An Overview of Drug-Resistant Epilepsies Based on Advances in Genetics: A Cohort Study

The etiology of drug-resistant epilepsy (DRE) is multifactorial. A small proportion of affected patients are diagnosed with genetics. Nowadays, specific gene panels and whole-exome sequencing (WES) have increased the opportunities for specific diagnosis and treatments with developments in genetics. In this cohort study, we determined the specific diagnostic value of gene panels and WES analysis in our cases with the diagnosis of DRE.

The medical records of 3727 cases were reviewed. The clinical features and genetic results of the cases who underwent TruSight One panel testing (116 cases) and WES (413 cases), followed by a diagnosis of DRE, were evaluated.

Significant pathogenic mutations were detected in 234 (56.7%) of 413 patients who underwent WES. The original diagnosis was made in 55 (47.4%) of 116 cases in which the TruSight One panel was studied. Significant mutations (49.3%) were detected in 261 of 529 patients. Pathogenic mutations were detected most frequently in SCN1A (n = 20), STXBP1(n = 9), and CDKL5 (n = 9) genes. Afterwards, significant pathogenic changes were found in MECP2, ADGRV1, CACNA1H, KCNQ2, RELN, TREX1, WWOX, CACNA1, PRUNE1, CLP1, CPA7, PNKP, IFIH1, SCN8A, SCN9A, NDUFA6, UBE3A, BRPF1, CHD2, CILK1, CLCN2, EEF1A2, FLNA, GABRG2, GRIN2A, HCN1, TPP1, CLN6, FLNA, KCTD7, MTHFR, ITPA, FOXG1, KCNMA1, KCNT1, KCTD7, LAMC3, MTO1, RHOBTB2, SCN2A, SCN3A, SLC2A1, SYNGAP1, NPRL3, ad PRRT2 genes.

Despite detecting the increasing number of DRE-associated genes, the clinical features of these disorders often overlap, making it difficult to make a systematic diagnosis. Genetic tests, especially WES analysis, significantly increase the rate of original diagnosis in DRE cases. A definite genetic diagnosis is very important in terms of avoiding unnecessary tests, choosing specific treatment, and genetic counseling.