Novel Genomic Disorders Causing Cardiovascular Malformations

导致心血管畸形的新型基因组疾病

• 批准号: 8019545
• 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
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019545
• 关键词: Affect; Cardiovascular system; Caring; Chromosome abnormality; Complex; Congenital Abnormality; Data; Diagnosis; Disease; Early treatment; Epidemiology; Event; Feasibility Studies; Frequencies; Functional disorder; Genes; Genetic; Genome; Genomics; Individual; Infant Mortality; Molecular; Molecular Abnormality; Mutation; Names; Neonatal; Patients; Phenotype; Play; Principal Investigator; Protocols documentation; Research; Role; Surveys; Variant; cost; genetic analysis; genome-wide; improved; malformation; novel; programs

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。大量的流行病学数据已经确定，遗传因素在CVM的病因中起着重要作用。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。已经发现亚显微镜下染色体不平衡在几种常见的复杂或综合征形式的CVM中是重要的。这些疾病最有可能在患有CVM加多发性先天性异常（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，全面调查基因组中的这种不平衡在技术上还不可行。在初步研究中，我们已经使用了几个新的微阵列平台，以建立在染色体拷贝数的改变全基因组调查的协议。在一项可行性研究中，我们发现约三分之一的CVM/MCA病例具有相对较大的亚显微染色体畸变。在这项研究计划中，我们建议扩大CVM/MCA病例的拷贝数分析。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不平衡事件的边界，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单个基因，然后检查这些基因中更微妙的突变是否在孤立或非综合征型CVM中发挥作用。确定导致脑血管畸形的特定基因将有助于了解这些常见异常的起源。提高筛查染色体不平衡和相关基因突变的能力将有助于诊断和早期干预CVM。

项目成果

Identification of chromosome abnormalities in subtelomeric regions by microarray analysis: a study of 5,380 cases.

• DOI: 10.1002/ajmg.a.32399
• 发表时间: 2008-09-01
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Shao, Lina;Shaw, Chad A.;Lu, Xin-Yan;Sahoo, Trilochan;Bacino, Carlos A.;Lalani, Seema R.;Stankiewicz, Pawel;Yatsenko, Svetlana A.;Li, Yinfeng;Neill, Sarah;Pursley, Amber N.;Chinault, A. Craig;Patel, Ankita;Beaudet, Arthur L.;Lupski, James R.;Cheung, Sau W.
• 通讯作者: Cheung, Sau W.

Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities.

• DOI: 10.1038/ng.279
• 发表时间: 2008-12
• 期刊: NATURE GENETICS
• 影响因子: 30.8
• 作者: Brunetti-Pierri, Nicola;Berg, Jonathan S.;Scaglia, Fernando;Belmont, John;Bacino, Carlos A.;Sahoo, Trilochan;Lalani, Seema R.;Graham, Brett;Lee, Brendan;Shinawi, Marwan;Shen, Joseph;Kang, Sung-Hae L.;Pursley, Amber;Lotze, Timothy;Kennedy, Gail;Lansky-Shafer, Susan;Weaver, Christine;Roeder, Elizabeth R.;Grebe, Theresa A.;Arnold, Georgianne L.;Hutchison, Terry;Reimschisel, Tyler;Amato, Stephen;Geragthy, Michael T.;Innis, Jeffrey W.;Obersztyn, Ewa;Nowakowska, Beata;Rosengren, Sally S.;Bader, Patricia I.;Grange, Dorothy K.;Naqvi, Sayed;Garnica, Adolfo D.;Bernes, Saunder M.;Fong, Chin-To;Summers, Anne;Walters, W. David;Lupski, James R.;Stankiewicz, Pawel;Cheung, Sau Wai;Patel, Ankita
• 通讯作者: Patel, Ankita

Strategic approaches to unraveling genetic causes of cardiovascular diseases.

• DOI: 10.1161/circresaha.110.236067
• 发表时间: 2011-05-13
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Marian AJ;Belmont J
• 通讯作者: Belmont J