Novel Genomic Disorders Causing Cardiovascular Malformations

描述（由申请人提供）：心血管畸形（CVM）是一种常见的出生缺陷，是婴儿死亡率和新生儿护理成本的主要原因。大量流行病学数据表明，遗传因素在CVM病因中起重要作用。一组重要的基因异常，称为基因组紊乱，涉及染色体拷贝数的不平衡-通常涉及一个或几个相邻基因的缺失或重复。亚显微镜下的染色体失衡已经被发现在几种常见的复杂或综合征形式的CVM中很重要。这些疾病最有可能在CVM合并多发性先天性异常（MCA）的患者中观察到，但只有大约10%的此类病例具有已知的基因组疾病。直到最近，在技术上还无法全面调查基因组中的这种不平衡。在初步研究中，我们使用了几个最新的微阵列平台来建立染色体拷贝数改变的全基因组调查方案。在一项可行性研究中，我们发现大约三分之一的CVM/MCA病例有相对较大的亚显微镜染色体畸变。在本研究计划中，我们建议扩展CVM/MCA病例的拷贝数分析。该结果将允许更精确地评估病理变异的频率，并更好地表征它们如何在CVM中发挥因果作用。我们建议描述染色体失衡事件的边界，并研究基因功能障碍的潜在分子机制。我们将优先考虑可能在CVM表型中起直接作用的单个基因，然后检查这些基因中更微妙的突变是否在孤立性或非综合征性CVM中起作用。识别CVM的特定基因将提高对这些常见异常起源的理解。提高筛查染色体失衡和相关基因突变的能力将有助于CVM的诊断和早期干预。

DESCRIPTION (provided by applicant): Cardiovascular malformations (CVM) are a common class of birth defects that are major contributors to infant mortality and cost of neonatal care. A large body of epidemiological data has established that genetic factors play a large role in the causes of CVM. An important group of genetic abnormalities, called genomic disorders, involve imbalances in chromosomal copy number - usually deletions or duplications involving one or a few adjacent genes. Submicroscopic chromosomal imbalances have already been found to be important in several common complex or syndromic forms of CVM. These disorders are most likely to be observed in patients affected with CVM plus multiple congenital anomalies (MCA), but only approximately 10% of such cases have a known genomic disorder. Until recently, it has not been technically feasible to comprehensively survey the genome for such imbalances. In preliminary studies we have used several newly available microarray platforms to establish protocols for genome-wide survey of alterations in chromosomal copy number. In a feasibility study we found that about one third of CVM/MCA cases have relatively large submicroscopic chromosomal aberrations. In this research program, we propose to expand the copy number analysis of CVM/MCA cases. The results will allow more precise assessment of the frequency of pathological variants and to better characterize how they play a causal role in CVM. We propose to characterize the boundaries of the chromosomal imbalance events and to investigate the potential molecular mechanisms of gene dysfunction. We will prioritize individual genes that might play a direct role in the CVM phenotype and then examine whether more subtle mutations in those genes play a role in isolated or non-syndromic CVM. Identification of specific genes that underlie CVM would improve understanding of the origins of these common anomalies. Improved ability to screen for chromosomal imbalances and mutations in relevant genes will aid in diagnosis and early intervention for CVM.