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The most notable phenotypes involve severe developmental delay, progressive brain atrophy, and drug\u2010resistant seizures. SGS is caused by spontaneous variants in <jats:italic>SETBP1<\/jats:italic>, which encodes for the epigenetic hub SETBP1 transcription factor (TF). <jats:italic>SETBP1<\/jats:italic> variants causing classical SGS cluster at the degron, disrupting SETBP1 protein degradation and resulting in toxic accumulation, while those located outside cause milder atypical SGS. Due to the multisystem phenotype, we evaluated gene expression and regulatory programs altered in atypical SGS by snRNA\u2010seq of the cerebral cortex and kidney of <jats:italic>Setbp1<\/jats:italic><jats:sup>S858R<\/jats:sup> heterozygous mice (corresponds to the human likely pathogenic <jats:italic>SETBP1<\/jats:italic><jats:sup>S867R<\/jats:sup> variant) compared to matched wild\u2010type mice by constructing cell\u2010type\u2010specific regulatory networks. <jats:italic>Setbp1<\/jats:italic> was differentially expressed in excitatory neurons, but known SETBP1 targets were differentially expressed and regulated in many cell types. Our findings suggest molecular drivers underlying neurodevelopmental phenotypes in classical SGS also drive atypical SGS, persist after birth, and are present in the kidney. Our results indicate SETBP1's role as an epigenetic hub leads to cell\u2010type\u2010specific differences in TF activity, gene targeting, and regulatory rewiring. This research provides a framework for investigating cell\u2010type\u2010specific variant impact on gene expression and regulation.<\/jats:p>","DOI":"10.1111\/jcmm.18001","type":"journal-article","created":{"date-parts":[[2023,10,24]],"date-time":"2023-10-24T06:25:06Z","timestamp":1698128706000},"page":"3565-3577","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Cell\u2010type\u2010specific gene expression and regulation in the cerebral cortex and kidney of atypical <scp><i>Setbp1<\/i><sup>S858R<\/sup><\/scp> Schinzel Giedion Syndrome mice"],"prefix":"10.1111","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9336-545X","authenticated-orcid":false,"given":"Jordan H.","family":"Whitlock","sequence":"first","affiliation":[{"name":"Department of Cell, Developmental and Integrative Biology, Heersink School of Medicine The University of Alabama at Birmingham  Birmingham Alabama 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