Improving Diagnosis of Congenital Genitourinary Anomalies

描述(由申请人提供)：目前儿科泌尿科面临的一个主要问题是生殖器和尿路发育障碍的诊断。虽然目前的诊断大多是描述性的(即隐睾症：睾丸无法下降)，但这些常见出生缺陷的分子基础在很大程度上是未知的。这项建议寻求支持使用比较基因组杂交微阵列，以改进对患有先天性泌尿生殖系统缺陷的儿童的染色体缺陷的诊断，并发现儿童中未识别的基因组疾病。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区分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，并保证了后代之间的遗传多样性。然而，当这一过程出错时，减数分裂重组的缺陷可能会导致不育，以及后代的染色体数量或结构异常。虽然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，但随着每一项新诊断技术的发展，以前未被识别的遗传缺陷已被发现。这项建议将检验这样一种假设，即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患有泌尿生殖系统异常儿童的细微亚微观染色体缺陷的能力，并优于目前用于患者诊断的高分辨率显带细胞遗传学和FISH分析。这项技术不仅将使我们能够定义异常区域，它还将识别未被识别的、不平衡的结构异常，并精确地定义受改变影响的基因。我们可以通过建立靶向缺失候选基因的小鼠模型，进一步确认在儿科泌尿科患者组中发现的任何新的基因组缺陷。这项研究的长期目标是提高对先天性泌尿生殖系统缺陷的诊断，并确定这一关键生物过程失败的遗传学基础，以治疗患有尿道下裂、隐睾症和性腺发育不全综合征的儿童。

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.