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

描述（由申请人提供）：原发性卵巢功能不全（POI）是一系列早期卵巢衰老疾病，其特征为卵泡刺激素（FSH）水平升高，范围从卵巢储备减少（DOR，FSH > 10 mIU/mL和月经规律）到卵巢早衰（POF，FSH > 40 mIU/mL和40岁以前闭经）。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FMR 1基因中约55 - 200个CGG重复）筛查。虽然已知5%的POF女性有脆性X前突变，但对DOR女性的CGG重复计数知之甚少。我们在65名DOR女性中的初步数据和27名POI女性（排除POF）的一份已发表报告（Streuli et al）表明，CGG重复序列35-44在具有这种表型的女性中明显过多（14-17%患病率）。目前的临床指南指出，FMR 1 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，确实存在与35-44个三联体重复相关的不育表型。该研究直接响应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FMR 1三联体重复计数与这种不育表型之间的关联。本研究将比较110例DOR病例的队列与2个比较队列（680名参与全国妇女健康研究（SWAN）的45岁以上自然绝经定义的具有已证实生育能力和正常卵巢老化的妇女，以及170名因解剖学原因（如输卵管闭塞）而不孕的妇女）的CGG重复计数。已经收集了SWAN队列的DNA样本。第二个对照组将通过这笔赠款招募。具体目的是（1）确定DOR受试者中FMR 1 CGG重复序列为35-44、45-54和>55的女性比例是否高于2个对照组，（2）估计DOR风险升高的CGG重复序列的最佳阈值，以及（3）表征这些表型不同队列中的CGG重复序列分布和潜在修饰剂。比较队列将提供关键信息，以区分DOR是否是与FMR 1基因相关的新表型，并将提供数据，以解开不孕症和卵巢老化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，减少的生殖窗口），因此可以在临床上用于为患有POI的育龄妇女及其雌性后代的个体决策提供医学指导。我们的研究结果预计将挑战目前FMR 1 CGG参考范围的解释，这是基于儿童及其前突变携带者父母的脆性X综合征的诊断，可能不适合筛查成年女性POI。 公共卫生相关性：我们的初步NIH资助的研究和一项小型已发表的研究发现，一些卵巢老化早期的不孕妇女有一种与以前不同的遗传疾病，与绝经早期有关。这项研究将在现有的不孕症研究组中比较这种特殊的遗传疾病（脆性X三核苷酸重复水平）与两个对照组：由于与卵巢无关的解剖原因而不孕的妇女，以及卵巢正常老化的妇女队列。

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.