1. ¹Institut für Humangenetik, Universitätsklinikum, Essen, Germany
2. ²Abteilung für pädiatrische Genetik der Kinderpoliklinik, Ludwig-Maximilian-Universität, München, Germany
3. ³Institut für Humangenetik, Medizinische Hochschule, Hannover, Germany
4. ⁴South Australian Clinical Genetics Service, Women's & Children's Hospital, Adelaide, Australia
5. ⁵Institut für Humangenetik, Universitätsklinikum, Lübeck, Germany
6. ⁶Humangenetik, Ruhr-Universität, Bochum, Germany
7. ⁷Institut für Humangenetik, Universität des Saarlandes, Homburg/Saar, Germany
8. ⁸Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus der TU, Dresden, Germany
9. ⁹Institut für Humangenetik, Universität Frankfurt, Germany
10. ¹⁰Institut für Humangenetik, Charité, Berlin, Germany
11. ¹¹Institut für Humangenetik, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany
12. ¹²Praxis für Humangenetik, Bremen, Germany
13. ¹³Klinik für Mund-, Kiefer- und Gesichtschirurgie, Universitätsklinikum Kiel, Germany
14. ¹⁴Institut für Humangenetik, Universität Göttingen, Germany

Correspondence: DR Lohmann, Institut für Humangenetik, Universitätsklinikum, 45122 Essen, Germany. Tel. +49 201 7234562; Fax +49 201 7235900; E-mail: dr.lohmann@uni-essen.de

Received 23 March 2004; Revised 26 May 2004; Accepted 8 June 2004; Published online 1 September 2004.

Abstract

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' 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.