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)是一种早期卵巢老化的疾病，特征是卵泡刺激素(FSH)水平升高，范围从卵巢储备减少(DOR，FSH和GT；10mIU/毫升和定期月经)到卵巢早衰(POF，FSH和GT；40mIU/毫升和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会(ACMG)建议对POI女性进行遗传咨询和脆性X预突变(定义为FMR1基因中约55-200个CGG重复)筛查。虽然已知5%患有POF的女性具有脆性X预突变，但对患有DOR的女性CGG重复数知之甚少。我们在65名DOR妇女中的初步数据和在27名POI妇女(不包括POF)中发表的一份报告(Streuli等人)表明，CGG重复35-44在这一表型的妇女中明显过度表达(患病率为14-17%)。目前的临床指南指出，FMR1 CGG重复计数和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，确实存在与35-44个三联体重复相关的不孕不育表型。这项拟议的研究是对NIH脆性X综合征和相关疾病研究计划目标1.4和3.1的直接回应，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。这项研究将比较110例DOR病例和2个对照队列(680名年龄在45岁以上的自然绝经定义为生育能力和卵巢正常老化的妇女，参与全国妇女健康研究(SWAN)，以及170名因输卵管闭塞等解剖学原因而不孕的妇女)的CGG重复计数。来自天鹅队列的DNA样本已经收集完毕。第二个对照小组将通过这笔赠款招募。研究的具体目的是(1)确定DOR患者中携带35-44、45-54和&gt；55个FMR1 CGG重复的女性比例是否高于两个对照组，(2)估计CGG重复的最佳阈值，以增加DOR的风险，以及(3)描述CGG重复在这些不同表型的队列中的分布和潜在的修饰因素。这些比较队列将提供关键信息，以区分DOR是否是与FMR1基因相关的一种新表型，并将提供数据，以解开对不孕症和卵巢老化的潜在独立机制影响。通过拟议的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，生殖窗口缩短)，因此可以用于临床，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。我们的发现预计将挑战对当前FMR1 CGG参考范围的解释，该参考范围基于对儿童及其前突变携带者父母的脆性X综合征的诊断，可能不适合筛查患有POI的成年女性。

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.