Neurogenetic biomarkers in epilepsy: A comprehensive narrative review of progression and therapeutic approaches

Abstract

Epilepsy is a multifaceted and heterogenous neurological disorder that affects an estimated 70 million people worldwide and is identified by recurrent or unprovoked seizure activity. Although there have been advances in pharmacotherapeutic treatments, approximately one-third of patients with epilepsy remain drug resistant, highlighting the need for personalised and mechanism-based strategies. Neurogenetic biomarkers are emerging as valuable instruments for translating the genetic findings to the bedside and may provide new opportunities within a more precise treatment paradigm in epilepsy. Neurogenetic biomarkers include single-nucleotide polymorphisms (SNPs), copy number variants (CNVs), and mutations in disease-specific genes that inform our knowledge about the genetic architecture of seizure susceptibility, seizure progression and therapeutic response. The main genes, such as SCN1A, KCNQ2, GRIN2A, LGI1, GABRA1, and CHRNA4, impact neuronal excitability, ion channel dynamics, and synaptic interactions. Variations of mTOR signaling pathways (TSC1, TSC2, DEPDC5) and mutations in epigenetic regulators (MECP2, CDKL5) implicated a multilayered structure in the mechanistic underpinnings of epileptogenesis. Neurogenetic biomarkers are increasingly relevant to clinical practice for refining diagnosis, predicting seizure onset, guiding drug selection, and determining surgical intervention. The integration of neurogenetic sampling with neuroimaging, electrophysiological, inflammatory, and molecular signatures can improve diagnostic precision and provide an evidence-based framework towards therapeutic stratification. Although challenges remain-such as genetic heterogeneity, variant interpretation, cost barriers, and ethical considerations, advances in next-generation sequencing, pharmacogenomics, and artificial intelligence are rapidly transforming these limitations into opportunities. Neurogenetic biomarkers hold transformative potential to redefine epilepsy care, enabling earlier diagnosis, individualized therapy, and improved long-term outcomes. As the field advances, they are poised to shift epilepsy management from reactive to predictive, and from generalized to precision-driven, initiating a new era of neurology.