Despite progress in understanding the genetics of rare childhood epilepsies, the common adult forms of epilepsy have proven less amenable to traditional gene-discovery analyses (Swansea University, 2017).

The Epi4K consortium of experts, which includes academics from Swansea University, decided to assess the contribution of genome-wide ultra rare genetic variation in the common epilepsies. The results of the study could lay the foundation for future precision medicine.

The study established that there was a clear connection between the genetics of common and rare severe epilepsies and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. The results suggest that the emerging pattern of targeting treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients and lay the foundation for possible precision treatments in the future.

Professor Mark Rees, Dr Owen Pickrell and Dr Seo-Kyung Chung from The Neurology and Neuroscience Research team at Swansea University Medical School are co-authors of the study, published in Lancet Neurology. The Swansea University team’s contribution to the study was the submission over four hundred Welsh epilepsy patient samples and anonymised clinical data from the Swansea Neurology Biobank to the Epi4K consortium.

Mark Rees, Professor of Neurology & Molecular Neuroscience Research, Swansea University Medical School said “This represents one of the largest studies into the genetics of common epilepsy disorders using thousands of patients with epilepsy & healthy controls in conjunction with modern statistical methods. The outcome definitively confirms that common forms of epilepsy have a genetic fingerprint that is not found in a normal control population. It means investigators can proceed with confidence into larger and more specific studies that are meaningful to individual patients and their families.”

Owen Pickrell and Seo-Kyung Chung added “Our contribution to Epi4K was the result of many years of collecting and archiving epilepsy samples / data across NHS clinics in Wales and patient home visits. Only with patient advocacy, NHS collaboration and a professional Biobanking infrastructure can such large numbers be submitted to meaningful international studies.”

The published paper describes a case control sequencing study of unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: genetic generalised epilepsy, or sporadic non-acquired focal epilepsy.

Individuals of any age were recruited between 2007 and 2013, through the multi-centre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine in New York between 2013 and 2015. To identify epilepsy risk signals, all protein coding genes were tested for an excess of ultra rare genetic variation among the cases, compared with control samples with no known epilepsy or sequenced through unrelated studies.

The researchers separately compared the sequence data from six hundred and forty individuals with genetic generalised epilepsy (seizures with no evidence of focal onset ) and five hundred and twenty five individuals with non-acquired focal epilepsy (seizures with no evidence of focal onset) to the same group of 3,877 controls, and found significantly higher rates of ultra rare deleterious variation in causative genes for dominantly inherited epilepsy disorders.

For the individuals with non-acquired focal epilepsy, the researchers found that five known epilepsy genes ranked as the top five genes enriched for ultra rare deleterious variation. After accounting for the control data, they estimated that these five genes contribute to approximately 8% of the risk of epilepsy in individuals with non-acquired focal epilepsy.