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The oculo-auriculo-vertebral spectrum (OAVS) (OMIM % 164210) is a common developmental disorder characterized by hemifacial microsomia, epibulbar tumours, ear malformation and vertebral anomalies. Although rare familial cases suggest that OAVS has a genetic basis, no genetic defect has been identified so far. In a patient with OAVS and a chromosomal translocation t(4;8) we have found that the chromosome 4 breakpoint is 76.4 kb distal to the BAPX1 gene, which plays an essential role in craniofacial development. We did not detect any BAPX1 mutation in 105 patients, but observed a strong allelic expression imbalance (sAEI) in fibroblasts from five of 12 patients, but not in nine normal controls (Fisher's exact test, P=0.038). sAEI was de novo in one patient and inherited in two other patients. Prolonged cell culture or treatment with the histone deacetylase inhibitor Trichostatin A led to reactivation of the downregulated allele. We propose that epigenetic dysregulation of BAPX1 plays an important role in OAVS.

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To define the range of phenotypic expression in Treacher Collins syndrome (TCS; Franceschetti-Klein syndrome), we performed mutation analysis in the TCOF1 gene in 46 patients with tentative diagnosis of TCS and evaluated the clinical data, including a scoring system. A total of 27 coding exons of TCOF1 and adjacent splice junctions were analysed by direct sequencing. In 36 patients with a clinically unequivocal diagnosis of TCS, we detected 28 pathogenic mutations, including 25 novel alterations. No mutation was identified in the remaining eight patients with unequivocal diagnosis of TCS and 10 further patients, in whom the referring diagnosis of TCS was clinically doubtful. There is no overt genotype-phenotype correlation except that conductive deafness is significantly less frequent in patients with mutations in the 3 0 part of the open reading frame. Inter-and intrafamilial variation is wide. Some mutation carriers, parents of typically affected patients, are so mildly affected that the diagnosis might be overlooked clinically. This suggests that modifying factors are important for phenotypic expression. Based on these findings, minimal diagnostic criteria were defined: downward slanting palpebral fissures and hypoplasia of the zygomatic arch. The difficulties in genetic counselling, especially diagnosis of family members with a mild phenotype, are described.