Abstracts

Summary: Progress in the genetics of the epilepsies continues at a striking pace. Real clinical benefits are being realised for patients, for diagnosis, prognosis and management. Dravet syndrome stands out as a dramatic example of genetic causation providing diagnostic clarity, basic explanation of disease biology and treatment guidance. In common with many other neuropsychiatric diseases, copy number variants (microdeletions and duplications) are emerging as an important category of genetic causation in the epilepsies. Several recurrent microdeletions/duplications have been described, with a larger number of private or unique variants. Much remains to be done from a genetic perspective in understanding the mechanisms whereby these variants lead to epilepsy phenotypes, especially as the same variant can lead to other neuropsychiatric, or entirely extra-neurological, phenotypes. Many hypotheses have been proposed, including unmasking of recessive alleles, gene interruption, gene fusion, imprinting, alteration of long-range control elements and alteration of chromatin structure/position. Clear explanations have yet to be discovered, though the methods to explore causality and mechanisms are being employed, with the tantalising prospect of the discovery of more epilepsy genes being one reason to pursue basic science research in this area. From a clinical perspective, more and more copy number changes are likely to be found during routine clinical investigation, as more laboratories move to tools for examination of chromosomal rearrangements that produce high-resolution data on structural genetic variants. Practicing clinicians will therefore find themselves faced with often detailed reports, for example listing variants of likely pathological significance , no clinical significance and unknown significance . This is one area in particular, however, where close collaboration between basic scientists and clinicians will prove informative and productive. Clinicians with access to the patients they are caring for will be able to provide clinical and investigational data from individual patients that inform genetic studies; widely-accessible databases, such as DECIPHER, will allow the sharing of information; geneticists and bioinformaticians will be able to apply burgeoning web resources in detailed dissection of copy number changes. The integration of all these approaches promises to allow us to make the most of these new discoveries, to illuminate our understanding of the epilepsies and hopefully to help improve the lives of people with epilepsy. This translational workshop aims to illustrate these concepts and place copy number change in the broader context of epilepsy genetics.