Mouse Models of Human Conotruncal Defects

22q11.2缺失综合征(22q11DS)是一种先天性异常疾病，发生在1/4000活产婴儿中。 这是由于染色体22在q11.2带上的3MB缺失所致。大约70%的儿童患有 22q11d患有圆锥干型先天性心脏病(CTD)，而30%没有心脏病 超声心动图确定的畸形。很可能是许多因素，如随机事件， 环境暴露和特定的基因或基因途径在改变表型方面起着作用。这 该项目计划探索和发现22q11DS之间差异的遗传因素 有CTD和无CTD的患者。为了确定CTD的遗传修饰物，我们进行了基因组- 应用Affymetrix 6.0阵列对650例22q11DS患者进行广谱CNV和SNP相关性研究我们发现了 稀有的具有生物学意义的CNV。为了加强CNV发现和SNP关联的重要性，我们 建议扩大对已确定的稀有和常见CNV的研究，将队列扩大到包括 共1150例22q11 DS患者。因此，我们将运行500个额外的Affymetrix 6.0微阵列。一个GWAS将会 在基于SNP的修饰基因座的整个队列中执行。我们会将我们的候选基因与 项目2的结果。项目2将复制他们之前的非综合征性CTD的GWA 患者和正常对照组，通过增加700个额外病例和额外对照来确定危险因素 对于CTDS来说。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 归罪后，因为研究使用了不同的平台(llLumina和Affymetrix)。以确认这些基因座 确定CTD候选基因，将在小鼠胚胎上进行原位杂交。这是有可能的 位于缺失区间的基因TBX1的遗传途径中的基因可以作为修饰物。TBX1 编码一种T-box转录因子，在小鼠模型中，它负责许多 22q11DS。因此，将对22q11DS小鼠模型进行评估，以确定这些基因是否存在于 途径，如Tbx1途径(项目3)。项目确定的相关遗传路径 3将在本项目中确定的CNV和SNP基因座中进行检查。有针对性的重新排序将是 试图确定改变22q11DS个体CTD表型的致病基因。 人类和老鼠联合计划的总体结果将使我们能够系统地探索 CTD的遗传风险因素。这个项目将扩大我们对CTD的遗传基础的了解，以及 为开发新的治疗和预防战略迈出第一步。 相关性(请参阅说明)： 在22q11 DS患者中，70%的患者存在圆锥干型先天性心脏病，而30%的患者没有 心血管异常。我们的目标是在我们的1150名受试者中找到基因修饰物 全基因组的方法。这项工作将发现可能改变心脏缺陷风险的新基因 22q11 DS和非综合征患者。这将通过将我们的数据与项目2中的数据进行比较来进行测试 来源于非综合征圆锥干缺陷受试者。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