Improving Diagnosis of Congenital Genitourinary Anomalies

描述（由申请人提供）：小儿泌尿外科目前面临的一个主要问题涉及生殖器和泌尿道发育障碍的诊断。虽然目前的诊断大多是描述性的（即隐睾症：睾丸下降失败），但这些常见出生缺陷的分子基础在很大程度上是未知的。该提案寻求支持使用比较基因组杂交微阵列来改善先天性泌尿生殖缺陷儿童的染色体缺陷诊断，并发现儿童中未被识别的基因组疾病。我们假设，我们可以通过使用分子核型来改善这些儿童的诊断。我们诊断这些染色体异常的能力受到当前技术对识别细微缺陷的敏感性的限制。减数分裂过程中的同源重组为物种进化提供了基础，并确保了后代的遗传多样性。然而，当这个过程出错时，减数分裂重组的缺陷会导致不育，以及后代染色体数量或结构异常。虽然染色体核型分析是目前泌尿生殖系统异常患者常规评估的一部分，但随着每种新诊断技术的发展，以前未被识别的遗传缺陷已经被确定。该提案将测试染色体微阵列分析和全基因组比较基因组杂交平铺微阵列可以提高我们检测泌尿生殖系统异常儿童中细微亚显微染色体缺陷的能力，并且上级目前可用的高分辨率显带细胞遗传学和FISH分析用于患者诊断的假设。这项技术不仅可以让我们确定畸变区域，还可以识别未识别的、不平衡的结构异常，并精确地定义受改变影响的基因。我们可以通过建立候选基因靶向缺失的小鼠模型，进一步确认在儿科泌尿系统患者组中发现的任何新的基因组缺陷。本研究的长期目标是提高先天性泌尿生殖系统缺陷的诊断水平，并确定尿道下裂、隐睾和性腺发育不全综合征患儿这一关键生物学过程失败的遗传基础。

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.