{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T17:45:09Z","timestamp":1788975909152,"version":"build-2803163510"},"reference-count":105,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2023,5,9]],"date-time":"2023-05-09T00:00:00Z","timestamp":1683590400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2023,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Kabuki syndrome type 1 (KS1), a rare multisystem congenital disorder, presents with characteristic facial features, intellectual disability, persistent fetal fingertip pads, skeletal abnormalities, and postnatal growth delays. KS1 results from pathogenic variants in the <jats:italic>KMT2D<\/jats:italic> gene, which encodes a histone methyltransferase protein involved in chromatin remodeling, promoter and enhancer regulation, and scaffold formation during early development. KMT2D also mediates cell signaling pathways, responding to external stimuli and organizing effector protein assembly. Research on KMT2D's molecular mechanisms in KS1 has primarily focused on its histone methyltransferase activity, leaving a gap in understanding the methyltransferase\u2010independent roles in KS1 clinical manifestations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This scoping review examines KMT2D's role in gene expression regulation across various species, cell types, and contexts. We analyzed human pathogenic <jats:italic>KMT2D<\/jats:italic> variants using publicly available databases and compared them to research organism models of KS1. We also conducted a systematic search of healthcare and governmental databases for clinical trials, studies, and therapeutic approaches.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our review highlights KMT2D's critical roles beyond methyltransferase activity in diverse cellular contexts and conditions. We identified six distinct groups of KMT2D as a cell signaling mediator, including evidence of methyltransferase\u2010dependent and \u2010independent activity. A comprehensive search of the literature, clinical databases, and public registries emphasizes the need for basic research on KMT2D's functional complexity and longitudinal studies of KS1 patients to establish objective outcome measurements for therapeutic development.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We discuss how KMT2D's role in translating external cellular communication can partly explain the clinical heterogeneity observed in KS1 patients. Additionally, we summarize the current molecular diagnostic approaches and clinical trials targeting KS1. This review is a resource for patient advocacy groups, researchers, and physicians to support KS1 diagnosis and therapeutic development.<\/jats:p><\/jats:sec>","DOI":"10.1002\/bdr2.2183","type":"journal-article","created":{"date-parts":[[2023,5,10]],"date-time":"2023-05-10T18:55:45Z","timestamp":1683744945000},"page":"1809-1824","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Molecular insights of KMT2D and clinical aspects of Kabuki syndrome type 1"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2855-8500","authenticated-orcid":false,"given":"Carly S.","family":"Golden","sequence":"first","affiliation":[{"name":"Center for Regenerative Medicine, Section of Vascular Biology, Department of Medicine Boston University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2727-6459","authenticated-orcid":false,"given":"Saylor","family":"Williams","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Section of Vascular Biology, Department of Medicine Boston University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4318-3746","authenticated-orcid":false,"given":"Maria A.","family":"Serrano","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Section of Vascular Biology, Department of Medicine Boston University  Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,5,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2018-105625"},{"key":"e_1_2_10_3_1","article-title":"Kabuki Syndrome","author":"Adam M. 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