Improving Diagnosis of Congenital Genitourinary Anomalies

改善先天性泌尿生殖系统异常的诊断

基本信息

批准号：
7983894
负责人：
Dolores Jean Lamb
金额：
$ 15.98万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-11-25 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7983894
关键词：
Affect Aneuploidy Arts Binding Birth Candidate Disease Gene Cell physiology Child Childhood Chromosomal Rearrangement Chromosomal translocation Chromosome Painting Chromosome Pairing Chromosome Structures Chromosome abnormality Chromosomes Clinic Clinical Complex Congenital Abnormality Cryptorchidism Cytogenetic Analysis Cytogenetics DNA Sequence Rearrangement Defect Detection Development Diagnosis Diagnostic Procedure Diagnostic tests Disease Embryo Endocrine Ensure Equilibrium Evaluation Evolution Failure Fluorescent in Situ Hybridization Gametogenesis Gender Gene Dosage Gene Expression Alteration Genes Genetic Genetic Variation Genetic screening method Genital system Genitalia Genitourinary system Genome Genomics Goals Gonadal Dysgenesis Human Hypospadias Individual Infertility Karyotype Klinefelter&apos s Syndrome Knowledge Laboratories Laboratory Research Male Infertility Medical Genetics Meiosis Meiotic Recombination Mental Retardation Methodology Microarray Analysis Molecular Molecular Abnormality Mutation Oligospermia Patients Pattern Phenotype Physicians Polymerase Chain Reaction Process Proteomics Reproductive Process Research Personnel Resolution Sequence Analysis Series Sex Chromosomes Site Spermatogenesis Staining method Structural Chromosomal Abnormality Syndrome System Techniques Technology Testing Testis Translating Turner&apos s Syndrome Urinary tract Urogenital Abnormalities Urogenital Diseases Urologic Diseases Urology Y Chromosome Y chromosome microdeletions base carcinogenesis clinical Diagnosis clinical practice comparative genomic hybridization design fetal gene discovery genome-wide homologous recombination improved male men metabolomics mouse model novel novel diagnostics offspring programs urologic

项目摘要

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.

描述（由申请人提供）：目前面临的儿科泌尿外科的一个主要问题涉及生殖器和尿路发育中疾病的诊断。尽管目前的许多诊断都是描述性的（即隐齿术：睾丸降低的失败），但这些常见的先天缺陷的分子基础在很大程度上是未知的。该建议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。我们假设我们可以使用分子核型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，并确保后代之间的遗传多样性。但是，当此过程出现问题时，减数分裂重组的缺陷可能导致不育症，以及后代的数值或结构性染色体异常。尽管核型分析是当前对泌尿生殖率异常患者的常规评估的一部分，并且随着每种新诊断技术的发展，已经确定了以前未被认可的遗传缺陷。该提案将检验以下假设：染色体微阵列分析和基因组广泛的基因组杂交瓷砖微阵列可以提高我们检测到刚毒素异常儿童的细微微观染色体缺陷的能力，并且优于当前可用的高分辨率型带养细胞遗传学和鱼类分析的患者。这项技术不仅可以允许我们定义畸变区域，还将确定未识别的，不平衡的结构异常，并精确地定义受改变的基因。我们可以通过创建具有靶向候选基因的靶向缺失的小鼠模型来进一步确认在小儿泌尿科患者群体中鉴定出的任何新的基因组缺陷。这项研究的长期目标是改善先天性泌尿生殖器缺陷的诊断，并为患有卧床，隐齿术和性腺发育不全综合症的儿童失败的遗传基础。