TCOF1 – Treacher Collins Syndrome

Treacher Collins Syndrome (TCS) is an autosomal dominant craniofacial disorder characterized by mandibulofacial dysostosis, downward‐slanting palpebral fissures, hypoplasia of the zygomatic arches and mandible, coloboma of the lower eyelids, cleft palate, and conductive hearing loss. The syndrome is caused predominantly by loss‐of‐function mutations in the TCOF1 gene (treacle ribosome biogenesis factor 1), which encodes a nucleolar phosphoprotein essential for ribosomal RNA transcription and neural crest cell survival (PMID:9096354).

Extensive genetic studies encompassing over 350 affected individuals from more than 100 unrelated families have identified over 200 distinct pathogenic variants in TCOF1, the vast majority introducing premature termination codons and leading to haploinsufficiency. Mutations cluster throughout the gene, with recurrent 5‐bp deletions in exon 24 and splice‐site and frameshift variants observed in multiple kindreds (PMID:9042910; PMID:11013442).An illustrative intronic deletion is c.376_378+15del, which disrupts the 5′ splice site of exon 4 and abolishes nucleolar localization signals in treacle (PMID:14598341).

Segregation analysis in familial TCS confirms autosomal dominant inheritance with high penetrance; affected individuals often have additional first‐degree relatives carrying the same TCOF1 variant. Mosaicism and nonpenetrance have been documented, underscoring the need for comprehensive testing even in mildly affected relatives.

Functional assays demonstrate that TCOF1 haploinsufficiency impairs ribosomal RNA biogenesis, triggers p53‐mediated apoptosis of neuroepithelial and neural crest cells, and results in craniofacial hypoplasia. Mouse Tcof1+/- models recapitulate TCS phenotypes and rescue of craniofacial defects by p53 inhibition confirms the mechanistic link between treacle deficiency, nucleolar stress, and cell death (PMID:19027870).

Clinical and molecular data show no clear genotype–phenotype correlation; severity varies widely even among carriers of the same mutation, implicating modifying genetic and environmental factors. Genetic counseling, prenatal and preimplantation genetic diagnosis, and multidisciplinary management are essential for optimal outcomes.

Key Take-home: Definitive association of TCOF1 loss-of-function with autosomal dominant Treacher Collins Syndrome underpins routine genetic testing for diagnosis, recurrence risk assessment, and targeted patient management.

References

• Proceedings of the National Academy of Sciences of the United States of America • 1997 • TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region PMID:9096354
• American Journal of Human Genetics • 1997 • The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon PMID:9042910
• Human Mutation • 2000 • High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes PMID:11013442
• American Journal of Medical Genetics. Part A • 2003 • Novel mutation in the 5' splice site of exon 4 of the TCOF1 gene in the patient with Treacher Collins syndrome PMID:14598341
• Human Molecular Genetics • 1998 • Mutations in the Treacher Collins syndrome gene lead to mislocalization of the nucleolar protein treacle PMID:9736782
• BMC Medical Genetics • 2009 • Reduced transcription of TCOF1 in adult cells of Treacher Collins syndrome patients PMID:20003452
• The International Journal of Biochemistry & Cell Biology • 2009 • Treacher Collins syndrome: unmasking the role of Tcof1/treacle PMID:19027870

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