Improving Diagnosis of Congenital Genitourinary Anomalies

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DESCRIPTION (provided by applicant): A major problem currently facing pediatric urology involves the diagnosis of disorders in genital and urinary tract development. Although much of the current diagnosis is descriptive (i.e. cryptorchidism: a failure of the testis to descend), the molecular basis for these common birth defects are largely unknown. This proposal seeks support to use comparative genomic hybridization microarrays to improve the diagnosis of chromosome defects in children with congenital genitourinary defects and to discover unrecognized genomic diseases in children. We hypothesize that we can improve the diagnosis of these children by using a molecular karyotype. Our ability to diagnose these chromosome abnormalities is limited by the sensitivity of current technology towards discriminating subtle defects. Homologous recombination during meiosis provides the basis for species evolution and ensures genetic diversity among offspring. However, when this process goes awry, defects in meiotic recombination can result in infertility, as well as numerical or structural chromosomal abnormalities in offspring. Though karyotype analysis is part of the current routine evaluation of patients with genitourinary anomalies, with the development of each new diagnostic technique, previously unrecognized genetic defects have been identified. This proposal will test the hypothesis that chromosome microarray analysis and genome wide comparative genomic hybridization tiling microarrays can improve our ability to detect subtle submicroscopic chromosomal defects in children with genitourinary anomalies and is superior to the currently available High Resolution Banding Cytogenetic and FISH analyses for patient diagnosis. This technology will not only allow us to define regions of aberrations, it will also identify unrecognized, unbalanced structural abnormalities and define, with precision, the genes affected by the alteration. We can further confirm any new genomic defects identified in pediatric urologic patient groups by creating mouse models with targeted deletion of candidate genes. 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 hypospadias, cryptorchidism and gonadal dysgenesis syndromes.