Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation.
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.
Teber
Ozge Altug
OA
Institut für Humangenetik, Universitätsklinikum, Essen, Germany.
Gillessen-Kaesbach
Gabriele
G
Fischer
Sven
S
Böhringer
Stefan
S
Albrecht
Beate
B
Albert
Angelika
A
Arslan-Kirchner
Mine
M
Haan
Eric
E
Hagedorn-Greiwe
Monika
M
Hammans
Christof
C
Henn
Wolfram
W
Hinkel
Georg Klaus
GK
König
Rainer
R
Kunstmann
Erdmute
E
Kunze
Jürgen
J
Neumann
Luitgard M
LM
Prott
Eva-Christina
EC
Rauch
Anita
A
Rott
Hans-Dieter
HD
Seidel
Heide
H
Spranger
Stephanie
S
Sprengel
Martin
M
Zoll
Barbara
B
Lohmann
Dietmar R
DR
Wieczorek
Dagmar
D
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
D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human