Gross deletions in TCOF1 are a cause of Treacher-Collins-Franceschetti syndrome - PubMed (original) (raw)

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

Michael Bowman et al. Eur J Hum Genet. 2012 Jul.

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 ~5.2% 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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Figures

Figure 1

Figure 1

Dosage results for the five patients with a partial TCOF1 deletion. A 50% relative bar height indicates a heterozygous deletion. MLPA detected a heterozygous deletion of: (452) exons 1–15; (170) exon 1; (96) exon 26; (8) exons 23–26; (226) exons 1–6. Grey bars on the left represent control probes, white bars represent probes located within or nearby to all _TCOF1-_coding exons except exons 19 and 20. The grey bar on the right represents the untranslated TCOF1 exon 26 (3′UTR).

Figure 2

Figure 2

Schematic illustrating results of MLPA and quantitative PCR analysis of TCOF1 in (a) 5′-UTR region in case 170 and (b) 3′-UTR region in case 96. Coding sequence (black boxes), UTR (hatched boxes) and introns (thin black lines). Black lines above the figure indicate the target sites for the MLPA probes and the amplicons for qPCR relative copy number calculated from the quantitative PCR assay in the respective patient and a deletion control are shown in the graphs above each amplicon. ATG is the translation initiation signal, TGA is the translation termination signal and AATAAA is the polyadenylation signal. The dark grey line below the figure indicates deleted sequence where probes/amplicons show 50% dosage; the light grey line indicates sequence that is not deleted where probes/amplicons show normal dosage. Grey dashed lines show regions of uncertainty. Not to scale.

References

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