Summary, Project 1 Tracheal esophageal birth defects (TEDs) occur when the separation of the trachea and esophagus from the common foregut is disrupted during early fetal development. TEDs often present at birth without a prenatal diagnosis and if left uncorrected, TEDs disrupt proper breathing and/or feeding and are usually life threatening. Even when corrected surgically, they are often associated with long-term comorbidity. Although there is compelling evidence for a major genetic component, the etiology of TEDs is largely unknown. About 40 candidate mutations have been associated with TEDs with varying degrees of confidence, but only a dozen of these genes have been validated in animal models and even then the development mechanisms they regulate are poorly understood. Our Premise is that there are unique unstudied genetic mutations that cause TEDs and that these act in distinct developmental pathways to determine the TED anatomic and histological phenotype and ultimately the clinical outcome of these patients. Our understanding of the clinical pathology of TEDs has been hampered by the lack of a detailed large scale genetic, anatomic, and clinical investigation of this patient population. Therefore, the primary goal of this project is to improve our understanding of the genetic and anatomic basis of tracheal esophageal birth defects (TEDs) in order to enhance diagnosis, determine factors that influence prognosis and advance treatment strategies. The second goal is to serve as catalyst for the developmental biology studies in projects 2 and 3 through the creation of a comprehensive database that will integrate histological and anatomic phenotype, genotype, and clinical outcome data. Aim 1: Identify candidate causative mutations in patients with TEDs using trio genomic sequencing of TED patients and their parents. Aim 2: Investigate the esophageal, tracheal, mediastinal and pulmonary anatomy in patients with TEDs before and after surgical repair. Aim 3: Create a multi-center TED registry that integrates a detailed description of the clinical and anatomic phenotype, genotype, surgical repair strategy, and long term clinical outcome in TED patients.