RNA Polymerase I Dysfunction Underlying Craniofacial Syndromes: Integrated Genetic Analysis Reveals Parallels to 22q11.2 Deletion Syndrome.

BACKGROUND/

objectivePOLR1A and related gene variants cause craniofacial and developmental syndromes, including Acrofacial Dysostosis-Cincinnati, Treacher-Collins types 2-4, and TWIST1-associated disorders. Using a patient case integrated with molecular analyses, we aimed to clarify shared pathogenic mechanisms and propose these conditions as part of a spectrum of RNA polymerase I (Pol I)-related ribosomopathies.

methodsA patient with a heterozygous POLR1A variant underwent clinical evaluation. Findings were integrated with a literature review of craniofacial syndromes to identify overlapping fea tures. Protein-protein and gene-gene interactions were analyzed with STRING and Pathway Commons, a structural modeling of POLR1A assessed the mutation's impact.

resultsThe patient exhibited features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins types 2-4, supporting a shared spectrum. Computational analyses identified POLR1A-associated partners and pathways converging on Pol I function, ribosomal biogenesis, and nucleolar processes. Structural modeling of the Met496Ile variant suggested disruption of DNA binding and polymerase activity, linking molecular dysfunction to the clinical phenotype.

conclusionSignificant clinical and genetic overlap exists among Saethre-Chotzen, Sweeney-Cox, Treacher-Collins types 2-4, and Acrofacial Dysostosis-Cincinnati. POLR1A and related Pol I subunits provide a mechanistic basis through impaired nucleolar organization and rRNA transcription, contributing to abnormal craniofacial development. Integrative protein, gene, and structural analyses support classifying these syndromes as Pol I-related ribosomopathies, with implications for diagnosis, counseling, and future mechanistic or therapeutic studies.