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 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.

Ribosome biogenesis in skeletal development and the pathogenesis of skeletal disorders

“…No genotype-phenotype correlation has been observed with respect to Treacher Collins syndrome and similarly there is no clear evidence of an association between disease severity and parental origin or type of pathogenic mutation, male or female, sporadic or familial [38,44-47]. The variable severity indicates that genetic background, environmental factors and stochastic events may contribute to the clinical variation observed in patients with Treacher Collins syndrome [48].…”

Common mechanisms in development and disease: BMP signaling in craniofacial development

“…TCS is autosomal dominant disorder characterized by abnormal craniofacial development such as micrognathia, hypoplastic zygomatic arches, microtia, and coloboma of the eyelid (OMIM ID:154500) [9-11]. DGS is usually sporadic and results from de novo deletion within chromosome 22.…”

Goldenhar-Syndrom mit Aplasie des rechten oberen und mittleren Lungenlappens

“…Die Mikrognathie und die beschriebenen Ohrabnormitäten können außer-dem Teilaspekte einer akrofazialen Dysostose [15] vom "Nager-Typ" sein oder einer Dysostosis mandibulofacialis ("mandibulofacial dysostosis"/MFD, auch TreacherCollins-Franceschetti-Syndrom/TCS [16]). Die MFD führt jedoch in aller Regel auch zur Hypoplasie der Maxilla und des Jochbogens beider Gesichtshälften mit einer typischen Physiognomie und einer antimongoloiden Lidachse.…”