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

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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.