We propose a research-training program to prepare an independent young investigator focused on understanding the genetic causes of neurodevelopmental disorders. 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 20 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 project, have demonstrated the importance of noncoding elements in controlling how and when genes are expressed. We hypothesize that noncoding mutations cause EE 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 ou 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. This training program implements the use of epigenomic data and interpretation to identify important noncoding DNA regions in EE. Dr. Mefford is an expert in human molecular genetics research and has made a significant contribution to the understanding of genetic mutation in neurodevelopmental disorders, including epilepsy. Dr. Mefford will serve as primary mentor for the scientific and professional development of the candidate. Moreover, the candidate has assembled an advisory committee of experts in the fields in which she requires training and mentorship;Dr. Stamatoyannopoulos will support generation of epigenomic data, as well as establishing novel computational pipelines for interpretation, Dr. Shendure will advise in the development of a novel targeted RNA expression methodology, and Dr. Doherty will assist in neuronal cellular differentiation techniques. Moreover, the Department of Pediatrics, University of Washington, has an excellent track record of assisting fellows'transition to independence. Overall, the University of Washington School of Medicine is an ideal setting for acquiring new research skills, performing didactic training and benefiting from excellent mentorship from field leaders towards becoming a successful independent investigator. This career award will allow the candidate to develop a framework to identify candidate EE noncoding regions, using the genes that we have already defined as causes of EE as a model. First by identifying the neuronal- specific cis-regulatory regions around known EE genes. Second, using CHD2 as a model, we will identify the noncoding DNA targets of this protein, and examine how the function of these noncoding regions is affected by CHD2 loss. Together these noncoding DNA regions move towards the development of a 'regulatory epileptogenesis atlas'for prioritizing variants from whole-genome sequencing studies. 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.

Public Health Relevance

Epilepsy affects 1 in 26 individuals across the globe, including ~22 million people in the US alone;making it one of the most common neurodevelopmental disorders. Many children with the most severe types of epilepsy do not respond to current treatments, making seizures difficult to control and the look-term outcome for these patients is poor. Finding the genetic mutations that cause these disorders is the first step towards understanding the pathways that are disrupted in epilepsy, and facilitates the ultimate goal of identifying new treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Career Transition Award (K99)
Project #
1K99NS089858-01
Application #
8804829
Study Section
NST-2 Subcommittee (NST)
Program Officer
Whittemore, Vicky R
Project Start
2014-09-30
Project End
2016-07-31
Budget Start
2014-09-30
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$91,098
Indirect Cost
$6,748
Name
University of Washington
Department
Pediatrics
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195