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.
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.
|Visootsak, Jeannie; Huddleston, Lillie; Buterbaugh, Allison et al. (2016) Influence of CHDs on psycho-social and neurodevelopmental outcomes in children with Down syndrome. Cardiol Young 26:250-6|
|Espinel, Whitney; Charen, Krista; Huddleston, Lillie et al. (2016) Improving Health Education for Women Who Carry an FMR1 Premutation. J Genet Couns 25:228-38|
|Hipp, Heather S; Charen, Krista H; Spencer, Jessica B et al. (2016) Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI). Menopause 23:993-9|
|Xie, Nina; Gong, He; Suhl, Joshua A et al. (2016) Reactivation of FMR1 by CRISPR/Cas9-Mediated Deletion of the Expanded CGG-Repeat of the Fragile X Chromosome. PLoS One 11:e0165499|
|Myrick, Leila K; Deng, Pan-Yue; Hashimoto, Hideharu et al. (2015) Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures. Proc Natl Acad Sci U S A 112:949-56|
|Suhl, Joshua A; Muddashetty, Ravi S; Anderson, Bart R et al. (2015) A 3' untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR. Proc Natl Acad Sci U S A 112:E6553-61|
|Myrick, Leila K; Hashimoto, Hideharu; Cheng, Xiaodong et al. (2015) Human FMRP contains an integral tandem Agenet (Tudor) and KH motif in the amino terminal domain. Hum Mol Genet 24:1733-40|
|Johnston, Henry Richard; Hu, Yijuan; Cutler, David J (2015) Population genetics identifies challenges in analyzing rare variants. Genet Epidemiol 39:145-8|