Abstract
Structural chromosome abnormalities have aided in gene identification for over three decades. Delineation of the deletion sizes and rearrangements allows for phenotype/genotype correlations and ultimately assists in gene identification. In this report, we have delineated the precise rearrangements in four subjects with deletions, duplications, and/or triplications of 1p36 and compared the regions of imbalance to two cases recently published. Fluorescence in situ hybridization (FISH) analysis revealed the size, order, and orientation of the duplicated/triplicated segments in each subject. We propose a premeiotic model for the formation of these complex rearrangements in the four newly ascertained subjects, whereby a deleted chromosome 1 undergoes a combination of multiple breakage-fusion-bridge (BFB) cycles and inversions to produce a chromosome arm with a complex rearrangement of deleted, duplicated and triplicated segments. In addition, comparing the six subjects' rearrangements revealed a region of overlap that when triplicated is associated with craniosynostosis and when deleted is associated with large, late-closing anterior fontanels. Within this region are the MMP23A and -B genes. We show MMP23 gene expression at the cranial sutures and we propose that haploinsufficiency results in large, late-closing anterior fontanels and overexpression results in craniosynostosis. These data emphasize the important role of cytogenetics in investigating and uncovering the etiologies of human genetic disease, particularly cytogenetic imbalances that reveal potentially dosage-sensitive genes.
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Acknowledgements
We thank the subjects and their families for their participation in this research. We thank Dr Helen E Roberts, Norfolk, VA, for clinical information on subject 64. We also thank Dr J Ohnishi (Hokkaido University, Sapporo, Japan) for the Mmp23 mRNA probe. This study was supported in part by grants from the NIH National Institute of Deafness and Other Communication Disorders K08 DC00169 (HAH) and NIH National Institute for Child Health and Development P01 HD39420 (LGS).
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Gajecka, M., Yu, W., Ballif, B. et al. Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure. Eur J Hum Genet 13, 139–149 (2005). https://doi.org/10.1038/sj.ejhg.5201302
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DOI: https://doi.org/10.1038/sj.ejhg.5201302
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