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Acrofacial dysostosis Cincinnati type is a rare mandibulofacial dysostosis syndrome with variable limb anomalies characterized by hypoplastic zygomatic arches, micrognathia, and radial malformations. Heterozygous mutations in POLR1A, encoding the largest subunit of RNA polymerase I, underlie this autosomal dominant disorder by disrupting ribosome biogenesis and neural crest cell survival.
Genetic analyses of three unrelated probands identified de novo POLR1A variants, each presenting with mandibulofacial dysostosis and two with additional limb anomalies ([PMID:25913037]). No affected first‐degree relatives have been reported, consistent with a de novo autosomal dominant inheritance. There is no evidence of germline mosaicism or transmission in these families.
The variant spectrum includes frameshift and missense alleles. For example, the missense change c.1777G>C (p.Glu593Gln) (PMID:25913037) alters a conserved residue in the jaw domain. An additional truncating allele (c.3649del (p.Gln1217fsTer)) further supports loss‐of‐function as a mechanism. No recurrent or founder variants have been described to date.
Functional modeling in zebrafish demonstrated that polr1a loss of function recapitulates the human cranioskeletal phenotype ([PMID:25913037]). Mutant fish exhibit reduced craniofacial cartilage elements and p53‐mediated apoptosis in neural‐crest–derived cells. Mechanistic studies revealed impaired ribosomal RNA processing leading to nucleolar stress and activation of the p53 pathway.
These data establish a haploinsufficiency mechanism: POLR1A disruption perturbs ribosome assembly, triggers p53‐dependent cell death, and depletes skeletal progenitors. The consistency between human phenotypes and zebrafish models underscores the critical role of Pol I in craniofacial development.
Integration of genetic and experimental evidence supports a Moderate clinical validity classification. POLR1A testing should be included in diagnostic panels for mandibulofacial dysostosis syndromes. Future work may explore p53 modulation as a therapeutic avenue.
Gene–Disease AssociationModerateThree unrelated probands with de novo POLR1A variants ([PMID:25913037]) and concordant zebrafish model Genetic EvidenceModerate3 de novo heterozygous variants in POLR1A in unrelated individuals with consistent phenotype ([PMID:25913037]) Functional EvidenceModeratepolr1a zebrafish mutants display cranioskeletal anomalies; LOF leads to perturbed ribosome biogenesis and p53‐dependent cell death ([PMID:25913037]) |