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: 8195141
• 负责人: LISA M PASTORE
• 金额: $ 48.79万
• 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/8195141
• 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. PUBLIC HEALTH RELEVANCE: Our preliminary NIH-funded research and one small published study have found that some infertile women with early ovarian aging have a different genetic disorder than previously has been linked with early menopause. This study will compare this particular genetic disorder (Fragile X trinucleotide repeat level) in an existing infertile study group with two comparison groups: women who are infertile due to an anatomical cause unrelated to their ovaries, and a cohort of women with normal ovarian aging.

描述（由申请人提供）：原发性卵巢功能不全 (POI) 是一系列卵巢早期老化疾病，其特征是卵泡刺激素 (FSH) 水平升高，范围从卵巢储备减少（DOR、FSH > 10 mIU/mL 和月经规律）卵巢早衰（POF、FSH > 40 mIU/mL 和 40 岁之前闭经）。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 前突变（定义为 FMR1 基因中约 55 - 200 个 CGG 重复）筛查。虽然已知 5% 的 POF 女性存在脆弱的 X 前突变，但我们对 DOR 女性的 CGG 重复计数知之甚少。我们对 65 名患有 DOR 的女性进行的初步数据以及一份针对 27 名患有 POI（排除 POF）女性的已发表报告（Streuli 等）表明，35-44 的 CGG 重复在具有这种表型的女性中明显过多（患病率为 14-17%） ）。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 Streuli 的数据表明这是不正确的，并且确实存在与 35-44 个三联体重复相关的不育表型。拟议的研究直接响应 NIH 脆性 X 综合征和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表型之间的关联。本研究将比较 110 个 DOR 病例队列中的 CGG 重复计数与 2 个比较队列（参与全国妇女健康研究 (SWAN) 的 680 名已证明具有生育能力且卵巢正常老化（定义为 45 岁以上自然绝经）的女性），以及 170 名因解剖原因（如输卵管阻塞）而无法生育的女性）。 SWAN 队列的 DNA 样本已经收集完毕。第二个对照组将通过这笔赠款招募。具体目标是 (1) 确定 DOR 受试者中具有 35-44、45-54 和 >55 FMR1 CGG 重复的女性比例是否高于 2 个比较组，(2) 估计 CGG 重复的最佳阈值DOR 风险升高，(3) 描述这些表型不同的群体中 CGG 重复分布和潜在修饰因素。比较队列将提供关键信息来区分 DOR 是否是与 FMR1 基因相关的新表型，并将提供数据来阐明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力的影响（例如，缩短生殖窗口），因此可在临床上用于为患有 POI 的育龄妇女及其女性后代的个人决策提供医疗指导。我们的研究结果预计将挑战当前 FMR1 CGG 参考范围的解释，该参考范围基于儿童及其突变前携带者父母的脆性 X 综合征诊断，可能不适合筛查患有 POI 的成年女性。 公共健康相关性：我们由美国国立卫生研究院 (NIH) 资助的初步研究和一项小型已发表的研究发现，一些卵巢早衰的不孕女性患有与早期更年期相关的不同遗传疾病。这项研究将现有不孕症研究组中的这种特殊遗传性疾病（脆性 X 三核苷酸重复水平）与两个对照组进行比较：由于与卵巢无关的解剖原因而导致不孕的女性，以及卵巢正常老化的女性群体。