1. ¹Health Research and Education Center, Washington State University, Spokane, WA, USA
2. ²Sacred Heart Medical Center, Spokane, WA, USA
3. ³Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
4. ⁴Department of Medicine, Children's Hospital, Boston, MA, USA
5. ⁵Department of Craniofacial Development, King's College, London

Correspondence: Dr LG Shaffer, Health Research and Education Center, Washington State University, Box 1495, Spokane, WA 99210-1495, USA. Tel: 509 368 6710; Fax: 509 358 7627; E-mail: lshaffer@wsu.edu

Received 13 April 2004; Revised 21 July 2004; Accepted 1 September 2004; Published online 13 October 2004.

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.