Genetic modifiers of epilepsy: A narrative review

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• Epilepsy exhibits strong genetic influence on symptom onset and drug response.
• While monogenic mutations cause some epilepsy syndromes, polygenic factors and genetic modifiers shape disease severity and treatment outcomes.
• Genetic modifiers regulate crucial biological networks, leading to varied clinical presentations even with identical primary mutations.

Purpose of the Study:

• To comprehensively review the genetic determinants of epilepsy, differentiating between single-gene and polygenic causes.
• To examine the role and mechanisms of genetic modifiers in epilepsy, including their impact on drug resistance, seizure risk, and associated comorbidities.
• To explore the integration of Genome-Wide Association Studies (GWAS) and epigenetics in identifying key modifying genes.

Main Methods:

• Comprehensive literature review of epilepsy genetics.
• Analysis of genetic determinants, including single-gene and polygenic factors.
• Examination of genetic modifiers' mechanisms and their influence on biological pathways.

Main Results:

• Identified standard and minority genetic determinants in epilepsy.
• Detailed the mechanisms by which genetic modifiers influence synaptic plasticity, ion channels, neurodevelopment, and neuroinflammation.
• Highlighted the role of GWAS and epigenetics in discovering genes like SCN1A and KCNQ2 that modify epilepsy phenotypes.
• Emphasized the impact of genetic modifiers on network excitability, blood-brain barrier function, and neurodevelopmental pathways.

Conclusions:

• Genetic modifiers play a critical role in modulating epilepsy severity, drug response, and clinical course.
• Understanding these modifiers is essential for developing targeted epilepsy treatments.
• Future research directions include precision medicine approaches guided by genetic modifier-directed therapies and novel drug development.