aimed analytics logo

The Genetic Mechanisms of Clustering Epilepsy

A new study sheds light on the complex genetic factors involved in Clustering Epilepsy. By examining the interplay between the PCDH19 gene and key hormonal pathways, researchers are uncovering new insights that could inform future therapeutic approaches. Stay tuned for an in-depth look at these latest findings in epilepsy research.

Unraveling the Genetic Mechanisms of Clustering Epilepsy: A Multifaceted Study

Understanding the genetic underpinnings of Clustering Epilepsy (CE) has been a journey of complex discoveries. A new study has delved into the epigenomic, transcriptomic, and proteomic landscape of CE to unravel the role of the Protocadherin 19 (PCDH19) gene and its interactions with the Nuclear Hormone Receptor (NHR) pathway. The results shed light on the dysregulation of Androgen Receptor (AR) signaling, providing insights that could pave the way for novel therapeutic strategies.

Epigenetic and Transcriptional Changes in CE Pathogenesis

Researchers have taken a closer look at the transcriptomic profiles of individuals with CE to understand the disorder's genetic regulation. By analyzing the skin fibroblasts from affected females and comparing them with healthy controls, they found significant differences in methylation patterns and gene expression, particularly in genes regulated by the AR.

To expand our understanding of the role of PCDH19 variants in CE pathogenesis, we performed CE methylome, transcriptome and proteome studies in diverse cellular models of CE. Our multidimensional analyses implicate PCDH19 in the NHR pathways at the level of methylation, gene regulation and protein-protein interaction and suggests that this pathway plays a critical role in CE pathology.
de Nys, R., van Eyk, C.L., Ritchie, T. et al. Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy. Transl Psychiatry 14, 65 (2024).

Key findings include:

  • Differential methylation in multiple genomic regions, including promoters and gene bodies, in both affected females and transmitting males.

  • Clustering of affected females separate from female controls based on differentially methylated probes.

  • Enrichment of genes regulated by the AR, suggesting a disrupted steroid hormone biosynthesis pathway.

The Power of Transcriptomics

Transcriptomic analyses have been particularly revealing in this study. They have confirmed the dysregulation of genes involved in critical biological processes, including brain development and cell migration. Through meticulous examination, researchers identified that AR is significantly upregulated in affected females, indicating a novel aspect of CE pathology.

PCDH19 Regulation by Steroid Hormones

Intriguingly, the study found that the expression of PCDH19 is repressed by steroid hormones, particularly through the action of ERα and its co-regulator FOXA1. This repression appears to be a pivotal mechanism that influences the onset and progression of CE.

Overall, our results showed that ERα-dependent repression of PCDH19 is mediated by FOXA1 through its binding to the PCDH19 promoter.
de Nys, R., van Eyk, C.L., Ritchie, T. et al. Multiomic analysis implicates nuclear hormone receptor signalling in clustering epilepsy. Transl Psychiatry 14, 65 (2024).

Interaction with Androgen Receptor

A groundbreaking discovery from the study was the protein-protein interaction between PCDH19 and AR. This interaction was not affected by PCDH19 pathogenic variants or alternative splicing, implicating a fundamental link to the NHR pathway that remains intact despite the genetic mutations associated with CE.

Implications and Future Directions

The comprehensive approach taken by the researchers to dissect the molecular intricacies of CE has provided a wealth of information that could be translated into clinical benefits. By highlighting the role of AR and its targets, the study suggests potential biomarkers for CE and targets for therapeutic intervention.


The study's multi-angled analysis has painted a detailed picture of the genetic mechanisms underlying CE. The benefits of transcriptomics and related analyses are clear, as they uncover layers of regulation that contribute to the pathogenesis of this disorder. The results underscore the potential for developing targeted therapies that could significantly improve the lives of individuals affected by CE.