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

苗勒管异常的遗传学和外显率：解决替补与床边差距的挑战。

• 批准号: 10668122
• 负责人: David M Hedges
• 金额: $ 24.03万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-29 至 2025-08-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668122
• 关键词: Address; Adolescence; Affect; Amenorrhea; Anatomy; Auditory; Basic Science; CRISPR/Cas technology; Candidate Disease Gene; Cardiovascular system; Caring; Childhood; Client; Clinical; Clinical Sciences; Cohort Studies; Collaborations; Complex; Congenital Abnormality; Data; Data Science; Data Set; Development; Developmental Biology; Diagnosis; Disease; Dysmenorrhea; Economics; Ensure; Epidemiology; Etiology; Evaluation; Face; Failure; Family; Family member; Female; Fertility; Frequencies; Future; Genes; Genetic; Genomics; Goals; Gynecologic; Gynecology; Health; Health Personnel; Heritability; Heterozygote; Infertility; Inheritance Patterns; Interdisciplinary Study; International; Investigation; Kidney; Knowledge; Malignant - descriptor; Medical Records; Modernization; Molecular; Mutation; Organ; Organogenesis; Outcome; Parents; Pathogenesis; Pathway interactions; Patients; Pattern; Penetrance; Phenotype; Physicians; Population; Pregnancy Complications; Prevalence; Principal Investigator; Prognosis; Provider; Publishing; Race; Records; Reproductive Health; Research; Role; Scientist; Siblings; Signal Pathway; Site; Spontaneous abortion; Structure of paramesonephric duct; Technology; Testing; Uterus; Vagina; Variant; Woman; Women' s Health; bench to bedside; candidate identification; candidate selection; care outcomes; clinical translation; cohort; comorbidity; data harmonization; diagnostic strategy; diversity and equity; exome sequencing; functional genomics; genetic testing; genetic variant; genome editing; genome-wide; improved; in vivo; insight; knowledge translation; long-term sequelae; malformation; multidisciplinary; novel; patient population; programs; recruit; reproductive; reproductive tract; skeletal; translational impact; transmission process

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.

项目概要： 拟议的合作将结合以下领域的专业知识来开发多管齐下的研究计划 多个合作者来解决苗勒管异常 (MA) 的遗传原因是一个相对的问题。 女性苗勒管的常见发育异常，导致苗勒管的非典型变异 子宫和阴道解剖结构异常是复杂的妇科出生缺陷，发生率一般为 5.5%。 女性人口中，8%的不孕妇女、13%的流产妇女和24.5%的流产妇女 尽管流产和不孕症对女性健康有巨大影响，但 MA 的病因仍然存在。 尽管MA的家族遗传已被描述，但尚无单一基因或突变。 被发现与 MA 的遗传性和更广泛的健康影响有关。 迫切需要这种多学科合作提供了独特的研究机会。 MA 涉及的群体表型、遗传因素和分子机制，以连接临床和 关于这种先天缺陷的基础科学研究将重点放在这些补充性的调查上。 组建一个多学科团队来解决我们对该疾病知识的重大差距。 此外，我们的儿科妇科、基因组学、发育生物学和现代数据专家团队 科学将制定协作实验方法来收集宝贵的初步数据 支持未来的 R01 应用。该研究将解决 MA 研究中的三个关键差距：(1) 分析 MA 诊断的表型谱和患病率（包括群体频率和 表型簇）通过使用Cerner真实世界数据集（2）识别候选基因 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) 分析 MA 患者及其未受影响的家庭成员，以及 (3) 通过体内功能对 MA 发病机制中选定的候选基因进行系统功能测试 该团队成功实现的目标将解决几个问题。 公认的具有关键临床转化价值的短期和长期研究目标。