A novel intronic TCOF1 pathogenic variant in a Chinese family with Treacher Collins syndrome

Treacher Collins syndrome (TCS; OMIM 154500) is a craniofacial developmental disorder. To investigate the genetic features of a four-generation Chinese family with TCS, clinical examinations, hearing tests, computed tomography, whole-exome sequencing (WES), Sanger sequencing, reverse transcription (RT) -PCR, and the Minigene assay were performed. The probands, an 11-year-old male and his cousin exhibited typical clinical manifestations of TCS including conductive hearing loss, downward slanting palpebral fissures, and mandibular hypoplasia. Computed tomography revealed bilateral fusion of the anterior and posterior stapedial crura and malformation of the long crura of the incus. WES of both patients revealed a novel heterozygous intronic variant, i. e. , c. 4342 + 5₄342 + 8delGTGA (NM₀01371623. 1) in TCOF1. Minigene expression analysis revealed that the c. 4342 + 5₄342 + 8delGTGA variant in TCOF1 caused a partial deletion of exon 24 (c. 4115₄342del: p. Gly1373Arg1448del), which was predicted to yield a truncated protein. The deletion was further confirmed via RT-PCR and sequencing of DNA from proband blood cells. A heterozygous variant in the POLR1C gene (NM₂03290; exon6; c. 525delG) was found almost co-segregated with the TCOF1 pathogenic variant. In conclusion, we identified a heterozygous TCOF1 splicing variant c. 4342 + 5₄342 + 8delGTGA (splicing) in a Chinese TSC family with ossicular chain malformations and facial anomalies. Our findings broadened the spectrum of TCS variants and will facilitate diagnostics and prognostic predictions.