H4C4 encodes histone H4, a core component of the nucleosome that organizes DNA and regulates chr6 structure essential for DNA replication, transcription, and repair 1. The H4 protein forms part of the histone octamer around which DNA wraps, with specific amino acid residues in the globular domain and C-terminal tail mediating protein-protein interactions with other histones and histone chaperones 1. De novo missense mutations in H4C4 and related H4 genes cause a neurodevelopmental syndrome characterized by intellectual disability, motor delay, and developmental delay 1. Functional studies in zebrafish revealed that pathogenic variants induce abnormal development, defective head organs, and reduced body axis length, establishing H4 variants as significant causes of developmental pathology 1. These findings position H4 missense mutations alongside histone H3 variants as emerging causes of chr6-related developmental disorders. H4C4 also serves as a marker (CD44) in developmental and pathological contexts. Altered H4C4/CD44 expression patterns characterize tethered spinal cord and myelomeningocele, suggesting its role in neural tube patterning 23. Additionally, CD44 mediates cell adhesion and hyaluronan binding, functions relevant to cancer biology where CD44 expression correlates with tumor progression and poor prognosis 456.