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We show that <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>tm1d\/+<\/jats:italic><\/jats:sup> mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>tm1d\/+<\/jats:italic><\/jats:sup> growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> chondrogenic cell lines. Similar to our prior <jats:italic>in vitro<\/jats:italic> model of KS1, we found that <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> cells undergo premature, enhanced differentiation towards chondrocytes compared to <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>+\/+<\/jats:italic><\/jats:sup> controls. RNA-seq showed that <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on <jats:italic>Kmt2d<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>, <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup>, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between <jats:italic>Kmt2d<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> and <jats:italic>Kdm6a<\/jats:italic><jats:sup><jats:italic>-\/-<\/jats:italic><\/jats:sup> at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.<\/jats:p>","DOI":"10.1371\/journal.pgen.1011310","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T17:44:19Z","timestamp":1718041459000},"page":"e1011310","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Growth deficiency in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2298-2239","authenticated-orcid":true,"given":"Christine W.","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WanYing","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7265-6939","authenticated-orcid":true,"given":"Ryan C.","family":"Riddle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheetal","family":"Chopra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0291-1759","authenticated-orcid":true,"given":"Jiyoung","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6464-867X","authenticated-orcid":true,"given":"Leandros","family":"Boukas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0086-0687","authenticated-orcid":true,"given":"Kasper D.","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans T.","family":"Bj\u00f6rnsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5506-8780","authenticated-orcid":true,"given":"Jill A.","family":"Fahrner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,6,10]]},"reference":[{"key":"pgen.1011310.ref001","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1146\/annurev-genom-090613-094245","article-title":"Mendelian disorders of the epigenetic machinery: Tipping the balance of chromatin States","volume":"15","author":"JA Fahrner","year":"2014","journal-title":"Annu Rev Genomics Hum Genet"},{"issue":"2","key":"pgen.1011310.ref002","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1136\/jmedgenet-2018-105625","article-title":"Kabuki syndrome: International consensus diagnostic criteria","volume":"56","author":"MP Adam","year":"2019","journal-title":"J Med Genet"},{"issue":"9","key":"pgen.1011310.ref003","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1002\/humu.23026","article-title":"Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2","volume":"37","author":"N B\u00f6gershausen","year":"2016","journal-title":"Hum Mutat"},{"issue":"9","key":"pgen.1011310.ref004","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1038\/ng.646","article-title":"Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome","volume":"42","author":"SB Ng","year":"2010","journal-title":"Nat Genet"},{"issue":"24","key":"pgen.1011310.ref005","doi-asserted-by":"crossref","first-page":"2749","DOI":"10.1101\/gad.203356.112","article-title":"Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4","volume":"26","author":"SS Dhar","year":"2012","journal-title":"Genes Dev"},{"issue":"2","key":"pgen.1011310.ref006","first-page":"1","article-title":"H3K4 mono- And di-methyltransferase MLL4 is required for enhancer activation during cell differentiation","volume":"2013","author":"JE Lee","year":"2013","journal-title":"Elife"},{"issue":"1","key":"pgen.1011310.ref007","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41588-017-0018-3","article-title":"Is H3K4me1 at enhancers correlative or causative?","volume":"50","author":"A. 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