Monogenic no more: are all epilepsies polygenic?

Abstract

The etiology of epilepsy has long been framed by dichotomies, classifying epilepsies as genetic or nongenetic, and genetic epilepsies as monogenic or polygenic. Emerging evidence challenges these divisions. Genome-wide association and sequencing studies show that both common and rare variants contribute to risk, with the phenotype of rare high-impact variants being influenced by an individual's polygenic background. Polygenic burden modifies penetrance, treatment response, and severity, blurring boundaries between common and rare epilepsies and between genetic and acquired forms. We argue that the concept of monogenic epilepsy is outdated and propose a new paradigm: all epilepsies exist on a spectrum shaped by the polygenic interplay of rare and common variants, with important implications for diagnosis, prognosis, and clinical care.