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

项目1：TE出生缺陷患者的综合表型和遗传评估

• 批准号: 10458160
• 负责人: Wendy K Chung
• 金额: $ 49.78万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10458160
• 关键词: 3-Dimensional; Accounting; Anatomy; Animal Model; Animals; Biological Models; Birth; Breathing; Candidate Disease Gene; Cells; Clinical; Clinical Pathology; Collaborations; Congenital Abnormality; Congenital diaphragmatic hernia; Craniofacial Abnormalities; DNA Sequence Alteration; Data; Databases; Defect; Development; Developmental Biology; Diagnosis; Diagnostic; Early Intervention; Effectiveness; Enrollment; Esophageal Atresia; Esophageal motility disorders; Esophagus; Etiology; Fetal Development; Fistula; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genomics; Genotype; Goals; Growth; Human; Inherited; Intervention; Laboratories; Left; Life; Liquid substance; Magnetic Resonance Imaging; Measurement; Measures; Medical; Molecular; Mutation; Neurodevelopmental Disorder; Operative Surgical Procedures; Organ; Organoids; Outcome; Parents; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Prenatal Diagnosis; Primitive foregut structure; Prognosis; Registries; Research; Respiratory physiology; Sample Size; Statistical Data Interpretation; Testing; Trachea; Variant; Xenopus; autism spectrum disorder; catalyst; clinical diagnostics; clinical investigation; clinical phenotype; comorbidity; congenital anomaly; congenital heart disorder; developmental disease; feeding; functional genomics; genetic disorder diagnosis; genetic variant; genome sequencing; genomic data; improved; malformation; mutation carrier; neonate; novel; patient population; proband; programs; repaired; risk variant; transcriptomics; treatment strategy; whole genome

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.

项目1|总结 气管食管出生缺陷（TEDs）发生时，气管和食管分离的， 前肠在胎儿发育早期被破坏。TED通常在出生时出现，而没有产前检查 如果不进行纠正，TED会扰乱正常的呼吸和/或进食，通常会危及生命。 即使手术矫正，它们也常常与长期合并症有关。虽然 尽管有令人信服的证据表明TED是一种主要的遗传成分，但TED的病因在很大程度上尚不清楚。约50名候选人 突变与TED有不同程度的相关性，但这些基因中只有20个 在TED中是决定性的原因。我们假设有独特的基因突变导致 TED和这些行为在不同的发育途径，以确定TED解剖表型， 相关异常，以及这些患者的临床结局。此外，我们假设，前- 修复和修复后早期的解剖学、遗传学、手术和临床变量可用于预测 TED患者的短期和长期临床特征和临床结局，以推进治疗 战略布局我们对TED的临床病理学的理解受到缺乏详细的 对该患者人群进行大规模遗传学、解剖学和临床研究。因此， 这个项目是为了提高我们对TED的遗传和解剖基础的理解， 诊断，确定影响预后的因素和先进的治疗策略。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， 综合数据库，将整合解剖表型，基因型和临床结果数据。 目的1：维护和扩展多中心TED表型-基因型注册。 目的2：通过对新发和罕见遗传变异的统计分析， 与其他发育障碍和单细胞功能基因组学数据的综合分析。