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 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.
Clinical Molecular Genetics Laboratory, Churchill Hospital, Oxford, UK.
Michael
M
Bowman
Michael
M
Oldridge
Caroline
C
Archer
Anthony
A
O'Rourke
Joanna
J
McParland
Roel
R
Brekelmans
Anneke
A
Seller
Tracy
T
Lester
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis / Q000379:methods*; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D018628:Gene Dosage; D015321:Gene Rearrangement; D005820:Genetic Testing / Q000379:methods; D015894:Genome, Human; D006801:Humans; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000175:diagnosis / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D059372:Nucleotide Motifs; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity
D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human