Genomic integrity of the X chromosome & Ovary-Specific Autosomal Genes

描述（申请人提供）：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。1-2%的女性患有卵巢功能不全，而遗传因素对卵巢功能不全的影响高达70%。除了不孕症，POI女性患骨质疏松症、心血管疾病发病率和死亡率的风险增加。目前，只有核型和FMR 1前突变检测提供给POI的妇女。目前，对于有卵巢功能丧失风险的女性来说，生育力保留是可行的，但仍然非常需要能够预测卵巢功能不全的强大和更好的生物标志物。我们有兴趣确定与POI相关的遗传生物标志物。在人类POI的病因学中，X染色体和与敲除动物模型相关的候选常染色体基因的作用已经被假设了很长时间，但在基因水平上几乎没有显示。我们构建了一种新的高分辨率基因组阵列，询问X染色体和134个候选常染色体基因拷贝数。我们表明，该阵列可以检测到小至500个碱基对的基因组不平衡，并且上级商业阵列。我们推测，病理性基因组不平衡，涉及X染色体和候选常染色体位点，将存在于超过10%的妇女患有POI。此外，我们将对X染色体外显子组以及134个候选常染色体基因的外显子组进行测序，以确定致病性突变对POI的贡献。我们的提案将测试我们的靶向方法在识别POI女性致病突变方面的相关性，并将刺激进一步研究这种靶向方法预测卵巢衰竭的可行性。拟议中的研究可能会发现新的途径，并为人类POI相关的基础科学研究提供未来的方向。

DESCRIPTION (provided by applicant): 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.