A YAC CONTIG ENCOMPASSING THE TREACHER-COLLINS SYNDROME CRITICAL REGION AT 5Q31.3-32

Treacher Collins syndrome (TCOF1) is an autosomal dominant disorder of craniofacial development the features of which include conductive hea ring loss and cleft palate. Previous studies have localized the TCOF1 locus between D5S519 (proximal) and SPARC (distal), a region of 22 cen tirays as estimated by radiation hybrid mapping. In the current invest igation we have created a contig across the TCOF1 critical region, usi ng YAC clones. Isolation of a novel short tandem repeat polymorphism c orresponding to the end of one of the YACs has allowed us to reduce th e size of the critical region to similar to 840 kb, which has been cov ered with three nonchimeric YACs. Restriction mapping has revealed tha t the region contains a high density of clustered rare-cutter restrict ion sites, suggesting that it may contain a number of different genes. The results of the present investigation have further allowed us to c onfirm that the RPS14 locus lies proximal to the critical region and c an thereby be excluded from a role in the pathogenesis of TCOF1, while ANX6 lies within the TCOF1 critical region and remains 21 potential c andidate for the mutated gene.