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

项目1|总结 气管食道出生缺陷(TED)发生在气管和食道从气管和食道分离 在胎儿早期发育过程中，常见的前肠被破坏。Ted通常在出生时出现，而不是产前 诊断和如果不加以纠正，TED会扰乱正常的呼吸和/或喂养，通常会危及生命。 即使经过手术矫正，它们也往往与长期的合并症有关。尽管有 TEDS的病因在很大程度上是未知的，这是一个主要遗传成分的令人信服的证据。大约50名候选人 突变与TED有不同程度的可信度，但只有20个这样的基因 在TED中是决定性的致因。我们假设有独特的基因突变会导致 TED和它们在不同的发育途径中起作用，以确定TED的解剖表型， 相关异常，以及这些患者的临床结果。此外，我们假设Pre- 修复和修复后早期解剖学、遗传学、外科和临床变量可用于预测 TED患者的近期和远期临床特征和临床结果以推进治疗 战略。我们对TEDS临床病理的了解因缺乏详细的 对该患者群体进行大规模的遗传学、解剖学和临床研究。因此，其首要目标是 这项计划是为了加深我们对TEDS的遗传学和解剖学基础的了解，以便加强 诊断，确定影响预后的因素，并提出治疗策略。第二个目标是 作为项目2和3中发育生物学研究的催化剂，通过创建一个 将整合解剖表型、基因和临床结果数据的综合数据库。 目的1：维护和扩展多中心TED表型-基因登记系统。 目的2：通过对新发现的和罕见的遗传变异的统计分析，识别新的TED危险基因和变异。 综合分析来自其他发育障碍和单细胞功能基因组学的数据。

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.