant epilepsy was investigated and discerned whether this method could facilitate the management of drug-resistant epilepsy through personalized medicine. Eventually, functional annotation was performed and drug-gene interaction networks were constructed to find potential therapeutic targets. Results We found eleven novel variants in various genes including IRF2BPL, ST3GAL3, and GPAA1, for which a few epilepsy-related variants are available in public databases. The overall diagnostic yield for likely pathogenic and pathogenic variants and the detection rate of novel variants were 25% and 84.6%, respectively. Based on the results, two patients were considered potential candidates for personalized medicine. The highest number of interaction with drugs was demonstrated for SCN1A, SCN2A, and GRIN2A genes. Conclusions This study highlighted the importance of consanguineous marriage in drug-resistant epilepsy and suggested the possibility of reduced penetrance and variable expressivity in some of the autosomal dominant cases. We also suggest that whole-exome sequencing could facilitate personalized management of drug-resistant epilepsy. Regarding drug-gene interactions, some genes such as SCN1A and SCN2A might serve as therapeutic targets in drug-resistant epilepsy.

Automated summary

This study identified novel variants in multiple genes in patients with epilepsy, and suggested that whole-exome sequencing could facilitate personalized management of drug-resistant epilepsy. The study also highlighted the importance of consanguineous marriage in drug-resistant epilepsy and identified some genes that might serve as therapeutic targets.