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PubMed2026

Molecular Characterisation of Treacher Collins Syndrome in a South African Cohort: Novel Disease-Causing Variants in TCOF1 and POLR1D.

BACKGROUND: Treacher Collins syndrome (TCS) is a rare craniofacial disorder characterised by variable expressivity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, or POLR1B genes. Common clinical features include hypoplasia of the zygomatic complex and mandible, downward-slanting palpebral fissures, lower eyelid anomalies, microtia, and hearing loss. Owing to its phenotypic overlap with other craniofacial syndromes, molecular testing is essential for establishing an accurate diagnosis and guiding effective clinical management. METHODS: Ten South African patients with a suspected clinical diagnosis of TCS underwent targeted next-generation sequencing (NGS) using a custom gene panel including TCOF1, POLR1C, and POLR1D genes. Variants were classified according to ACMG/AMP guidelines, with validation by Sanger sequencing where necessary. RESULTS: Disease-causing variants were identified in six of the ten patients (60%). These included five heterozygous variants in TCOF1 and one homozygous variant in POLR1D. Notably, five of the six variants were identified for the first time in this study. Additionally, a recurrent TCOF1 deletion was identified for the first time in an African family. CONCLUSION: This study expands the mutational spectrum of TCS in general and provides African data in particular. Findings support the use of panel-based NGS for diagnosis in resource-limited settings and highlight the need for population-specific variant data to improve diagnostic accuracy, guide clinical care, and support genetic counselling for affected individuals and their families.

Humans↗

PubMed2026

Novel TCOF1 Frameshift Variant and Phenotypic Heterogeneity in a Chinese Family With Treacher Collins Syndrome.

BACKGROUND: Treacher Collins syndrome (TCS) is a congenital craniofacial disorder characterized by malar and mandibular hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. Pathogenic variants in TCOF1 account for most cases, with POLR1D, POLR1C, and POLR1B also implicated. METHODS: Whole-exome sequencing was performed in a two-generation Chinese family with TCS, followed by Sanger sequencing validation. Clinical features were systematically evaluated, and bioinformatic analyses combined with structural modeling were employed to assess the potential pathogenicity of the identified variant. RESULTS: In this study, a novel heterozygous frameshift variant in TCOF1 (NM_001371623.1:c.1601_1602delCC, p.Pro534Leufs*15) was identified in the proband and his affected father. The proband presented classic TCS features including craniofacial skeletal hypoplasia, downward-slanting palpebral fissures, and conductive hearing loss. He also carried a right-sided preauricular fistula, a nonclassical feature of TCS. The same variant was detected in his affected father with a substantially milder phenotype, indicating marked intrafamilial phenotypic variability. Bioinformatic analysis and structural modeling predicted that this variant produces a severely truncated Treacle protein lacking key functional domains, which is predicted to disrupt nucleolar localization and ribosome biogenesis. CONCLUSION: Our findings expand the variant spectrum of TCOF1, highlight phenotypic heterogeneity in TCS, and reinforce the critical role of molecular diagnosis in distinguishing TCS from phenotypically overlapping craniofacial syndromes.

Humans↗

PubMed2026

Peroxiredoxin 1 safeguards the nucleolar genome from oxidative damage.

Peroxiredoxin 1 (PRDX1) is a highly conserved, thiol-dependent peroxidase that rapidly scavenges reactive oxygen species to modulate redox signaling. PRDX1-null mice exhibited genomic instability, shortened life span, and accelerated tumorigenesis, including development of lymphomas, sarcomas, and carcinomas. Despite extensive characterization of these phenotypes, the molecular mechanism by which PRDX1 loss causes genomic instability remains poorly understood. Here, we show that PRDX1 deficiency alters nucleolar morphology, impairs RNA polymerase I (POL-I)-dependent transcription of pre-ribosomal RNAs, and triggers nucleolar genomic instability. This oxidative stress-induced nucleolar dysfunction promotes the stability of secondary DNA structures, such as RNA-DNA hybrids and G-quadruplex DNA, contributing to nucleolar genomic instability. We demonstrate that PRDX1 loss reduces nascent ribosomal RNA (rRNA) levels and impairs rRNA processing, further affecting ribosome biogenesis. Mechanistically, we established that PRDX1 loss triggers activation of the nucleolar DNA damage response characterized by activation of the DNA repair kinase ATM and elevated TCOF1 within the nucleolus. In addition, we observed recruitment of the MRE11-RAD50-NBS1 (MRN) complex subunit NBS1 to ribosomal DNA (rDNA) loci and this was further increased under oxidative stress. NBS1 accumulation correlates with the repression of rDNA transcription by POL-I, potentially delaying rRNA synthesis, and safeguarding the nucleolar genome from further oxidative damage. Collectively, these findings uncover a previously unrecognized, but critical role, for PRDX1 in maintaining nucleolar integrity and ribosomal biogenesis through redox-dependent regulation of rDNA transcription and processing machinery.

Oxidative Stress↗