OVERALL | PROJECT SUMMARY The goal of the CLEAR Consortium is to elucidate the developmental and genetic mechanisms of trachea- esophageal birth defects (TEDs) to better understand their etiology, enhance diagnosis, improve treatment, and inform strategies to generate tissue in vitro that might ultimately be used for repair. The trachea and esophagus arise from the separation of a common foregut tube during early fetal development. Defects in trachea- esophageal development cause a spectrum of life-threatening TEDs, which occur in ~1:3500 births and prevent proper breathing and feeding in newborn infants. Gene mutations are known to cause TEDs but have only been identified in ~15% of cases and how these cause congenital malformations is poorly defined. To address this unmet need we have assembled an experienced and highly collaborative multi-disciplinary team of clinicians, surgeons, geneticists, computational scientists, and developmental and stem cell biologists that use an innovative combination of patient genome sequencing, neonatal MRI, animal models, quantitative cell biology, single cell genomics, CRISPR gene editing and human PSCs-derived organoids to study TEDs. This Multi-PI project centered at Cincinnati Children’s Hospital (CCHMC) and Columbia University Medical Center (CUMC) is led by Wendy Chung MD PhD (CUMC), Paul Kingma MD PhD (CCHMC), Yufeng Shen PhD (CUMC), James Wells PhD (CCHMC) and Aaron Zorn PhD (contact PI; CCHMC). Our program has 3 projects linked together by an Integrated Genomics Core. Project-1: Comprehensive phenotypic and genetic assessment of TED patients. Project-2: Defining the developmental mechanisms of TEDs in animal models. Project-3: Modeling EA in human PSC-derived embryonic tissues.