Improving Diagnosis of Congenital Genitourinary Anomalies

描述（由申请人提供）：小儿泌尿外科面临的挑战是手术治疗男孩下尿路和泌尿生殖道出生缺陷。虽然泌尿生殖系统出生缺陷是最常见的诊断之一，但缺乏这些缺陷的分子基础。这个应用程序寻求支持，以继续我们对这些出生缺陷的基因组基础的调查。我们使用最先进的技术，比较基因组杂交微阵列（aCGH），来识别先天性泌尿生殖系统缺陷儿童染色体的亚显微增益或损失。这项工作确定了染色体区域，在这些区域中，具有相同出生缺陷的不相关患者表现出从头结构染色体重复或太小而无法在核型上看到的缺失。一项经临床验证的aCGH在大约20%的泌尿生殖系统先天性缺陷儿童中发现了结构性染色体缺陷——这一进步今天可以被儿科泌尿科医生使用。因此，我们的第一个假设得到了证实：我们提高了对这些aCGH儿童的诊断。我们继续寻找先天性泌尿生殖系统缺陷的遗传热点。重要的是，这项工作确定了一些与正常的人类泌尿生殖系统发育和出生缺陷有关的候选基因。基于目前的研究，我们有许多与人类泌尿生殖道发育有关的候选基因有待分析，我们的aCGH研究将继续提供信息，并提出新的研究领域。因此，我们的具体目标仍然与我们目前资助的提案相似。我们试图确定这些常见的出生缺陷背后的遗传和基因组缺陷。我们将继续通过小鼠模型的生成和组织形态发生过程中基因功能的定义来展示基因特异性因果关系，而不仅仅是与出生缺陷的简单关联。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，并确定泌尿生殖道出生缺陷儿童这一关键生物学过程失败的遗传基础。虽然大多数泌尿系统缺陷是由儿科泌尿科医生通过手术矫正的，但我们试图了解出生缺陷的原因，并了解未来儿童是否会受到类似折磨的可能性。本建议采用新颖的方法来提高我们对分子基础的理解，并提高我们诊断这些常见的下尿路和泌尿生殖道出生缺陷的能力。

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.