Genetic Factors in the Etiology of Congenital Diaphragmatic Hernia

Congenital Diaphragmatic Hernia (CDH) is a relatively common birth defect in which a defect in diaphragm formation is associated with lung hypoplasia and pulmonary hypertension. CDH has a significant mortality of 50-80%, depending on the presence of associated anomalies and on the severity of the pulmonary abnormalities. The etiology of CDH is not known, but it is believed that both environmental and genetic factors contribute to its development. We have collected clinical data of approximately 400 CDH patients. DNA, cell lines and karyotypes are available of ~250 patients. To identify chromosomal regions and genes that play a role in the etiology of CDH we have used complementary molecular (cyto)genetic techniques to identify chromosomal abnormalities. Two of the regions we have identified are the CDH critical region on chromosome 15q26 and a larger region on chromosome 11q23-qter. We have also used high-resolution techniques, such as oligonucleotide-based array-CGH, combined with quantitative PCR, which has proven a fast and reliable method to screen for cryptic chromosomal anomalies in children with non-isolated CDH and which can be used for other congenital anomalies and/or mental retardation as well. The commonly deleted or duplicated regions and their candidate genes identified in patients with non-isolated CDH almost all play a role in retinoic acid metabolism and / or neural crest cell migration. Therefore we propose in the general discussion that both pathways are necessary for normal diaphragm- and lungdevelopment and that disruption at any point in these mechanisms can lead to the development of congenital diaphragmatic hernia.

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