Abstract for presentation at 11th International Congress of Human Genetics

Congenital diaphragmatic hernia (CDH) is a developmental anomaly that affects approximately 1 in 2500 newborns with mortality varying from 30-60%. We hypothesized that mutations in specific genes either cause or predispose an individual to develop CDH. The location of some CDH-related genes can be inferred by identifying chromosomal regions that are commonly deleted or duplicated in CDH. To identify CDH-related chromosomal regions, we screened 15 individuals with CDH and other non-pulmonary anomalies (CDH+) using G-banded chromosome analysis and genome-wide array CGH (aCGH). Chromosomal anomalies were found in five (33%) individuals, and in two cases (13%), the anomalies were only identified by aCGH. In one individual with a normal G-banded chromosomal analysis, aCGH detected a deletion of 15q26, a region deleted in at least 19 published cases of CDH. This individual helps to define a CDH minimal deleted region that contains COUP-TFII, a gene encoding a transcription factor that is regulated by retinoic acid. The presence of COUP-TFII within this region is of particular interest given that disruption of the retinoid-signaling pathway is known to cause CDH in mice and that a mouse model of CDH was recently created by targeted ablation of COUP-TFII. When considered together, these data strongly suggest that haploinsufficiency of COUP-TFII can cause or predispose an individual to develop CDH. To identify additional CDH-related chromosomal regions, we performed a literature review that revealed 16 other chromosomal regions that are recurrently [3 cases or more] associated with CDH. We have selected 10 genes located in these cytogenetic regions that we are presently screening for CDH-related mutations in a cohort of 70 CDH patients. It is likely that direct sequencing of these positional candidate genes will lead to identification of mutations associated with the development of CDH.