Identification of Pericentromeric Imbalances

描述（由申请人提供）：核型异常约占所有新生儿的0.3%。其中，间隙性缺失可能是失衡的重要原因。基于对人类染色体缺失和重复导致畸形的文献回顾，似乎基因组的任何区域都可能受到重排的影响，但基因组的某些部分比其他部分更容易受到影响。其中包括染色体的近中心点区域，它似乎比染色体臂的其他内部片段更容易被删除。人们在开发端粒区域特异性探针装置方面付出了很多努力。在这些研究中，有7-23%的病例发现了基因失衡。没有努力去开发中心点周围的FISH探针。已知的缺失综合征存在于着丝粒附近（如Williams综合征、Potocki-Shaffer综合征、DiGeorge综合征）。本项目拟通过以下具体目标，确定新的染色体不平衡区域：1)构建人类所有常染色体和X染色体的染色体不平衡区域的比较基因组杂交（CGH）微阵列（array CGH）；2)检测智力迟钝患者中心点周围区域的微缺失和微重复（缺失和重复分别太小而无法在显微镜下观察到）。中心周围区域的阵列CGH将揭示基因组区域的染色体不平衡，目前无法用传统的细胞遗传学或荧光原位杂交（FISH）很好地询问。阵列CGH提供了一个平台，有效地筛选所有染色体的中心点周围区域，以发现新的失衡。很可能有相当比例的智力迟钝患者存在基因组中中心点周围区域的微缺失（也可能是相互的微重复），这是目前任何FISH探针都无法检测到的。在中心点周围区域的缺失或重复的鉴定可能划定新的综合征或揭示既定综合征的病因。

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.