Mojdeh Mahdiannasser1, Ali Rashidi-Nezhad2,3, Reza Shervin Badv4, Seyed Mohammad Akrami5. 1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Poursina St., P.O. Box:14176-13151, Tehran, Iran. 2. Maternal, Fetal and Neonatal Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran. 3. Genetics Ward, Yas Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. 4. Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran. 5. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Poursina St., P.O. Box:14176-13151, Tehran, Iran. akramism@tums.ac.ir.
Abstract
BACKGROUND: By affecting about 50 million people worldwide, epilepsy is considered a global concern in neurology. Intolerable enough, up to ¼ 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.
BACKGROUND: By affecting about 50 million people worldwide, epilepsy is considered a global concern in neurology. Intolerable enough, up to ¼ 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.
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