Menke–Hennekam Syndrome as a Domain-Resolved Disorder of the Transcriptional Coactivators CBP and p300

Menke–Hennekam syndrome (MKHK) is a rare neurodevelopmental disorder caused by pathogenic variants in discrete regions of the transcriptional coactivators CBP and p300, encoded by CREBBP and EP300. Recent genotype–phenotype and DNA methylation studies support a domain-resolved classification involving their ZZ, TAZ2 and ID4 regions and distinguish MKHK from classical Rubinstein–Taybi syndrome. Here, we review the genetic and clinical architecture of MKHK, the regulatory functions of the affected CBP/p300 domains and the emerging epigenomic taxonomy of the disorder. We discuss emerging evidence that localized variants may alter specific protein interactions, chromatin engagement or inter-domain regulation rather than uniformly reducing coactivator activity. On this basis, we propose domain-selective transcriptional rewiring as a testable framework for MKHK pathogenesis. We further consider experimental models required to establish causal mechanisms and implications for therapeutic development. MKHK provides an informative example of how pathogenic variants in multidomain regulatory proteins can produce domain-specific developmental disorders.