22q11.2 deletion--Mechanisms and consequences

心血管综合征(VCFS)是由22q11.2缺失引起的几种疾病之一。这种缺失在普通人群中发生的频率极高(1/3,000-4,000活产婴儿)。这些从头开始的22q11.2缺失的流行表明在该基因组区域内有极高的“突变”率(约2.5x10/-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22q11.2易感于频繁缺失事件的细胞遗传学机制(S)和基因组构型。虽然少数患者有变异的缺失终点(DEP)，但超过85%的患者存在较大的(&gt；2.3Mb)典型缺失区域(TDR)。DEPS呈簇状分布，有典型的近端和远端DEP，以及两个变异的远端DEPS。包含缺失区间的区域包含至少4个重复的DNA序列块，它们似乎与DEPS的位置一致。在这个建议中，我们将检验这样的假设，即DEPS附近重复区域的位置、组织和方向在缺失形成的机制和后果中起着重要作用。在目标1中，我们将通过FISH将22q11.2 DEPS定位于其他22q11.2缺失综合征患者，以确定我们已确定的两个变异的DEPS是否是唯一复发的。在AIM II中，我们将利用DNA微阵列技术创建一种“芯片”，旨在检测患者及其父母的非典型缺失和剂量差异。在目标III中，我们将对22q11.2进行分离、测序和鉴定。在目标IV中，我们将检查具有典型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上紧密聚集，并深入了解导致频繁的大缺失事件的机制。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。在目标V中，通过单倍型重建，我们将检查导致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，以及发生缺失的个体的性别在减数分裂事件中所起的作用。

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.