22q11.2 deletion--Mechanisms and consequences

22q11.2缺失——机制和后果

• 批准号: 6564044
• 负责人: BEVERLY S EMANUEL
• 金额: $ 21.13万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564044
• 关键词: clinical research; congenital oral /facial /cranial defect; cytogenetics; family genetics; fluorescent in situ hybridization; gene deletion mutation; gene expression; human subject; microarray technology; molecular genetics; nucleic acid sequence; syndrome

Velocardiofacial syndrome (VCFS) is one of several disorders caused by a deletion of 22q11.2. The deletion occurs at an extremely high frequency in the general population (1/3,000-4,000 live births). The prevalence of these de novo 22q11.2 deletions indicates an extremely high "mutation" rate within this genomic region (approximately 2.5 x 10/-4). Little attention has been paid to elucidating the mechanism which gives rise to this "genomic disorder." Thus, we will investigate the cytogenetic mechanism(s) and genomic configuration which predispose 22q11.2 to frequent deletional events. Although a minority of patients have variant deletion endpoints (DEPs), there is a large (>2.3 Mb) typically deleted region (TDR) in over 85% of patients. The DEPs cluster such that there are a typical proximal and distal DEP as well as two variant distal DEPs. The region which comprises the deletion interval contains at least 4 large blocks of duplicated DNA sequence which appear to coincide with the location of the DEPs. In this proposal, we will examine the hypothesis that the location, organization and orientation of the duplicated regions in the vicinity of the DEPs play a significant role in the mechanism and consequences of deletion formation. In Aim 1, we will position the 22q11.2 DEPs by FISH in additional patients with the 22q11.2 deletion syndrome to determine whether the two variant DEPs we have identified are the only ones that recur. In Aim II we will utilize DNA microarray technology to create a "chip" designed to detect atypical deletions and dosage differences in patients and their parents. In Aim III, we will isolate, sequence and characterize 22q11.2. In Aim IV we will examine the similarity between 22q11.2 DEPs for different individuals with the typical 22q11.2 deletion (TDR) to determine whether the proximal and distal DEPs are tightly clustered molecularly on 22q11.2 and gain insights into the mechanisms responsible for the frequent large deletion events. Further, we will examine the similarity between the different distal DEPs to determine whether the basis for the deletion can be determined. In Aim V, by haplotype reconstruction, we will examine the meiotic mechanism responsible for the generation of the standard and the variant deletions to determine whether they are inter- or intra-chromosomal events and the role, if any, that the sex of the individuals in whom the deletion occurred plays in the meiotic event.

心面快速综合征（VCFS）是由22q11.2缺失引起的几种疾病之一。这种缺失在一般人群中发生的频率非常高（1/ 3000 - 4000活产婴儿）。这些从头开始的22q11.2缺失的流行表明该基因组区域的“突变率”极高（约2.5 x 10/-4）。很少有人注意阐明导致这种“基因组紊乱”的机制。因此，我们将研究使22q11.2易发生频繁缺失事件的细胞遗传学机制和基因组结构。虽然少数患者有变异缺失终点（DEPs），但在85%以上的患者中存在一个大的（bb0 2.3 Mb）典型缺失区（TDR）。DEP集群这样有一个典型的近端和远端DEP以及两个不同的远端DEP。包含缺失间隔的区域包含至少4个大的重复DNA序列块，其似乎与dep的位置一致。在这一提议中，我们将检验一个假设，即dep附近的重复区域的位置、组织和方向在缺失形成的机制和后果中起着重要作用。在Aim 1中，我们将通过FISH在其他22q11.2缺失综合征患者中定位22q11.2 dep，以确定我们发现的两种变体dep是否是唯一复发的dep。在Aim II中，我们将利用DNA微阵列技术创建一个“芯片”，用于检测患者及其父母的非典型缺失和剂量差异。在Aim III中，我们将分离、测序和表征22q11.2。在Aim IV中，我们将研究具有典型22q11.2缺失（TDR）的不同个体的22q11.2 dep之间的相似性，以确定近端和远端dep是否在22q11.2分子上紧密聚集，并深入了解导致频繁大缺失事件的机制。此外，我们将检查不同远端dep之间的相似性，以确定是否可以确定缺失的基础。在Aim V中，通过单倍型重建，我们将检查负责产生标准和变异缺失的减数分裂机制，以确定它们是染色体间事件还是染色体内事件，以及如果有的话，发生缺失的个体的性别在减数分裂事件中所起的作用。