Case Report: A novel heterozygous variant of the TCOF1 gene in Treacher Collins syndrome

Treacher Collins syndrome (TCS) is a craniofacial malformation caused by the abnormal development of the first and second pharyngeal arches during embryogenesis. While pathogenic variants in <i>POLR1B</i>, <i>POLR1C</i>, and <i>POLR1D</i> are implicated, the <i>TCOF1</i> gene represents the primary causative locus. This case report describes a novel heterozygous frameshift variant, <i>TCOF1</i>:NM_001135243.2:c.3559delG (p.Ala1187GlufsTer21), identified in a child with TCS. This truncation disrupts the C-terminal nuclear localization signal (NLS), specifically ablating a phosphorylation site at residues 1,199-1,200. Consequently, ribosome biosynthesis and craniofacial neural crest cell development are impaired, culminating in characteristic clinical manifestations, including downslanting palpebral fissures, depressed nasal bridge, marked malar hypoplasia, mandibular hypoplasia, and microtia. Although the mother carried the same variant, she exhibited no clinical symptoms, suggesting incomplete penetrance. This variant is the first internationally reported instance. Its identification reinforces the central pathogenic role of <i>TCOF1</i> in TCS, underscores the functional significance of the treacle protein's NLS, and expands the variant database. Penetrance variability complicates genetic counseling, necessitating future research into its genetic characteristics to enhance prenatal diagnostic accuracy.