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Novel Genomic Disorders Causing Cardiovascular Malformations

导致心血管畸形的新型基因组疾病

基本信息

批准号：
7556772
负责人：
John William Belmont
金额：
$ 38.38万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7556772
关键词：
Affect Alleles BMP2 gene Biochemical Bioinformatics Candidate Disease Gene Cardiac Cardiovascular system Caring Cell Line Chromosome abnormality Clinic Clinical Complex Congenital Abnormality Congenital Heart Defects DNA Sequence DNA Sequence Rearrangement Data Databases Defect Development Developmental Delay Disorders Diagnosis Disease Early treatment Epidemiology Etiology Event Feasibility Studies Follow-Up Studies Frequencies Functional RNA Functional disorder Gene Expression Gene Structure Genes Genetic Genome Genomics Genotype Human In Vitro Individual Infant Mortality Inherited Interruption Investigation Maps Measures Mental Retardation Methods Modeling Molecular Molecular Abnormality Mutation Mutation Analysis Mutation Detection Neonatal Oligonucleotide Microarrays Patients Penetrance Phenotype Play Procedures Protocols documentation Research Research Subjects Resolution Role Sampling Screening procedure Sequence Tagged Sites Signal Transduction Southern Blotting Structure Surveys Testing VAV3 gene Variant apoAI regulatory protein-1 base cohort comparative genomic hybridization cost fusion gene genome-wide improved insight malformation mutant novel programs tissue culture

项目摘要

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.

描述（由申请人提供）：心血管畸形（CVM）是一类常见的出生缺陷，是婴儿死亡率和新生儿护理费用的主要原因。大量流行病学数据表明，遗传因素在 CVM 的病因中发挥着重要作用。一组重要的遗传异常，称为基因组疾病，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。亚微观染色体失衡已被发现在几种常见的复杂或综合征形式的 CVM 中很重要。这些疾病最有可能出现在患有 CVM 和多种先天性异常 (MCA) 的患者中，但此类病例中只有大约 10% 患有已知的基因组疾病。直到最近，全面调查基因组的这种不平衡在技术上还不可行。在初步研究中，我们使用了几个新可用的微阵列平台来建立用于染色体拷贝数改变的全基因组调查的方案。在一项可行性研究中，我们发现大约三分之一的 CVM/MCA 病例具有相对较大的亚显微染色体畸变。在本研究计划中，我们建议扩大 CVM/MCA 病例的拷贝数分析。这些结果将有助于更精确地评估病理变异的频率，并更好地描述它们如何在 CVM 中发挥因果作用。我们建议表征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 表型中发挥直接作用的个体基因，然后检查这些基因中更细微的突变是否在孤立性或非综合征性 CVM 中发挥作用。识别 CVM 背后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。