PROJECT I: GENOMIC AND GENE EXPRESSION ANALYSES TO DISCOVER GENES AND PATHWAYS IN HUMAN CONGENITAL DIAPHRAGMATIC HERNIA ABSTRACT: This project focuses on the characterization of genomic variation in human patients with congenital diaphragmatic hernia (CDH) to identify novel genes and pathways causing CDH. We will use whole genome sequencing (WGS) and whole exome sequencing (WES) to identify rare and predicted pathogenic de novo and inherited sequence, copy number, and structural variants in sporadic CDH cases, and inherited variants in families containing more than one affected individual. A challenge in studying CDH, like most birth defects, has been its genetic heterogeneity. To overcome this obstacle, we have maximized our sample size by combining two well-established CDH research studies, generating one of the largest and most well-characterized cohorts of patients with CDH in the world. We have recruited 1500 patients to date, with WES or WGS data completed or in the pipeline for approximately 800 proband-parent trios. We show that this will provide sufficient power to identify multiple CDH genes with statistical significance. These data will be analyzed using novel and well- established bioinformatics tools to prioritize variants and identify molecular pathways that are likely to be disease-associated. In addition, the DHREAMS consortium has collected diaphragm specimens from a large number of patients, allowing for the study of somatic mutations and tissue-specific gene expression changes that may be associated with genetic subtypes of CDH. Together, the data derived from these large-scale genomic experiments have already identified key candidate genes that are being pursued in functional experiments in Projects II and III, and will continue to provide novel candidates that will allow identification of genotype-phenotype associations, help inform and refine prognosis for patients with CDH, and will elucidate molecular pathways that could be targets for future therapeutic strategies.
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