Project-1: Comprehensive phenotypic and genetic assessment of TE birth defects in patients

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PROJECT 1 | SUMMARY 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 50 candidate mutations have been associated with TEDs with varying degrees of confidence, but only a 20 of these genes are conclusively causative in TEDs. We hypothesize that there are unique genetic mutations that cause TEDs and that these act in distinct developmental pathways to determine the TED anatomical phenotype, associated anomalies, and the clinical outcome of these patients. Furthermore, we hypothesize that pre- repair and early post- repair anatomic, genetic, surgical, and clinical variables can be used to predict short and long-term clinical features and clinical outcomes in TED patients to advance treatment strategies. 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 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 anatomic phenotype, genotype, and clinical outcome data. Aim 1: Maintain and expand the multi-center TED phenotype-genotype registry. Aim 2: Identify new TED risk genes and variants by statistical analysis of de novo and rare inherited variants and integrative analysis with data from other developmental disorders and single cell functional genomics.