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Understanding their pathogenic mechanisms is critical for developing precision gene therapies. An autosomal recessive NDD associated with variants in the Mediator complex subunit 27 (\n                    <jats:italic>MED27<\/jats:italic>\n                    ) gene is previously identified. The Mediator complex is essential for transcription initiation by bridging transcription factors (TFs) at enhancers to RNA polymerase II at promoters. All patients with\n                    <jats:italic>MED27<\/jats:italic>\n                    variants exhibit cerebellar hypoplasia or atrophy, underscoring the cerebellum's heightened vulnerability to MED27 dysfunction. To investigate the disease mechanisms, in vitro stem cells carrying patient\u2010specific\n                    <jats:italic>MED27<\/jats:italic>\n                    variants and in vivo mouse models with\n                    <jats:italic>Med27<\/jats:italic>\n                    loss\u2010of\u2010function (LoF) are generated. These preclinical models recapitulate key patient phenotypes, including progressive cerebellar atrophy and motor deficits. Molecular analyses reveal that mutant MED27 destabilizes the Mediator complex, impairing its chromatin occupancy and altering chromatin interactions. Comprehensive transcriptomic profiling, including single\u2010cell resolution spatial transcriptomics, identifies dysregulation of downstream targets regulated by\n                    <jats:italic>MED27<\/jats:italic>\n                    , such as critical master regulatory TFs involved in neurogenesis and cerebellar development. This study elucidates a partial LoF mechanism underlying\n                    <jats:italic>MED27<\/jats:italic>\n                    \u2010associated NDDs and establishes a prototype for investigating NDDs caused by pathogenic variants in Mediator subunits.\n                  <\/jats:p>","DOI":"10.1002\/advs.202505535","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T08:35:16Z","timestamp":1759134916000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Pathogenicity of Mediator Complex Subunit 27 (\n                    <i>MED27<\/i>\n                    ) in a Neurodevelopmental Disorder with Cerebellar Atrophy"],"prefix":"10.1002","volume":"12","author":[{"given":"Nuermila","family":"Yiliyaer","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences Faculty of Medicine The Chinese University of Hong Kong (CUHK)  Hong Kong SAR China"},{"name":"Gerald Choa 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