DELIMITING THE WOLF-HIRSCHHORN-SYNDROME CRITICAL REGION TO 750 KILOBASE PAIRS

Wolf-Hirschhorn syndrome (WHS) is a multiple anomaly condition charact erized by mental and developmental defects, resulting from the absence of the distal segment of one chromosome 4 short arm (4p16.3). Owing t o the complex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. The 2.2 Mbp genomic segment prev iously defined as the critical region by the analyses of patients with terminal or interstitial deletions is extremely gene dense and an int ensive investigation of the developmental role of all the genes contai ned within it would be daunting and expensive, Further refinement in t he definition of the critical region would be valuable but depends on available patient material and accurate clinical evaluation. In this s tudy, we have utilized fluorescence in situ hybridization to further c haracterize a WHS patient previously demonstrated to have an interstit ial deletion and demonstrate that the distal breakpoint occurs between the loci FGFR3 and D4S168. This reduces the critical region for this syndrome to less than 750 kbp. This has the effect of eliminating seve ral genes previously proposed as contributing to this syndrome and all ows further research to focus on a more restricted region of the genom e and a limited set of genes for their role in the WHS syndrome. (C) 1 997 Wiley-Liss, Inc.