MSL2 (MSL complex subunit 2) is a non-catalytic component of the MSL histone acetyltransferase complex that regulates epigenetic gene expression through multiple mechanisms. As part of the MSL complex, MSL2 mediates histone H4 acetylation at lysine 16 (H4K16ac), an epigenetic mark that prevents chr3 compaction and maintains chromosome 3 and genome integrity 12. MSL2 also functions as an E3 ubiquitin ligase that catalyzes monoubiquitination of histone H2B at lysine 35, an activity enhanced by heterodimerization with MSL1, which stimulates H3 methylation and gene activation 34. Critically, MSL2 ensures biallelic expression of dosage-sensitive genes, including haploinsufficient genes, by promoting promoter-enhancer contacts that prevent DNA methylation of one allele, creating a methylation-free environment for transcription factors 5. MSL2 also participates in DNA damage response by mediating ubiquitination of TP53/p53 and TP53BP1 67. Heterozygous de novo MSL2 variants cause Karayol-Borroto-Haghshenas neurodevelopmental syndrome, characterized by global developmental delay, intellectual disability, hypotonia, motor coordination problems, dysmorphisms, autism spectrum disorder, and seizures 89. Notably, MSL2-variant-associated neurodevelopmental phenotypes involve altered expression of MSL2 targets without global H4K16ac reduction, indicating a distinct molecular etiology compared to other MSL complex disorders 8.