Treacher Collins syndrome is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. In the absence of a candidate gene, a positional cloning approach has been used to isolate the mutated gene which maps to chromosome 5q31.3-32. Flanking markers were identified and a yeast artificial chromosome and cosmid contig of the region defined by these markers was created as a prelude to the creation of a transcript map of the region. Analysis of genes isolated using this approach resulted in the identification of the mutated gene. While the function of the gene remains unknown, the identification of 20 mutations spread throughout the gene, all of which would result in the insertion of a premature termination codon into the reading frame, suggests that the mechanism underlying the disease is haploinsufficiency.