Histone acetylation and methylation in rare diseases: from molecular mechanisms to clinical presentations

Rare diseases, which collectively affecting millions of people worldwide, present unique diagnostic and therapeutic challenges due to their low prevalence and phenotypic heterogeneity. The importance of epigenetic deregulations in the pathophysiology of rare diseases has been highlighted by recent research on neurodevelopmental diseases and congenital malformation syndromes. Among these, abnormalities in histone modifications (especially lysine methylation and acetylation) have emerged as one of the key mechanisms underlying disease phenotypes. Histone-modifying enzyme mutations result in a variety of developmental diseases, including Kabuki, Rubinstein-Taybi and Weaver syndromes, often manifesting as cognitive impairments, craniofacial abnormalities and growth deficiencies. This review explores the functional convergence of genes encoding histone modifiers and their roles in chromatin regulation. It also analyzes the distribution of variants in these genes and their association with overlapping phenotypes across rare diseases. The findings highlight how different variants within the same gene can result in diverse phenotypic outcomes, and how variants in distinct genes may manifest convergent phenotypes underscoring the interconnected nature of epigenetic deregulations and their implications for understanding genotype-phenotype relationships. By focusing on the subunits of key histone-modifying complexes, we also systematically mapped associated Mendelian phenotypes and highlighted a subset of genes not yet linked to defined syndromes but showing strong intolerance to loss-of-function variants, suggesting their potential involvement in undiagnosed or emerging neurodevelopmental disorders.