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

Abstract

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.

Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

“…As described in the literature, the majority of TCOF1 mutations were frameshift mutations, 8 yielding to haploinsufficiency of the Treacle protein. [20][21][22] Bowman et al 8 also described five large deletions in TCOF1 in patients with typical TCS, although the full extent of each deletion was not known because they involved either the first or last exon.…”

“…In the literature, the percentage of patients with mutations in TCOF1 ranged from 53% (97/182) 8 to 93% (26/28). 2,8,18 In the study by Bowman et al, 8 the proportion increased from 53 to 71% if patients with a high clinical suspicion of TCS are considered, and in the study by Teber et al 2 it increased from 61 to 78%.…”

“…[20][21][22] Bowman et al 8 also described five large deletions in TCOF1 in patients with typical TCS, although the full extent of each deletion was not known because they involved either the first or last exon. In this series we identified four intragenic microdeletions within TCOF1 in patients with typical TCS and two large deletions in 5q32 encompassing TCOF1 and neighboring genes in patients with TCS and ID.…”

“…7 Heterozygous intragenic deletions in TCOF1 have been recently described as a rare cause of TCS. 8,9 To date, no correlations have been established between phenotypic variability and the location of the mutations within TCOF1. 2,10 Mutations and intragenic deletions in the POLR1D and POLR1C genes have been observed in a small subset of patients with TCS.…”

Genetic Factors in Selected Complex Congenital Malformations with Cleft Defect

“…Further use of this model should demonstrate the exact role of TCOF1 in the formation of TCS. The other studies of TCS1 etiology that have been carried out on the human genome have revealed that not only single mutations are responsible for the TCS; it can also occur on the basis of the total rearrangement of the TCOF1 gene [60].…”