Monogenic no more: are all epilepsies polygenic?

Area of Science:

• Neurogenetics
• Epilepsy Research

Background:

• Traditional epilepsy classification divides causes into genetic/nongenetic and monogenic/polygenic.
• This dichotomy is challenged by emerging genetic evidence.

Purpose of the Study:

• To propose a new paradigm for understanding epilepsy etiology.
• To highlight the role of polygenic background in influencing epilepsy phenotypes.

Main Methods:

• Review of genome-wide association studies (GWAS) and sequencing data.
• Analysis of the interplay between common and rare genetic variants.

Main Results:

• Both common and rare genetic variants contribute to epilepsy risk.
• Polygenic burden influences key aspects of epilepsy, including penetrance, treatment response, and severity.
• Boundaries between epilepsy types (e.g., common vs. rare, genetic vs. acquired) are blurred.

Conclusions:

• The concept of "monogenic epilepsy" is outdated.
• A spectrum model, where all epilepsies result from the polygenic interaction of rare and common variants, is proposed.
• This new understanding has significant implications for epilepsy diagnosis, prognosis, and clinical management.