Piet et al. (1) challenge the traditional dichotomy behind epilepsy genetics. Rare severe epilepsies are often considered monogenic, while milder phenotypes are presumed polygenic. Identifying a pathogenic variant in an individual with epilepsy is often considered sufficient for diagnosis. However, their diagnostic yield remains low across common and rare epilepsies, highlighting substantial missing heritability.
Recent genome-wide association studies (GWAS) and sequencing studies indicate that epilepsy lies on a spectrum at the interplay between rare high-impact variants and a polygenic background composed of multiple common variants. The ILAE (International League Against Epilepsy) Consortium on Complex Epilepsies showed that 2850 common variants account for approximately two-thirds of the risk of genetic generalised epilepsy.
Polygenic risk scores (PRS) capture the cumulative effect of common variants across the genome, providing a measure of epilepsy susceptibility. PRS illustrate how common variants can modify penetrance, severity, and treatment response. They can also distinguish epilepsy subtypes and predict familial risk. In Dravet syndrome, Martins Custodio et al. showed that genomic variation beyond SCN1A contributes to phenotypic diversity: individuals sharing the same SCN1A variant differed in phenotype partly due to differences in epilepsy and intelligence PRS (2). Even acquired epilepsies, such as post-stroke epilepsy, are influenced by polygenic susceptibility. This research will shortly support the clinical implementation of PRS, which has not yet been achieved (3).
Rare high-impact variants remain important determinants of disease severity, even in common epilepsies. Pathogenic variants in genes associated with severe DEEs (Developmental and Epileptic Encephopathies) , including STXBP1, can manifest across a broad phenotypic spectrum, thereby bridging rare and common epilepsies
Key Points:
- The monogenic versus polygenic distinction is increasingly artificial in epilepsy genetics.
- Polygenic background modifies penetrance, phenotype, and drug response in all epilepsies.
- The interaction between rare and common variants shapes the penetrance and phenotypic spectrum. For example, the risk of DEE is largely determined by rare high-impact variants, with a smaller contribution from common variants. Conversely, in common GGE syndromes, risk is primarily driven by common variants, though rare pathogenic variants contribute in some individuals.
- This spectrum model improves diagnosis, risk prediction, and personalised care.
- In clinical practice, increasing availability of whole genome sequencing, will soon allow to incorporate PRS alongside rare variant detection.
References:
- Piet MM, Braun KPJ, Koeleman BPC, Stevelink R. Monogenic no more: are all epilepsies polygenic? Trends Genet. 2026 Feb 10:S0168-9525(26)00005-3.
- Martins Custodio H, Clayton LM, Bellampalli R, Pagni S, Silvennoinen K, Caswell R; Genomics England Research Consortium; Brunklaus A, Guerrini R, Koeleman BPC, Lemke JR, Møller RS, Scheffer IE, Weckhuysen S, Zara F, Zuberi S, Kuchenbaecker K, Balestrini S, Mills JD, Sisodiya SM. Widespread genomic influences on phenotype in Dravet syndrome, a 'monogenic' condition. Brain. 2023 Sep 1;146(9):3885-3897.
- Heyne HO. Polygenic risk scores in epilepsy. Med Genet. 2022 Sep 22;34(3):225-230. doi: 10.1515/medgen-2022-2146.
Co Author(s):
- Marianne de Visser, Amsterdam University Medical Centre, the Nederlands
- Guido Rubboli, Danish Epilepsy Center, Dianalund, Denmark. University of Copenhagen, Copenhagen, Denmark
- João Durães, University of Coimbra, Coimbra, Portugal.
Publish on behalf of the Coordinating Panel on Rare Neurological Disease