The goal of this proposal is to identify and characterize novel genes for congenital diaphragmatic hernia (CDH). CDH occurs in ~1/3000 live births and has a mortality rate of 30-60% caused mostly by pulmonary hypoplasia and pulmonary hypertension. 30-40% of CDH cases are associated with other severe birth defects including heart anomalies. Although genetic factors clearly play an important role in diaphragm development only a few CDH genes have been identified and little is known about the mechanisms by which they cause CDH.
The Specific Aims for this study are: 1) map and identify genes that contribute to human CDH, 2) determine the histopathologic mechanisms that lead to development of anterior CDH in the Sox7 mouse model, and 3) determine if Sox7 interacts with Gata4 in development of anterior CDH. Array comparative genomic hybridization (aCGH) has been shown to be an effective non-biased method for identifying genes in sporadic disorders like CDH. DNA from a cohort of 150 CDH patients will be screened for small CDH-related chromosomal deletions/duplications using a custom designed exon-focused aCGH array. Candidate genes will be selected from these regions and screened for additional mutations in our CDH cohort. Genotype-phenotype correlations will then be made based on clinical information from individual patients. aCGH studies have revealed that one of the most common chromosomal regions deleted in CDH is a portion of 8p23.1 which contains the S0X7 gene. A newly-created Sox7 mouse model of CDH will be used to explore the histopathologic mechanisms that underlie the formation of anterior CDH. Studies will look for changes that could compromise the structural integrity of the diaphragm and evidence of abnormal expansion of the peritoneal mesothelial folds that separate the diaphragm from the liver. It is likely that these mechanisms will be similar to those which cause anterior CDH in humans. Sox7 is required for upregulation of Gata4, another CDH-related gene located in the CDH critical region on 8p23.1. In vivo mouse studies will be used to determine if Sox7 and Gata4 interact genetically in anterior diaphragm development followed by in vitro studies to determine the molecular basis of this interaction. These studies will help identify genetic changes that cause some children to develop congenital diaphragmatic hernia (CDH), a life threatening birth defect. The knowledge gained will help doctors provide better medical care and genetic counseling to affected families and may lead to new ways to prevent or treat these hernias. Since 30-40% of all children with CDH have other severe birth defects, these studies may also help physicians and scientists understand what causes these defects and how to treat them.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F08-F (20))
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Colombini-Hatch, Sandra
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Baylor College of Medicine
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United States
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Wat, Margaret J; Veenma, Danielle; Hogue, Jacob et al. (2011) Genomic alterations that contribute to the development of isolated and non-isolated congenital diaphragmatic hernia. J Med Genet 48:299-307