Identification of Pericentromeric Imbalances

着丝粒周围不平衡的识别

• 批准号: 6807505
• 负责人: LISA SHAFFER
• 金额: $ 18.35万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6807505
• 关键词: aneuploidy; artificial chromosomes; autosome; centromere; chromosome aberrations; chromosome deletion; clinical research; comparative genomic hybridization; computer program /software; cytogenetics; diagnosis design /evaluation; digital imaging; disease /disorder etiology; family genetics; fluorescent in situ hybridization; genetic disorder diagnosis; genetic mapping; genetic screening; genetic susceptibility; human subject; karyotype; mental retardation; microarray technology; sex chromosomes; telomere

DESCRIPTION (provided by applicant): Abnormal karyotypes occur in approximately 0.3% of all newborn infants. Of these, interstitial deletions are likely to be a substantial cause of the imbalance. Based on a literature review of deletions and duplications of the human chromosomes that resulted in malformation, it appears that any region of the genome may be subject to rearrangement, but certain parts of the genome are more susceptible than others. Among these are the pericentromeric regions of chromosomes, which seem to be more susceptible to deletion than other internal segments of the chromosome arms. Much effort has gone into the development of telomere-region-specific probe sets. These sets have uncovered genetic imbalance in 7-23% of cases studied. No effort has been put forth to develop pericentromeric FISH probes. Known deletion syndromes exist close to the centromeres (e.g., Williams syndrome, Potocki-Shaffer syndrome, DiGeorge syndromes). This project proposes to identify new regions of chromosome imbalance of the pericentromeric regions through the following specific aims: 1) Construct a comparative genome hybridization (CGH) microarray (array CGH) for the pericentromeric regions of all human autosomes and the X chromosome; and 2) detect microdeletions and microduplications (deletions and duplications, respectively, too small to be viewed under a microscope) in the pericentromeric regions in a population of patients with mental retardation. Array CGH of the pericentromeric regions will uncover chromosome imbalances in regions of the genome currently not well interrogated with conventional cytogenetics or fluorescence in situ hybridization (FISH). Array CGH provides a platform for efficiently screening the pericentromeric regions of all chromosomes to uncover novel imbalances. It is likely that a substantial proportion of patients with mental retardation have microdeletions (and perhaps the reciprocal microduplications) of the pericentromeric regions of the genome, not detectable with any current FISH probe set. The identification of deletions or duplications in the pericentromeric regions may delineate new syndromes or uncover the etiology of established syndromes.

描述（由申请人提供）：所有新生儿中约有0.3%发生异常核型。其中，间质缺失可能是失衡的实质性原因。基于对导致畸形的人类染色体缺失和重复的文献综述，似乎基因组的任何区域都可能发生重排，但基因组的某些部分比其他部分更容易发生重排。其中包括染色体的着丝粒周围区域，该区域似乎比染色体臂的其他内部区段更容易缺失。许多努力已经进入端粒区域特异性探针组的发展。这些数据集在7-23%的研究病例中发现了遗传不平衡。尚未努力开发着丝粒周围FISH探针。已知的缺失综合征存在于着丝粒附近（例如，威廉姆斯综合征、波-谢二氏综合征、迪乔治综合征）。本项目拟通过以下几个方面的具体目标来鉴定着丝粒周围区染色体不平衡的新区域：1）构建比较基因组杂交（CGH）微阵列（阵列CGH）用于所有人类常染色体和X染色体的着丝粒周围区域;和2）检测微缺失和微重复（缺失和重复，分别太小，不能在显微镜下观察）在一个群体的精神发育迟滞患者的着丝粒周围区域。近着丝粒区域的阵列CGH将揭示目前用常规细胞遗传学或荧光原位杂交（FISH）不能很好地询问的基因组区域中的染色体不平衡。阵列CGH提供了一个平台，用于有效地筛选所有染色体的着丝粒周围区域，以发现新的不平衡。很可能相当大比例的精神发育迟滞患者具有基因组的着丝粒周围区域的微缺失（以及可能的相互微重复），这是用任何当前的FISH探针组都检测不到的。在着丝粒周围区域的缺失或重复的鉴定可以描绘新的综合征或揭示已建立的综合征的病因。