Novel mutations of TCOF1 gene in European patients with treacher Collins syndrome

In this study, the entire coding regions of the TCOF1 gene, including newly described exons 6A and 16A, were sequenced in 46 unrelated subjects suspected of TCS clinical indication.Fifteen mutations were reported, including twelve novel and three already described in 14 sporadic patients and in 3 familial cases. Moreover, seven novel polymorphisms were also described. Most of the mutations characterised were microdeletions spanning one or more nucleotides, in addition to an insertion of one nucleotide in exon 18 and a stop mutation. The deletions and the insertion described cause a premature termination of translation, resulting in a truncated protein.This study confirms that almost all the TCOF1 pathogenic mutations fall in the coding region and lead to an aberrant protein.Treacher Collins syndrome (TCS; OMIM #154500) is an autosomal dominant disorder that affects the craniofacial development during early embryogenesis [1]. TCS is characterized by bilaterally symmetric features, including downward slanting palpebral fissures and colobomata of the lower eyelids, hypoplasia of the midfacial bones, cleft palate, and abnormal development of the external/middle ear that often leads to conductive hearing loss [2-4]. TCS occurs with an incidence of 1/50.000 and more than 60% of TCS cases has no previous family history and arises as the result of de novo mutations [5]. The syndrome is caused by mutations in the TCOF1 gene (OMIM #606847), which encodes the nucleolar phosphoprotein Treacle that may serve as a link between rDNA gene transcription and pre-rRNA processing [6]. Recently, Dauwerse et al. detected mutations in genes encoding subunits of RNA polymerases I and III (POLR1C and POLR1D) in Treacher Collins patients [7].Thus far, most of the 200 disease-causing mutations described are deletions, insertions and nonsense, distributed along 28 exons [8]. Two additional exons have been reported: exon 6A, included in the most common isoform, and exon 16A, included in a minor