CREBBP variants underlying Menke–Hennekam syndrome exhibit histone acetyltransferase hyperactivity with divergent phase behaviors

Menke–Hennekam syndrome (MKHK) is a neurodevelopmental disease characterized by specific pathogenic regions within the transcriptional coactivator CREB–binding protein (CREBBP) . CREBBP regulates gene expression through histone acetyltransferase (HAT) activity and involves IDR–dependent transcriptional condensates. Although domain-specific phenotypes and distinct DNA methylation episignatures have been recognized in MKHK, the underlying molecular mechanisms remain widely unclear. In this study, we identified a recurrent missense variant, p.(R1868W) [R1868W]) and a novel splice variant r.5963_5969del,p.(Cys1723Thrfs*19) [C1723fs] in two families clinically diagnosed with MKHK and manifesting developmental delay, characteristic facial features, and growth impairment. R1868W and C1723fs exhibited increased auto–, nonhistone protein, and histone acetylation. Despite these shared enzymatic abnormalities, the variants promoted divergent disruption in liquid–liquid phase separation. The recurrent CBP–ID4 variant R1868W activated the formation of low-mobility aberrant nuclear condensates, whereas the C–terminal, truncating variant C1723fs, impaired condensate formation and showed diffuse nuclear localization. Treatment with the selective p300/CBP HAT inhibitor A485 partially restored condensate dynamics and fusion-relaxation behavior in R1868W. Furthermore, R1868W recruited BRD4 around condensates in an acetylation-dependent manner, which was suppressed by the BET inhibitor JQ1. Together, these findings suggest that aberrant condensate material properties arising from disrupted CREBBP IDR-dependent regulation play a critical role in the molecular pathogenesis of MKHK.