{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:01:32Z","timestamp":1791489692678,"version":"4.3.4"},"reference-count":46,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000071","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["HD02528"],"award-info":[{"award-number":["HD02528"]}],"id":[{"id":"10.13039\/100000071","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objective: POLR1A and related gene variants cause craniofacial and developmental syndromes, including Acrofacial Dysostosis-Cincinnati, Treacher-Collins types 2\u20134, 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)\u2013related ribosomopathies. Methods: A 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\u2019s impact. Results: The patient exhibited features overlapping with Sweeney-Cox, Saethre-Cox, Robinow-Sorauf, and Treacher-Collins types 2\u20134, 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. Conclusion: Significant clinical and genetic overlap exists among Saethre-Chotzen, Sweeney-Cox, Treacher-Collins types 2\u20134, 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\u2013related ribosomopathies, with implications for diagnosis, counseling, and future mechanistic or therapeutic studies.<\/jats:p>","DOI":"10.3390\/genes16091063","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T12:04:55Z","timestamp":1757505895000},"page":"1063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["RNA Polymerase I Dysfunction Underlying Craniofacial Syndromes: Integrated Genetic Analysis Reveals Parallels to 22q11.2 Deletion Syndrome"],"prefix":"10.3390","volume":"16","author":[{"given":"Spencer","family":"Silvey","sequence":"first","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3215-4472","authenticated-orcid":false,"given":"Scott","family":"Lovell","sequence":"additional","affiliation":[{"name":"Protein Structure and X-Ray Crystallography Laboratory, University of Kansas, Lawrence, KS 66047, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2911-0524","authenticated-orcid":false,"given":"Merlin G.","family":"Butler","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS 66160, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","first-page":"56","article-title":"A new syndrome involving cleft palate, cardiac anomalies, typical facies, and learning disabilities: Velo-cardio-facial syndrome","volume":"15","author":"Shprintzen","year":"1978","journal-title":"Cleft Palate J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1542\/peds.67.2.167","article-title":"The velo-cardio-facial syndrome: A clinical and genetic analysis","volume":"67","author":"Shprintzen","year":"1981","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1308\/003588413X13511609956372","article-title":"A quick guide to survey research","volume":"95","author":"Jones","year":"2013","journal-title":"Ann. 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