Unravelling the genetic complexity of drug-resistant epilepsy: a critical narrative review

Introduction: Drug-resistant epilepsy (DRE) affects 30% of epilepsy patients and represents a major therapeutic challenge. Understanding its genetic determinants is crucial for the development of effective precision medicine strategies. Areas covered: This review comprehensively evaluates genetic factors in DRE, including polymorphisms in pharmacokinetic (e.g. ABCB1) and pharmacodynamic (e.g. SCN1A), findings from genome-wide association studies (GWAS) that recently identified a significant locus at 1q42.11-q42.12 (CNIH3/WDR26) for focal DRE, the critical role of rare variants (e.g. in SCN1A, KCNQ2) and copy number variations (CNVs) in severe epileptic encephalopathies, and the emerging fields of epigenetics and polygenic risk scores (PRS). Expert opinion: Methodological limitations, including modest sample sizes and phenotypic heterogeneity, hamper genetic research on DRE. While common variants show little impact, rare variants, including CNVs, and epigenetic alterations offer promising opportunities. Future priorities include functional studies to clarify the impact of gene variants, the integration of multi-omics data and the development of advanced analytical techniques, such as machine learning and network approaches, to translate genetic discoveries into clinically actionable precision medicine and ultimately improve outcomes for DRE patients.