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The DS-specific CF features are an overall reduction in head dimensions (microcephaly), relatively wide and broad neurocranium (brachycephaly), reduced mediolaterally orbital region, reduced bizygomatic breadth, small maxilla, small mandible, and increased individual variability. Until now, the cellular and molecular mechanisms underlying the specific craniofacial phenotype have remained poorly understood. Investigating a new panel of DS mouse models with different segmental duplications on mouse chromosome 16 in the region homologous to human chromosome 21, we identified new regions and the role of two candidate genes for DS-specific CF phenotypes. First, we confirmed the role of <jats:italic><jats:italic>Dyrk1a<\/jats:italic><\/jats:italic> in the neurocranium brachycephaly. Then, we identified the role of the transcription factor <jats:italic><jats:italic>Ripply3<\/jats:italic><\/jats:italic> overdosage in midface shortening through the downregulation of <jats:italic><jats:italic>Tbx1<\/jats:italic><\/jats:italic>, another transcription factor involved in the CF midface phenotype encountered in DiGeorge syndrome. This last effect occurs during the development of branchial arches through a reduction in cell proliferation. Our findings define a new dosage-sensitive gene responsible for the DS craniofacial features and propose new models for rescuing all aspects of DS CF phenotypes. This data may also provide insights into specific brain, immune and cardiovascular phenotypes observed in DiGeorge and DS models, opening avenues for potential targeted treatment to soften craniofacial dysmorphism in Down syndrome.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011873","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T17:41:22Z","timestamp":1758562882000},"page":"e1011873","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Ripply3 overdosage induces mid-face shortening through Tbx1 downregulation in Down syndrome models"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2013-8417","authenticated-orcid":true,"given":"Jos\u00e9 Tom\u00e1s","family":"Ahumada 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