Fragile X Premutations Among Women Diagnosed with Diminished Ovarian Reserve

描述(申请人提供)：在无法怀孕的女性中，约10%被诊断为卵巢储备减少(DOR)。DOR描述了卵巢功能的下降。有这种诊断的妇女很少(5%)会自发怀孕，而且她们对生育药物的反应不正常。目前还没有有效的治疗方法来扭转这种情况。患有DOR的女性可能存在脆性X基因的预突变改变(“携带者”)。这种前突变的携带者也增加了卵巢早衰(POF)的风险，POF是比DOR更严重的卵巢功能障碍。大约5%-6%的POF妇女是前突变携带者(如果她有过早绝经的家族史，14%；否则2%)。目前尚不清楚患有DOR的女性中有多大比例是前突变携带者。我们将把目前关于POF的脆性X研究扩展到DOR人群。这项研究的具体目的是：(1)确定脆性X预突变在DOR妇女中的患病率；(2)确定脆性X预突变的患病率是否与绝经早期和/或不孕不育的家族史有关；(3)确定患者的年龄、卵泡刺激素水平和预突变的“大小”之间是否存在关系。在这一前瞻性队列中，65名符合条件的DOR患者将从三个学术医疗中心(弗吉尼亚州、北卡罗来纳州)和一个私人诊所招募。该方案包括检测前遗传咨询、用于脆性X检测的血液样本和问卷。血检结果将不会出现在病历中，女性将可以选择是否了解自己的脆性X检测结果。将为所有携带者提供检测后遗传咨询。我们目前正在对这项研究进行试点测试；在我们的第一批16名参与者中，有一名是携带者，15名想知道他们的测试结果。统计分析将由二项检验比例、Logistic回归模型和线性回归模型组成。这项研究可能会从脆性X前突变中识别出一种新的表型，开始开发一种临床工具来预测携带者的不孕年龄，并加强携带者的生殖计划和决策。生育治疗对脆性X携带者的影响是值得注意的，因为它会将脆性X综合征传播给通过生育治疗出生的儿童；因此，这项研究也适用于更大的问题，即意外基因检测对社会和个人的影响。

DESCRIPTION (provided by applicant): About 10% of women who are unable to get pregnant are diagnosed with diminished ovarian reserve (DOR). DOR describes a reduction in ovarian function. Few women (<5%) with this diagnosis will become pregnant spontaneously and they do not respond normally to fertility drugs. There are no effective treatments to reverse this condition. Women with DOR may have a premutation alteration of the Fragile X gene ("carriers"). Carriers of this premutation are also at increased risk for premature ovarian failure (POF), which is a greater degree of ovarian dysfunction than DOR. About 5-6% of the women with POF are premutation carriers (14% if she has a family history of premature menopause; 2% otherwise). It is unknown what percentage of women with DOR are premutation carriers. We will extend the current Fragile X research on POF to the DOR population. Specific aims of this study are: (1) to determine the prevalence of the Fragile X premutation among DOR women; (2) to determine if the prevalence varies with a family history of early menopause and/or infertility; and (3) to determine if there is a relationship between patient age, follicle stimulating hormone level, and the "size" of the premutation. In this prospective cohort, 65 eligible DOR patients will be enrolled from three academic medical centers (Virginia, North Carolina) and one private practice. The protocol includes pretest genetic counseling, a blood sample for Fragile X testing, and questionnaires. No blood test results will be filed in the medical charts, and women will have the option of learning their Fragile X test results or not. Post test genetic counseling will be provided to all carriers. We are currently pilot-testing this study; among our first 16 participants, one is a carrier and 15 have wanted to learn their test results. The statistical analysis will consist of proportions with binomial testing, logistic regression models, and linear regression models. This research may identify a new phenotype from Fragile X premutations, begin the development of a clinical tool to predict age-at-infertility among carriers, and enhance reproductive planning and decision-making by carriers. The implications of fertility treatment to Fragile X carriers is notable in terms of transmitting Fragile X Syndrome to the children born via fertility treatment; therefore, this research also has applications to the greater issue of the impact on society and individuals from unanticipated genetic testing.