Identification of Pericentromeric Imbalances

Washington State University, Pullman WA

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Abstract

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.