FMR1 CGG Repeats in Primary Ovarian Insufficiency Women vs. 2 Comparison Groups

原发性卵巢功能不全女性与 2 个比较组中的 FMR1 CGG 重复

• 批准号: 8328944
• 负责人: LISA M PASTORE
• 金额: $ 31.91万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328944
• 关键词: Adult; Age; Aging; Alleles; Amenorrhea; American; American College of Obstetricians and Gynecologists; Ataxia; Biological; Biological Assay; CGG repeat; California; Candidate Disease Gene; Child; Clinical; DNA; Data; Decision Making; Diagnosis; Disease; Enrollment; FMR1 Gene; Family; Female; Fertility; Follicle Stimulating Hormone; Fragile X Premutation; Fragile X Syndrome; Frequencies; Functional disorder; Funding; Future; Genes; Genetic; Genetic Counseling; Goals; Grant; Guidelines; Haplotypes; Hereditary Disease; Individual; Infertility; Interruption; Investigation; Laboratories; Link; Medical; Medical Genetics; Menopause; Menstruation; Mental Retardation; Mutation; Normal Range; North Carolina; Ovarian; Ovary; Parents; Phenotype; Physiological Processes; Premature Ovarian Failure; Prevalence; Process; Publishing; Recording of previous events; Recruitment Activity; Reference Values; Relative (related person); Reporting; Research; Risk; Risk Marker; Sampling; Sampling Studies; Screening procedure; Sensitivity and Specificity; Source; Trinucleotide Repeats; Tubal Occlusion; Turner' s Syndrome; United States National Institutes of Health; Virginia; Woman; Women' s Health; base; boys; cohort; college; comparison group; experience; insight; interest; offspring; older men; patient population; quality assurance; reproductive; reproductive success; response; sample collection

DESCRIPTION (provided by applicant): Primary Ovarian Insufficiency (POI) is a spectrum of disorders of early ovarian aging characterized by elevated follicle stimulating hormone (FSH) levels ranging from Diminished Ovarian Reserve (DOR, FSH > 10 mIU/mL and regular menses) to premature ovarian failure (POF, FSH > 40 mIU/mL and amenorrhea before age 40). The Genetics Committee of the American College of Obstetricians and Gynecologists and the American College for Medical Genetics (ACMG) have recommended genetic counseling and fragile X premutation (defined as ~55 - 200 CGG repeats in the FMR1 gene) screening for women with POI. While it is known that 5% of women with POF have a fragile X premutation, little is known about the CGG repeat count in women with DOR. Our preliminary data in 65 women with DOR and one published report (Streuli et al) in 27 women with POI (POF excluded) suggest that CGG repeats of 35-44 are markedly over-represented in women with this phenotype (14-17% prevalence). Current clinical guidelines state that an FMR1 CGG repeat count < 45 is not associated with an abnormal phenotype; however our data and that from Streuli suggest that this is incorrect, and that indeed there is an infertility phenotype associated with 35-44 triplet repeats. The proposed study, in direct response to the NIH Research Plan on Fragile X Syndrome and Associated Disorders Objectives 1.4 and 3.1, seeks to substantiate the association between the FMR1 triplet repeat count and this infertility phenotype. This study will compare the CGG repeat count in a cohort of 110 DOR cases with 2 comparison cohorts (680 women with proven fertility and normal ovarian aging defined by natural menopause over age 45 participating in the Study of Women's Health Across the Nation (SWAN), and 170 women who are infertile due to an anatomical reason such as tubal occlusion). DNA samples from the SWAN cohort have already been collected. The second comparison group will be recruited through this grant. The specific aims are to (1) determine if the proportion women with 35-44, 45-54 and >55 FMR1 CGG repeats is greater in subjects with DOR than in the 2 comparison groups, (2) estimate the optimal threshold of CGG repeats for an elevated risk of DOR, and (3) characterize the CGG repeat distribution and potential modifiers in these phenotypically distinct cohorts. The comparisons cohorts will provide critical information to distinguish whether DOR is a new phenotype associated with the FMR1 gene and will provide data with which to disentangle the potential separate mechanistic influences on infertility and ovarian aging. Data acquired by the proposed studies will clarify the effects of allele size on fertility (e.g., reduced reproductive window) and therefore can be used clinically to provide medical guidance for individual decision-making by reproductive age women with POI and their female offspring. Our findings are anticipated to challenge the interpretation of the current FMR1 CGG reference range, which is based on the diagnosis of Fragile X Syndrome in children and their premutation carrier parents, and may not be appropriate for screening adult females with POI.

描述（由申请人提供）：原发性卵巢功能不全（POI）是一种以促卵泡激素（FSH）水平升高为特征的早期卵巢衰老疾病，范围从卵巢储备减少（DOR, FSH > 10 mIU/mL和月经规律）到卵巢早衰（POF, FSH > 40 mIU/mL和40岁前闭经）。美国妇产科学院遗传学委员会和美国医学遗传学学院（ACMG）建议对POI女性进行遗传咨询和脆性X基因突变（定义为FMR1基因中约55 - 200个CGG重复序列）筛查。虽然已知5%的POF女性有脆性X基因突变，但对DOR女性的CGG重复计数知之甚少。我们对65名DOR女性的初步数据和一份已发表的报告（Streuli等）对27名POI女性（不包括POF）的数据表明，35-44的CGG重复序列在该表型女性中明显过高（14-17%的患病率）。目前的临床指南指出，FMR1 CGG重复计数< 45与异常表型无关；然而，我们的数据和来自Streuli的数据表明这是不正确的，并且确实存在与35-44三胞胎重复相关的不孕表型。拟议的研究直接响应了NIH脆性X综合征及相关疾病研究计划目标1.4和3.1，旨在证实FMR1三联体重复计数与这种不孕症表型之间的关联。本研究将比较110例DOR病例的CGG重复计数与2个比较队列（680名参加全国妇女健康研究（SWAN）的45岁以上经证实有生育能力且卵巢正常衰老的妇女，以及170名因解剖学原因（如输卵管闭塞）导致不孕的妇女）。已经收集了SWAN队列的DNA样本。第二个比较组将通过这笔赠款征聘。具体目的是：(1)确定DOR受试者中35-44、45-54和> - 55 FMR1 CGG重复序列的女性比例是否高于两个对照组，(2)估计CGG重复序列升高DOR风险的最佳阈值，(3)表征这些表型不同的队列中CGG重复序列的分布和潜在修饰因子。比较队列将提供关键信息，以区分DOR是否是与FMR1基因相关的新表型，并将提供数据，以解开对不孕症和卵巢衰老的潜在单独机制影响。拟议研究获得的数据将阐明等位基因大小对生育能力的影响（例如，生殖窗口减少），因此可用于临床，为患有POI的育龄妇女及其女性后代的个人决策提供医学指导。我们的研究结果有望挑战当前FMR1 CGG参考范围的解释，该参考范围是基于儿童及其突变前携带者父母对脆性X综合征的诊断，可能不适合筛查成年女性POI。