The Genetics and penetrance of the Mullerian Anomalies: Addressing the Challenges of the bench to bedside gap.

项目概要： 拟议的合作将通过结合以下方面的专业知识， 多个合作者，以解决穆勒异常（MA）的遗传原因。MA是一个相对 女性苗勒管常见发育异常，导致苗勒管非典型变异 子宫和阴道解剖学MA是复杂的妇科出生缺陷，发生在5.5%的一般 在女性人口中，8%的不孕妇女、13%的流产妇女和24.5%的 流产和不孕尽管对妇女的健康有着巨大的影响，但MA的病因学仍然是 大部分未知。虽然已经描述了MA的家族遗传，但没有单一基因或突变。 被发现对MA负责。了解遗传性和更广泛的健康影响， MAs是迫切需要的。这种多学科合作提供了一个独特的机会， 群体表型，遗传因素和分子机制参与MA，以桥梁临床和 对这种先天缺陷的基础科学研究在关注这些补充调查时，本研究将 召集一个多学科小组，以弥补我们对这一疾病的认识方面的重大空白。 此外，我们的儿科妇科专家团队，基因组学，发育生物学和现代数据 科学将制定合作实验方法，收集宝贵的初步数据， 支持将来的R01应用程序。该研究将解决MA研究中的三个关键空白：（1）分析 MA诊断的表型谱和患病率（包括人群频率和 表型聚类）通过使用Cerner真实世界数据集（2）候选基因的鉴定 通过基因检测可能导致生殖道发育和MA中断的变异， 使用全外显子组测序（WES）的MA患者及其未受影响的家族成员，和（3） 通过体内功能检测，对选定的候选基因在MA发病机制中的系统功能进行了检测。 基因组分析该团队成功实现目标将解决以下几个问题 具有重要临床转化价值的公认的短期和长期研究目标。

PROJECT SUMMARY: The proposed collaboration will develop a multi-pronged research program by combining the expertise of multiple collaborators to address the genetic causes of Müllerian anomalies (MAs). MAs are a relatively common developmental abnormality of the Müllerian ducts in females, leading to atypical variations of the uterine and vaginal anatomy. MAs are complex gynecological birth defects occurring in 5.5% of the general female population, 8% of infertile women, 13% of women with miscarriages and 24.5% of those with miscarriages and infertility. Despite the immense impact on woman’s health, the etiology of MAs remains largely unknown. Although familial inheritance of MAs has been described, no single gene or mutation has been found to be responsible for MAs. Understanding the heritability and broader health implications of MAs is desperately needed. This multidisciplinary collaboration provides a unique opportunity to examine population phenotypes, genetic factors, and molecular mechanisms involved in MAs to bridge clinical and basic science research on this birth defect. In focusing on these complementary inquiries, this research will bring together a multidisciplinary team to address significant gaps in our knowledge of this disease. Further, our team of experts in pediatric gynecology, genomics, developmental biology, and modern data science will formulate collaborative experimental approaches to collect invaluable preliminary data to support a future R01 application. The research will address three key gaps in MA studies: (1) analysis of the phenotypic spectrum and prevalence of MAs diagnoses (including population frequencies and phenotypic clusters) via the use of the Cerner Real-World Dataset (2) identification of candidate gene variants potentially causing disruption of reproductive tract development and MAs via genetic testing of patients with MAs and their unaffected family members using whole exome sequencing (WES) , and (3) systematic functional testing of selected candidate genes in the pathogenesis of MAs via in vivo functional genomic analyses. The successful accomplishment of the Aims by this team will address several recognized short-term and long-term research goals of critical clinical translational value.