MBD5 (methyl-CpG binding domain protein 5) functions as a non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, which specifically mediates deubiquitination of histone H2A monoubiquitinated at lysine-120 (H2AK119ub1) 1. MBD5 is critical for stability of PR-DUB components and stimulates ubiquitinase activity 2. Notably, MBD5 functions as an RNA m5C reader that binds 5-methylcytosine-modified mRNAs rather than methylated DNA 3. As part of the PR-DUB complex, MBD5 associates with chr2 enriched in active histone marks (H3K4me1, H3K4me3, H3K27Ac) and regulates gene expression involved in cell growth, development, cell communication, and proliferation 2. Clinically, MBD5 variants cause MBD5-associated neurodevelopmental disorder (MAND), characterized by intellectual disability, developmental delay, and behavioral impairments 4. De novo MBD5 mutations are significantly enriched in neurodevelopmental disorders with male-biased patterns 5, and represent a major cause of moderate to severe intellectual disability with diagnostic yield of approximately 29% 6. MBD5 variants are strongly associated with early-onset, refractory epilepsy featuring multiple seizure types, developmental delay, language impairment, and autism-like features 7. Notably, incomplete penetrance has been documented for inherited MBD5 variants in asymptomatic carriers 8, and epigenetic mechanisms involving MBD5-mediated DNA methylation contribute to epileptogenesis 9.