Kabuki Syndrome: Epigenetic Mechanisms, DNA Methylation Signatures, and Diagnostic Advances

Kabuki syndrome (KS) is a rare multisystem developmental disorder characterized by distinctive facial features, developmental delay, hypotonia, and variable congenital anomalies. Most molecularly confirmed cases are associated with pathogenic variants in KMT2D (KS type 1) or KDM6A (KS type 2), genes encoding regulators of chromatin modification and gene expression. However, a subset of individuals with a clinical diagnosis of KS remains molecularly unresolved, while variants of uncertain significance may complicate diagnostic interpretation. DNA methylation episignatures have emerged as complementary molecular biomarkers that may support the interpretation of uncertain genetic findings and help clarify selected diagnostically unresolved cases. This review examines the molecular and epigenetic mechanisms underlying KS, summarizes the evidence for KS-associated DNA methylation episignatures, and discusses their potential applications in clinical diagnostics. Particular attention is given to the interpretation of episignature classifier results, the available evidence on diagnostic performance, and methodological limitations, including the representation of different variant classes and the interpretation of negative or inconclusive results. The review also considers genotype–phenotype correlations, genetic counseling, and clinical management in the context of current diagnostic approaches. Although episignature analysis may provide valuable functional evidence complementary to genetic testing, its results should be interpreted alongside clinical findings and molecular data. Further validation in well-characterized cohorts is needed to define its diagnostic utility across the full spectrum of KS-associated genetic variation.