An epigenomic approach to identifying noncoding mutations in epilepsy

We propose a research program for the independent phase of this career development award focused on understanding the genetic causes of the pediatric epilepsies. The candidate has expertise in the use of next generation sequencing technologies to identify coding variations that cause genetic disease, these skills will be applied to addressing the role of noncoding DNA variation in epilepsy. Epilepsy affects 1 in 26 individuals across the globe, including ~22 million people in the US alone. The epileptic encephalopathies (EEs) are the most severe of all epilepsies and most do not respond to current treatments, necessitating the need for novel therapeutic interventions. The first step towards designing new treatments is to identify the genetic mutations that cause this disorder. Significant progress has been made in this regard; a quarter of patients with EE have causative de novo mutations in the protein-coding regions of over 50 genes. However, while a number of genes are yet to be identified, these coding mutations are unlikely to account for all remaining cases. Recent studies, including the NIH-funded ENCODE and the Roadpmap Epigenomics project, have demonstrated the importance of noncoding elements in controlling how and when genes are expressed. We hypothesize that noncoding mutations cause epilespy by disrupting the expression of target genes that are important in neurogenesis. The most unbiased way to detect all noncoding genetic variation in the human genome is to perform whole-genome sequencing, this technique will likely be prevalent in the future of genetics. However, a major challenge to its success lies in our ability to differentiate between the functional causal noncoding mutation and the millions of non-pathogenic variants identified. This challenge requires an understanding of how noncoding elements control gene expression during neurogenesis and neuronal function. During the mentored phase of this career development award the candidate established a framework for identifying candidate noncoding regions for epileptogenesis and showed that these regions are disrupted in patients with epilepsy. In the independent phase of this award the candidate will use this framework to identify additional noncoding regions that are either altered during epileptogenesis or control the expression of known epilepsy genes. The overall goal of this award is to build a ‘regulatory epigenome atlas’ for the interpretation of genomic variants. This experimental model can rapidly be applied to other genes that cause neurodevelopmental disorders, contributing more broadly to our understanding of disease and laying the foundation for the candidate’s independent research plan.