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.
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 and 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 “Ultra-rare genetic variation in common epilepsies: a case-control sequencing study” which has now been published in the February edition of Lancet Neurology.
The Swansea University team’s contribution to the study was the submission over 400 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.”
Dr Pickrell and Dr 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 multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) 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.
We separately compared the sequence data from 640 individuals with genetic generalised epilepsy (seizures with no evidence of focal onset ) and 525 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, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control data, we estimate that these five genes contribute to approximately 8% of the risk of epilepsy in individuals with non-acquired focal epilepsy.
- The findings from the Epi4K consortium, Epilepsy Phenome/Genome Project “Ultra-rare genetic variation in common epilepsies: a case-control sequencing study” have been published in The Lancet Neurology February 2017. Link to the paper http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30359-3/fulltext
- The Epi4K consortium is a NIH-funded initiative under the National Institute of Neurology, Dementia and Stroke (NINDS): http://www.epi4k.org/
- Swansea University Medical School, established in 2004, is an internationally-recognised centre of excellence in medical research, education and innovation. The Medical School has three main activities: learning and teaching, research, and business and innovation. Read about the history of the Medical School at http://www.scribd.com/doc/235047725/History-in-the-Making-College-of-Medicine-Swansea-University-10th-Anniversary-2004-2014
- Swansea University Medical School has had spectacular success in the Research Excellence Framework (REF) 2014. Achievements include; joint 1st in the UK for research environment rated as 100% world-leading and 2nd in the UK for research quality in our unit of assessment, scored 100% world-leading in terms of impact and 95 % of the research submitted was assessed as world-leading (54%) or internationally excellent (41%) Find out more about the REF2014 results at https://www.scribd.com/doc/250478133/College-of-Medicine-results-in-the-Research-Excellence-Framework-REF-2014
- Friday 10 March 2017 13.41 GMT
- Friday 10 March 2017 13.44 GMT
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