Deciphering the Role of Copy Number Variants in Neuroendocrine Disorders of Infertility

项目摘要 尽管世界上有6%-12%的女性和男性患有不孕不育，但 对人类生殖的控制还没有得到充分的描述。在这项研究中，PI将研究遗传 特发性促性腺激素减退症(IHH)的背景，这是一种罕见的神经内分泌疾病，由 促性腺激素释放激素(GnRH)神经元信号缺陷，导致青春期延迟和 不孕不育。60%的IHH患者的遗传病因尚不清楚。这种缺失的遗传性可以归因于 到对难以捉摸的遗传变异的糟糕描述，如难以识别的拷贝数变异(CNV) 使用核型和微阵列等传统测序技术进行捕获。最近的优势是 下一代测序已经能够从外显子组测序数据中检测到更小的CNV。在这 研究表明，PI将在一大批IHH受试者(1400人)中利用这种尖端的CNV呼叫算法来 研究CNV对IHH缺失遗传性的贡献，了解GnRH神经元生物学和 破译罕见和常见生殖障碍的基因控制。私人投资委员会将探讨 CNV到已知和新的IHH基因，并将利用IHH患者和受试者的人类表型 注册到MASH General Brigham生物库(将在其中调用来自ES的CNV)以确定 CNV在人类疾病表达中的后果。私隐专员公署将根据 塞米纳拉博士、塔科夫斯基博士和巴拉苏布拉曼尼亚博士的导师。塞米娜拉博士是NICHD的私家侦探- P50国家生殖和不孕不育翻译研究中心 马萨诸塞州综合医院(MGH)的生殖医学(CRM)，并将提供所有可用的 成功完成他的研究提案的资源(进入ES和表型数据库)如下 以及直接指导，以促进她过渡到独立的职业生涯，成为一名内科科学家。Dr。 Talkowski是MGH基因组医学中心(CGM)的主任，并开创了新型CNV 接近了。在他的指导下，PI将分析IHH、对照组和生物库受试者中来自ES的CNV。Dr。 Talkowski也是基因组学核心的主任，该核心容纳了所有用于功能验证的资源 将从PI的CNV分析(IPSC来源的GnRH细胞)中发现的新基因。最后，戴维斯博士说。 Balasubramanian是NCTRI-CRM的助理主任，在人口研究方面拥有丰富的专业知识 为人类基因研究提供生物库，并将为PI的成功提供重要指导 完成她的求婚。此外，候选人还将继续进行正式的课程学习和定期参与 有关生殖内分泌学和遗传学的研究会议。这个项目将促进 在临床研究和人类遗传学领域的技能发展，代表着一个全面的 计划确定CNV在罕见的遗传性不孕症神经内分泌疾病中的作用，为PI应用做准备 获得职业发展奖，继续接受培训，成为一名独立的临床调查员。

PROJECT ABSTRACT Despite 6-12% of women and men around the world suffering from infertility, the full ensemble of genes that control human reproduction has not been fully characterized. In this study, the PI will study the genetic background of Idiopathic Hypogonadotropic Hypogonadism (IHH), a rare neuroendocrine disorder caused by defects in Gonadotropin Releasing Hormone (GnRH) neuronal signaling, that leads to delayed puberty and infertility. The genetic etiology in 60% of IHH patients remains unknown. This missing heritability can be attributed to poor characterization of elusive genetic variation such as copy number variants (CNVs) that are hard to capture using traditional sequencing technologies, such as karyotypes and microarrays. Recent advantages in next generation sequencing have allowed detection of smaller CNVs from exome sequencing (ES) data. In this study, the PI will utilize such cutting edge CNV calling algorithms in a large cohort of IHH subjects (1,400) to examine the contribution of CNVs to the missing heritability of IHH, understand the GnRH neuronal biology and decipher the genetic control of rare and common reproductive disorders. The PI will explore the contribution of CNVs to known and novel IHH genes and will utilize human phenotypes from the IHH patients and subjects enrolled to the Mass General Brigham biobank (in whom CNVs from ES will be called) to determine the consequences of CNVs in human disease expression. The PI will complete the proposed work under the mentorship of Dr. Seminara, Dr. Talkowski and Dr. Balasubramanian. Dr. Seminara is the PI of a NICHD- sponsored P50 National Center of Translational Research in Reproduction and Infertility (NCTRI) – Center for Reproductive Medicine (CRM) at the Massachusetts General Hospital (MGH) and will provide all available resources (access to ES and phenotypic databases) for the successful completion of his research proposal as well as direct mentorship to facilitate her transition to an independent career as a physician scientist. Dr. Talkowski is the Director for the Center of Genomic Medicine (CGM) at MGH and has pioneered novel CNV approaches. Under his guidance, the PI will analyze ES derived CNVs in IHH, control and biobank subjects. Dr. Talkowski is also the Director of the Genomics Core that houses all the resources for the functional validation of the novel genes that will emerge from the PI’s CNV analyses (IPSc derived GnRH cells). Finally, Dr. Balasubramanian is the Assistant Director of the NCTRI-CRM with significant expertise in studying population biobanks for human genetic investigations and will provide important guidance to the PI for the successful completion of her proposal. In addition, the candidate will pursue formal coursework and regular engagement in research meetings related to both reproductive endocrinology and genetics. This project will facilitate development of skills in the areas of clinical investigation and human genetics and represents a comprehensive plan to identify the role of CNVs in rare inherited neuroendocrine disorders of infertility, preparing the PI to apply for a career development award to continue her training to become an independent clinical investigator.