Improving Diagnosis of Congenital Genitourinary Anomalies

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DESCRIPTION (provided by applicant): A challenge for pediatric urology is the surgical treatment of birth defects of the lower urinary and genitourinary tract in boys. While genitourinary birth defects are among the most common diagnosed, the molecular basis of these defects is lacking. This application seeks support to continue our investigations into the genomic basis of these birth defects. We used state-of-the-art technology, comparative genomic hybridization microarray (aCGH), to identify submicroscopic gains or losses on chromosomes in children with congenital genitourinary defects. This work identified chromosomal regions where unrelated patients with the same birth defect exhibited de novo structural chromosomal duplications or deletions too small to be seen on a karyotype. A clinically validated aCGH identified structural chromosome defects in about 20% of children with genitourinary birth defects-an advance that can be used today by pediatric urologists. Thus our first hypothesis is proven: we improved the diagnosis of these children with aCGH. We seek to continue to identify genetic hotspots for congenital genitourinary defects. Importantly, the work identified a number of candidate genes for both normal human genitourinary development and birth defects. Based upon the current studies, we have a number of candidate genes for human urogenital tract development remaining to be analyzed and our aCGH studies continue to be informative and to suggest new areas for investigation. Accordingly, our specific aims remain similar to our currently funded proposal. We seek to identify the genetic and genomic defects that underlie these common birth defects. We will continue to show gene specific causality, beyond simple association with a birth defect, through generation of mouse models and definition of gene function during tissue morphogenesis. The long-term goal of this study is to improve the diagnosis of congenital genitourinary defects and to define the genetic basis for the failure of this key biologic process for children with birth defects of the urogenital tract. Although most urogenital tract defects are surgically corrected in children by the pediatric urologist, we seek t understand the cause of the birth defect and to know the likelihood whether any future children will be similarly afflicted. This proposal uses novel approaches to improve both our understanding of the molecular basis and to improve our ability to diagnose these common birth defects of the lower urinary and genitourinary tracts.