Identification of Pericentromeric Imbalances

描述(申请人提供)：约0.3%的新生儿出现异常核型。其中，间隙缺失很可能是造成这种不平衡的重要原因。根据对导致畸形的人类染色体缺失和复制的文献回顾，基因组的任何区域似乎都可能发生重排，但基因组的某些部分比其他部分更容易受到影响。其中包括染色体的着丝粒周围区域，它们似乎比染色体臂的其他内部片段更容易缺失。在开发端粒区域特定的探针组方面已经付出了很大努力。这些集合在所研究的病例中发现了7-23%的遗传不平衡。还没有做出任何努力来开发着丝点周围的鱼类探测器。已知的缺失综合征存在于着丝粒附近(例如，Williams综合征、Potocki-Shaffer综合征、DiGeorge综合征)。该项目建议通过以下具体目标来确定着丝粒周围区域染色体失衡的新区域：1)构建针对所有人类常染色体和X染色体着丝粒周围区域的比较基因组杂交微阵列(阵列CGH)；以及2)检测一组智力低下患者的着丝粒周围区域的微缺失和微复制(分别缺失和复制，它们都太小，无法在显微镜下看到)。着丝粒周围区域的阵列CGH将揭示基因组中目前用传统细胞遗传学或荧光原位杂交(FISH)无法很好询问的区域的染色体不平衡。阵列CGH为有效筛选所有染色体的着丝粒周围区域提供了一个平台，以揭示新的不平衡。很可能有相当大比例的智力低下患者有基因组着丝粒周围区域的微缺失(也许还有相互的微复制)，这是目前任何FISH探针都无法检测到的。识别着丝粒周围区域的缺失或重复可能描绘出新的综合征或揭示已建立的综合征的病因。

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.