Mutation testing in Treacher Collins Syndrome

Ellis, Pamela; Dawson, Marcus; Dixon, Mike J.

doi:10.1093/ortho/29.4.293

Cited by 45 publications

(40 citation statements)

References 13 publications

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“…For example, none of our patients carries the deletion nt4135del(GAAAA) in exon 24 of the TCOF1 gene although, in previous reports, this mutation was identified in 20% of TCS patients. 17 Moreover, we identified significantly more single-base substitutions: 14 of 28 (50%) mutations in this study compared to 24 of 121 (19.8%) in previous reports (Fisher's test: P ¼ 0.02782). 11 -13,15 -17 Possibly, this difference is a consequence of the methods that were used for mutation detection.…”

Section: Discussionsupporting

confidence: 45%

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

et al. 2004

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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.

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Section: Discussionsupporting

confidence: 45%

Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation

et al. 2004

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“…Of the missense variants that were identified four could be categorised as being likely to be pathogenic based on their location at highly conserved residues within the LIS1 homology domain, where other pathogenic missense changes have been reported. 1,13,[17][18][19] Patient 443, who presented with micrognathia, deficient zygomatic arches, minor downslant of palpebral fissures, only rudimentary condyles, but no obvious hearing loss, was found to have c.42C4G (p.(Ile14Met)). Another variant at this residue, p.(Ile14Phe), has been reported previously in association with TCS.…”

Section: Discussionmentioning

confidence: 99%

Gross deletions in TCOF1 are a cause of Treacher–Collins–Franceschetti syndrome

et al. 2012

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Treacher-Collins-Franceschetti syndrome (TCS) is an autosomal dominant craniofacial disorder characterised by midface hypoplasia, micrognathia, downslanting palpebral fissures, eyelid colobomata, and ear deformities that often lead to conductive deafness. A total of 182 patients with signs consistent with a diagnosis of TCS were screened by DNA sequence and dosage analysis of the TCOF1 gene. In all, 92 cases were found to have a pathogenic mutation by sequencing and 5 to have a partial gene deletion. A further case had a novel in-frame deletion in the alternatively spliced exon 6A of uncertain pathogenicity. The majority of the pathogenic sequence changes were found to predict premature protein termination, however, four novel missense changes in the LIS1 homology motif at the 5¢ end of the gene were identified. The partial gene deletions of different sizes represent B5.2% of all the pathogenic TCOF1 mutations identified, indicating that gene rearrangements account for a significant proportion of TCS cases. This is the first report of gene rearrangements resulting in TCS. These findings expand the TCOF1 mutation spectrum indicating that dosage analysis should be performed together with sequence analysis, a strategy that is predicted to have a sensitivity of 71% for patients in whom TCS is strongly suspected.

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“…1,4,6 Computed tomography of the rhinopharynx is a useful method for defining anatomical airway obstruction. 5 This method may reveal detail of choanal atresia or other malformations that may result in airway obstruction. 1,3,5 Successful treatment of facial asymmetry appears to depend on the severity of the anomaly.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Traditionally, the diagnosis may be made prenatally by genetic studies of chorionic villus sampling or amniocentesis material, respectively on the 10th to 11th weeks or the 16th to 17th of gestation. 5 Ultrasound and fetoscopy may also provide the diagnosis. There is a published study in which ultrasound was used to detect the downward-slanting of ears and antimongoloid (downward-slanting) palpebral fissures.…”

Section: Introductionmentioning

confidence: 99%