Abstract
BackgroundTreacher Collins syndrome (TCS) is one of the most severe autosomal dominant congenital disorders of craniofacial development and shows variable phenotypic expression. TCS is extremely rare, occurring with an incidence of 1 in 50.000 live births. The TCS distinguishing characteristics are represented by down slanting palpebral fissures, coloboma of the eyelid, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches, and macrostomia. Conductive hearing loss and cleft palate are often present. TCS results from mutations in the TCOF1 gene located on chromosome 5, which encodes a serine/alanine-rich nucleolar phospho-protein called Treacle. However, alterations in the TCOF1 gene have been implicated in only 81-93% of TCS cases.MethodsIn 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.ResultsFifteen 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.ConclusionThis study confirms that almost all the TCOF1 pathogenic mutations fall in the coding region and lead to an aberrant protein.
Highlights
Treacher Collins syndrome (TCS) is one of the most severe autosomal dominant congenital disorders of craniofacial development and shows variable phenotypic expression
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 [2,3,4]
Summary
Treacher Collins syndrome (TCS) is one of the most severe autosomal dominant congenital disorders of craniofacial development and shows variable phenotypic expression. 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 [2,3,4]. The mutations observed in TCS are predominantly sporadic, and the vast majority results in the introduction of a premature termination codon that can lead to the truncation of protein or to nonsense-mediated mRNA decay [10,11]. This suggests in the developmental anomalies result from haploinsufficiency of TCOF1
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