Genetic analysis of congenital diaphragmatic hernia

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DESCRIPTION (provided by applicant): Long term objectives: We would like to investigate the genetic etiology of congenital diaphragmatic hernia (CDH) in humans. This common birth defect is associated with a significant prenatal mortality and long-term morbidity. There is significant evidence that genes are important in the etiology of CDH but Mendelian pedigrees suitable for gene mapping in this sporadic condition are rare. We are currently using array comparative genomic hybridization (array CGH) to identify submicroscopic chromosome aberrations in patients who have CDH and chromosome translocations. We have identified a proband with CDH who has a de novo chromosome translocation and reduced copy number for a single bacterial artificial chromosome (BAG) clone localized to the region of a translocation breakpoint on array CGH. We would like to confirm the CGH result and show that the translocation breakpoint is associated with a gene deletion or altered expression of a gene involved in the pathogenesis of CDH. If we can identify this gene, we would determine the degree of involvement of the gene in the pathogenesis of CDH in a cohort of patients with non-syndromic CDH and with CDH and malformations. We would also use a phylogenetic/genomic approach to ascertain gene and protein homologues with similar structural and functional motifs to the identified gene and protein. Our specific aims are 1. To identify a deleted gene(s) or altered expression of a gene at a chromosome breakpoint in a patient with CDH and a de novo chromosome translocation. 2. To determine the degree of involvement of the identified gene in the pathogenesis of CDH in humans by sequencing this gene in a cohort of 48 patients with non-syndromic CDH and in 24 patients CDH and additional malformations. 3. To use a genomic/phylogenetic approach to ascertain gene and protein homologues with similar structure and function to the identified gene and protein and to screen these new genes for sequence alterations by direct sequencing in the same patient cohort with CDH.