Molecular Genetic Analysis of Congenital Diaphragmatic Hernia

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DESCRIPTION (provided by applicant): Our overall goal is to identify the genetic causes of diaphragmatic hernia in humans. The diaphragm is a tissue composed of muscle and tendon that separates the chest and abdomen. If the diaphragm does not form normally, a hernia or protrusion of the abdominal contents into the chest can result. Diaphragmatic hernias are common and occur in 1 in 2500 live- and stillbirths. A diaphragmatic hernia is a devastating birth defect, and the mortality and morbidity associated with the hernias is very high. Little is known about the genetic causes of diaphragmatic hernia, and we therefore would like to discover which genes are important in determining which babies is susceptible to developing a hernia. We have used a technique called array comparative genomic hybridization to identify new, small chromosome deletions in patients with diaphragmatic hernias. These deleted regions contain genes that are needed for normal diaphragm development. We would like to develop this research further and use the same technique to continue to screen patients with diaphragmatic hernias for chromosome deletions. We would also like to determine which of the genes in the deleted regions are involved in diaphragm development. To do this, we propose to determine which of the genes from the deleted regions are expressed in the mouse diaphragm, as we hypothesize that the genes expressed in the mouse diaphragm will also be expressed in the human diaphragm. We will then compile a list of candidate genes for diaphragmatic hernias based on gene expression and published data on gene expression and function. We will sequence the candidate genes in a large cohort of patients with diaphragmatic hernias. Our purpose is to detect the genes that cause the hernias to improve patient counseling and to advance our understanding of the pathogenesis of this birth defect. Relevance to Public Health This project is directed at improving our understanding of the genetic causes of a common birth defect, congenital diaphragmatic hernia. An increase in our knowledge about the genes that cause some individuals to be affected and not others will allow us to optimize treatment and management for the families concerned and thus may help to reduce infant mortality and morbidity.