Unsolved genetic epilepsies- improve models first

The American Epilepsy Society does not recommend this for the top 4-5 priorities for the field. It should instead be a goal for 5-10 years from now, after the ability to develop improved models (priority #1 above) is achieved.

There are a myriad of known gene variants found within intronic or untranslated gene regions or at splice-sites that will require functional validation in vitro by expression of the variant in a CRISPR-edited cell and ultimately in a CRISPR-edited fly, fish, or mouse. Epigenetics (miRNAs, transposable elements, silencers) are tantalizing mechanisms for epileptogenesis but we are at embryonic stages in research. Efforts should bring in epigenetics experts from cancer, genetics, and immunology world to help drive this. We need a fresh canvas to think about this, as most existing studies on epigenetics are still focusing on gene/protein expression in a linear fashion. There needs to be a "big data" analysis of how non-coding, movable genetic elements affect the genome and in particular the epilepsy genome. The natural histories of genetic / phenotypic variants remain to be elucidated, and a clinical informatics approach is needed.