New insights from the Epi25 Collaborative highlight the complex genetic architecture of epilepsy, identifying distinct ultra-rare genetic risk factors across various disorder subtypes through the largest whole-exome sequencing study conducted to date.

Bonn, October 2024 – Identifying genetic risk factors for the highly heterogeneous disorder of epilepsy has long been a challenge for researchers. In a pivotal study, the Epi25 Collaborative has conducted what is believed to be the largest whole-exome sequencing analysis of epilepsy to date, involving over 54,000 human exomes. This extensive research includes 20,979 deeply phenotyped patients from diverse genetic ancestry groups and 33,444 controls, shedding light on the rare variants that contribute to disease risk. Our Bonn group has contributed 2,546 patient samples to this study which included samples from 59 study centers.

Epilepsy, characterized by recurrent seizures, encompasses a variety of subtypes, making the understanding of its genetic underpinnings complex. The findings of this study implicate seven individual genes, three gene sets, and four copy number variants that reach exome-wide significance. Notably, genes associated with ion channels demonstrate strong links to multiple epilepsy subtypes, including epileptic encephalopathies, generalized epilepsies, and focal epilepsies. In contrast, many of the other gene discoveries appear to be subtype-specific, underscoring the distinct genetic contributions associated with different forms of epilepsy.

The researchers combined data from rare single-nucleotide variants, short insertion and deletion variants, copy number variants, and common variants to present an expanded view of epilepsy’s genetic architecture. Their analyses revealed increasing evidence of convergence among various genetic risk loci affecting the same genes. The top candidate genes identified are notably enriched for roles in synaptic transmission and neuronal excitability, particularly during postnatal development and in the neocortex.

Interestingly, this study also highlights shared rare variant risks between epilepsy and other neurodevelopmental disorders, suggesting overlapping genetic vulnerabilities. To facilitate further research and diagnostic efforts, the data from this comprehensive study are accessible via an interactive browser, aimed at accelerating follow-up studies and enhancing our understanding of epilepsy.

For further details, please refer to the full publication https://doi.org/10.1038/s41593-024-01747-8

Publication: Epi25 Collaborative. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes. Nat Neurosci 27, 1864–1879 (2024).

Scientific contact:

Prof. Dr. Wolfram S. Kunz

Institute of Experimental Epileptology and Cognition Research (IEECR)

University of Bonn Medical Center

E-mail: wolfram.kunz@ukbonn.de

Written by: Dr Michela Barboni, Ph.D