Mouse Models of Human Conotruncal Defects

22q11.2缺失综合征（22 q11 DS）是一种先天性异常疾病，发生率为1/4,000。 它是由于22号染色体q11.2带的3 Mb缺失而发生的。大约70%的儿童 22 q11 DS有圆锥动脉干型先天性心脏病（CTD），而30%无心脏病。 通过超声心动图确定的畸形。很可能有许多因素，如随机事件， 环境暴露和特定基因或基因途径在改变表型中起作用。这 该项目旨在探索和发现22 q11 DS之间差异的遗传因素。 有和没有CTD的患者。为了识别CTD的遗传修饰剂，我们进行了基因组- 使用Affytron 6.0阵列对650名22 q11 DS受试者进行的广泛CNV和SNP关联研究。我们发现 罕见的生物学意义上的CNV为了提高CNV发现和SNP关联的重要性，我们 我建议通过扩大队列来扩大已经确定的罕见和常见CNV的研究，以包括 共1,150例22 q11 DS患者。因此，我们将运行500个额外的Affytron 6.0微阵列。GWAS将 对基于SNP的修饰基因座的整个群组进行。我们将比较我们的候选基因座与 项目2的成果。项目2将复制其先前的非综合征型CTD GWAS 患者和正常对照，通过增加700例额外病例和额外对照来确定风险因素 对于CTD。我们将比较两个数据集，以确定共同的基因座，需要选择重新基因分型 插补后，因为研究使用了不同的平台（Illumina与Affyoung）。为了证实这些基因座 确定CTD候选基因，将在小鼠胚胎上进行原位杂交。可以 TBX 1（缺失区间中的基因）遗传途径中的基因可以充当修饰剂。Tbx1 编码一个T盒转录因子，在小鼠模型中，它负责许多特征， 22q11DS。因此，将对22 q11 DS小鼠模型进行评价，以确定这些基因是否处于共享的基因组中。 途径，如Tbxl途径（项目3）。项目确定的相关遗传途径 3将在本项目鉴定的CNVs和SNP位点中进行检查。有针对性的重新测序将是 在试图确定致病基因，修改CTD表型在22 q11 DS个人进行。 人类和小鼠联合项目的总体结果将使我们能够系统地探索 CTDs的遗传风险因素。该项目将扩大我们对CTD遗传基础的理解， 为开发新的治疗和预防策略迈出了第一步。 相关性（参见说明）： 圆锥动脉干型先天性心脏缺陷发生在70%的22 q11 DS患者中，而30%的22 q11 DS患者没有圆锥动脉干型先天性心脏缺陷。 心血管异常我们的目标是在我们的1,150名受试者队列中找到遗传修饰剂， 全基因组方法。这项工作将揭示可能改变心脏缺陷风险的新基因， 22 q11 DS和非综合征患者。这将通过将我们的数据与项目2的数据进行比较来进行测试 来源于非综合征性圆锥动脉干缺陷受试者。D

The 22q11.2 deletion syndrome (22q11DS) is a congenital anomaly disorder occurring in 1/4,000 live births. It is occurs due to a 3Mb deletion of chromosome 22 at band q11.2. Approximately 70% of children with 22q11DS have congenital heart disease of the conotruncal type (CTD), while 30% have no cardiac malformations as determined by echocardiography. It is likely that many factors such as stochastic events, environmental exposures and specific genes or gene pathways play a role in modifying the phenotype. This project proposes to explore and discover genetic factors that underlie the differences between 22q11DS patients with and those without a CTD. To identify genetic modifiers of CTDs, we have performed a genome- wide CNV and SNP association study of 650 22q11DS subjects using Affymetrix 6.0 arrays. We have found rare CNVs of biological interest. To enhance the significance of the CNV findings and SNP associations, we propose to expand the study of already identified rare and common CNVs by expanding the cohort to include a total of 1,150 22q11 DS patients. Thus, we will run 500 additional Affymetrix 6.0 microarrays. A GWAS will be performed on the entire cohort for SNP based modifier loci. We will compare our candidate loci with results from Project 2. Project 2 will perform a replication of their previous GWAS of non-syndromic CTD patients and normal controls, by adding 700 additional cases and additional controls to identify risk factors for CTDs. We will compare the two datasets to identify loci in common, requiring selected re-genotyping after imputation, as the studies used different platforms (lllumina versus Affymetrix). To confirm that the loci identified are CTD candidate genes, in situ hybridization on mouse embryos will be performed. It is possible that genes in the genetic pathway of TBX1, a gene in the deleted interval, can serve as modifiers. TBX1 encodes a T-box transcription factor, which in mouse models is responsible for many of the features of the 22q11DS. Therefore, 22q11DS mouse models will be evaluated to determine if the genes are in a shared pathway, such as the Tbxl pathway (Project 3). Genetic pathways of relevance that are identified by Project 3 will be examined in the CNVs and SNP loci identified in this Project. Targeted re-sequencing will be performed in an attempt to identify causative genes that modify the CTD phenotype in 22q11DS individuals. The overall outcome of the combined human and mouse program will enable us to systematically explore genetic risk factors for CTDs. This project will expand our understanding of the genetic basis of CTDs, and provide a first step towards the development of novel therapeutic and preventive strategies. RELEVANCE (See instructions): Congenital heart defects of the conotruncal type occur in 70% of 22q11 DS patients while 30% have no cardiovascular anomalies. Our goal is to find genetic modifiers in our cohort of 1,150 subjects taking genome wide approaches. This work will uncover new genes that may alter risk of heart defects for 22q11 DS and non-syndromic patients. This will be tested by comparing our data to data from Project 2 derived from non-syndromic conotruncal defect subjects. D