Genomic integrity of the X chromosome and Ovary-Specific Autosomal Gene

摘要 原始卵泡池耗竭是大多数女性原发性卵巢功能不全(POI)的原因。POI困扰 1-2%的女性，遗传因素对POI的贡献高达70%。除了不孕不育，患有POI的女性还在 增加骨质疏松症、心血管发病率和死亡率的风险。目前只有核型和FMR1 对患有POI的女性提供突变前检测。目前，对有生育风险的妇女来说，保留生育能力是可行的 对于卵巢功能的丧失，仍然非常需要强大和更好的能够预测的生物标志物 卵巢功能不全。我们对识别与POI相关的遗传生物标记物感兴趣。的作用 从基因敲除的动物模型中发现的X染色体和候选常染色体基因 在人类POI的病因学中，假说由来已久，但在基因水平上却鲜有发现。我们 构建了一种新的询问X染色体和134候选染色体的高分辨率基因组阵列 常染色体基因拷贝数。我们表明，这种阵列可以检测到小到500个碱基的基因组不平衡 对，优于商用阵列。我们假设病理性基因组失衡涉及 X染色体和候选常染色体基因座将出现在超过10%的POI患者中。 此外，我们还将对X染色体外显子以及134个候选常染色体外显子体进行测序 定义致病突变对POI的贡献的基因。我们的提案将检验我们的 有针对性地识别POI女性的致病基因突变，并将推动进一步的研究 这种有针对性的方法来预测卵巢衰竭的可行性。拟议的研究可能会确定小说 并为与人类POI相关的基础科学研究提供了未来的方向。

Abstract Primordial follicle pool depletion is the cause of primary ovarian insufficiency (POI) in most women. POI afflicts 1-2% of women, and genetics contributes as much as 70% to POI. Besides infertility, women with POI are at increased risk for osteoporosis, cardiovascular morbidity and mortality. Currently only karyotype and FMR1 pre-mutation testing are offered to women with POI. Fertility preservation is currently feasible for women at risk for losing ovarian function, yet there is a great need for robust and better biomarkers capable of predicting ovarian insufficiency. We are interested in identifying genetic biomarkers that associate with POI. The role of the X chromosome and candidate autosomal genes implicated from knockout animal models has been hypothesized for a long time in the etiology of human POI, yet there is little to show at the gene level. We constructed a novel high-resolution genomic array that interrogates the X chromosome and 134 candidate autosomal gene copy numbers. We show that this array can detect genomic imbalances as small as 500 base pairs, and is superior to commercial arrays. We hypothesize that pathologic genomic imbalances involving the X chromosome and candidate autosomal loci, will be present in more than 10% of women who suffer POI. Moreover, we will sequence the X-chromosome exomes, as well as the exomes of 134 candidate autosomal genes to define contribution of pathogenic mutations to POI. Our proposal will test the relevance of our targeted approach in identifying pathogenic mutations in women with POI, and will stimulate further research into the feasibility of such targeted approaches to predict ovarian failure. Proposed studies may identify novel pathways, and provide future directions for basic science investigations relevant to human POI.