A TRANSCRIPT MAP OF THE NEWLY DEFINED 165 KB WOLF-HIRSCHHORN SYNDROMECRITICAL REGION

Wolf-Hirschhorn syndrome (WHS) is a multiple malformation syndrome cha racterised by mental and developmental defects resulting from the abse nce of a segment of one chromosome 4 short arm (4p16.3). Due to the co mplex and variable expression of this disorder, it is thought that the WHS is a contiguous gene syndrome with an undefined number of genes c ontributing to the phenotype, In an effort to identify genes that cont ribute to human development and whose absence results in this syndrome , we have utilised a series of landmark cosmids to characterise a coll ection of WHS patient derived cell lines. Fluorescence in situ hybridi sation with these cosmids was used to refine the WHS critical region ( WHSCR) to 260 kb, The genomic sequence of this region is available and analysis of this sequence through BLAST detected several cDNA clones in the dbEST data base, A total of nine independent cDNAs, and their p redicted translation products, from this analysis Show no significant similarity to members of DNA or protein databases, Furthermore, these genes have been localised within the WHS critical region and reveal an interesting pattern of transcriptional organisation, A previously pub lished report of a patient with proximal 4p- syndrome further refines the WHSCR to 165 kb defined by the loci D4S166 and D453327. This work provides the starting point to understand how multiple genes or other mechanisms can contribute to the complex phenotype associated with the Wolf-Hirschhorn syndrome.