title: Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation.
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.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum, Essen, Germany.
authors.forename: Ozge Altug
authors.initials: OA
authors.lastname: Teber
authors.forename: Gabriele
authors.initials: G
authors.lastname: Gillessen-Kaesbach
authors.forename: Sven
authors.initials: S
authors.lastname: Fischer
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.forename: Angelika
authors.initials: A
authors.lastname: Albert
authors.forename: Mine
authors.initials: M
authors.lastname: Arslan-Kirchner
authors.forename: Eric
authors.initials: E
authors.lastname: Haan
authors.forename: Monika
authors.initials: M
authors.lastname: Hagedorn-Greiwe
authors.forename: Christof
authors.initials: C
authors.lastname: Hammans
authors.forename: Wolfram
authors.initials: W
authors.lastname: Henn
authors.forename: Georg Klaus
authors.initials: GK
authors.lastname: Hinkel
authors.forename: Rainer
authors.initials: R
authors.lastname: König
authors.forename: Erdmute
authors.initials: E
authors.lastname: Kunstmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kunze
authors.forename: Luitgard M
authors.initials: LM
authors.lastname: Neumann
authors.forename: Eva-Christina
authors.initials: EC
authors.lastname: Prott
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
authors.forename: Hans-Dieter
authors.initials: HD
authors.lastname: Rott
authors.forename: Heide
authors.initials: H
authors.lastname: Seidel
authors.forename: Stephanie
authors.initials: S
authors.lastname: Spranger
authors.forename: Martin
authors.initials: M
authors.lastname: Sprengel
authors.forename: Barbara
authors.initials: B
authors.lastname: Zoll
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Lohmann
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
mesh_terms: D002874:Chromosome Mapping; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome
chemical_list: D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human