BACKGROUND The Treacher Collins syndrome (TCS) is an autosomal dominant hereditary syndrome with variable penetrance and expression. The clinical characteristics are the result of dysmorphogenesis of the first and second embryonal branchial arch systems. The gene responsible has been located on the long arm of chromosome 5. Treacher Collins syndrome is rare, and in 60% of the patients the family history is negative. Consequently, only a few family studies are available. This renders it difficult to make a diagnosis and to comply with the increasing demand for genetic counseling. To gain insight into the diagnosis and variation in expression and penetrance of TCS, a clinical study was started followed by gene linkage research. METHODS Audiological and physical tests were performed on 59 persons belonging to two families. In selected cases (n = 19), vestibular and radiological examinations were also conducted. Blood samples were taken from 55 persons for gene linkage studies. RESULTS The diagnosis of TCS could be made in 13 persons after clinical examination. The radiological detection of zygomatic hypoplasia or aplasia played an important supportive role. In addition to the 13 persons with TCS mentioned above, gene linkage studies showed positive linkage to chromosome 5q32-33.2 in three persons with clinical nonpenetrance. CONCLUSIONS This is the first time nonpenetrance of TCS has been demonstrated convincingly. In individual cases, clinical examination alone cannot always remove doubts about the diagnosis. Therefore, gene linkage studies will play a decisive role. Identification of the gene responsible for TCS is expected to be very useful in clinical practice.