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

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 consisten...

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Published in:	European journal of human genetics : EJHG 2012-07, Vol.20 (7), p.769-777
Main Authors:	BOWMAN, Michael, OLDRIDGE, Michael, ARCHER, Caroline, O'ROURKE, Anthony, MCPARLAND, Joanna, BREKELMANS, Roel, SELLER, Anneke, LESTER, Tracy
Format:	Article
Language:	eng
Subjects:	1-Alkyl-2-acetylglycerophosphocholine Esterase - genetics 1-Alkyl-2-acetylglycerophosphocholine Esterase - metabolism Alternative Splicing Biological and medical sciences Clonal deletion Cohort Studies Deafness Diagnosis Diseases of the osteoarticular system DNA Copy Number Variations DNA Mutational Analysis - methods Ear Exons Eyelid Female Frameshift Mutation Fundamental and applied biological sciences. Psychology Gene Deletion Gene Dosage Gene Rearrangement Genes Genetic Testing - methods Genetics of eukaryotes. Biological and molecular evolution Genome, Human Hereditary diseases Homology Hospitals Humans Hypoplasia Laboratories Male Malformations and congenital and or hereditary diseases involving bones. Joint deformations Mandibulofacial Dysostosis - diagnosis Mandibulofacial Dysostosis - genetics Medical genetics Medical sciences Microtubule-Associated Proteins - genetics Microtubule-Associated Proteins - metabolism Molecular and cellular biology Mutation Mutation, Missense Nuclear Proteins - genetics Nuclear Proteins - metabolism Nucleotide Motifs Nucleotide sequence Pathogenicity Pedigree Phosphoproteins - genetics Phosphoproteins - metabolism Predictive Value of Tests Ribosomal DNA Sensitivity and Specificity
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Summary:	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.
ISSN:	1018-4813 1476-5438