The goals of our Center, "Modifiers of FMR1-associated disorders: application of high throughput technologies", are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1 associated conditions. Project A will focus on the variable expression of epilepsy among boys with fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the premutation (PM), with a lifetime prevalence of 30% among males. Project C focuses fragile X association primary ovarian insufficiency (FXPOl), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistatic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. Specifically, the Recruitment Core will: 1) identify project-eligible probands from fragile X families;2) screen for initial eligibility, obtain consent, and collect samples;and 3) obtain pedigree histories to investigate clustering of phenotypes.

Public Health Relevance

The goal of Core B, the Recruitment Core, will be to efficiently recruit 600 probands into the study using established infrastructures that include a wealth of clinical data and, for FXTAS and FXPOl, stored DNA samples. The Core personnel have vast experience working with families who have fragile-X associated disorders and a strong track record of recruitment and collaboration with other research programs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
1U54NS091859-01
Application #
8795376
Study Section
Special Emphasis Panel (ZHD1-DSR-Y (53))
Project Start
Project End
Budget Start
2014-09-22
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$349,846
Indirect Cost
$125,586
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322