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Kabuki syndrome is a multisystem developmental disorder characterized by a distinctive facial gestalt, intellectual disability, skeletal anomalies, cardiac defects, and postnatal growth deficiency. While pathogenic variants in KMT2D account for the majority of cases, mutations in the X-linked lysine demethylase gene KDM6A underlie Kabuki syndrome type 2. Since the first report of a three-generation family with an inherited frameshift in KDM6A, a growing body of literature has established a definitive gene-disease relationship attributed to haploinsufficiency and escape from X-inactivation ([PMID:24664873]).
Genetic evidence supports X-linked dominant inheritance with variable expressivity in heterozygous females and full penetrance in hemizygous males. A pedigree documenting two affected brothers segregating a frameshift (c.2671_2674del (p.Asn891SerfsTer?)) from an attenuated maternal lineage provided initial segregation data ([PMID:24664873]). Subsequent reports include three de novo KDM6A deletions in unrelated probands ([PMID:22197486]) and over 50 additional cases harboring truncating, splice-site, and missense variants, including c.493C>T (p.Arg165Ter) in a neonate with hyperinsulinemic hypoglycemia ([PMID:37257167]).
Approximately 61 distinct pathogenic KDM6A variants (50 truncating, 11 missense) have been described in 80 patients, often arising de novo ([PMID:33674768]). Variant spectrum spans frameshifts, nonsense and splice-site mutations, and rare missense substitutions clustering in the tetratricopeptide repeat and Jumonji domains. No recurrent founder alleles have been identified, and genotype-phenotype correlations suggest more severe intellectual disability and congenital heart defects in males compared to females.
Functional concordance is demonstrated by animal models: zebrafish kdm6a morphants recapitulate craniofacial, cardiac, and neurodevelopmental defects analogous to human Kabuki syndrome ([PMID:25972376]), while Drosophila dUTX mutants display overproliferation and Notch-dependent tissue overgrowth, supporting a tumor-suppressor role of UTX homologs ([PMID:20212086]). In cell lines, nonsense mutations undergo nonsense-mediated decay, leading to reduced KDM6A protein levels and downstream dysregulation of H3K27me3 target genes.
No credible conflicting evidence has emerged; cases with blended phenotypes (e.g., co-occurring SCN1A variants) further underscore the specificity of KDM6A for Kabuki syndrome when phenotypic criteria are met. International consensus diagnostic criteria now include pathogenic or likely pathogenic KDM6A variants as a major criterion irrespective of facial features ([PMID:30514738]).
Collectively, genetic and experimental data provide definitive evidence that heterozygous loss-of-function variants in KDM6A cause X-linked Kabuki syndrome. Clinical testing for KDM6A sequence and copy-number variants is recommended in patients with suggestive features, including long palpebral fissures, persistent fingertip pads, hypotonia, growth retardation, cardiac anomalies, and intellectual disability. Early molecular diagnosis enables targeted surveillance and management, including endocrine and immunologic evaluations.
Key Take-home: Pathogenic KDM6A variants definitively cause X-linked Kabuki syndrome; incorporating KDM6A into diagnostic panels is crucial for early diagnosis, risk stratification, and personalized care.
Gene–Disease AssociationDefinitiveOver 80 probands across >15 studies, segregation in a three-generation family, multiple de novo loss-of-function variants, and concordant functional models Genetic EvidenceStrongMultiple de novo truncating and missense variants in >50 cases, including familial segregation and reach of genetic evidence cap Functional EvidenceModerateZebrafish and Drosophila models recapitulate key human phenotypes, and cellular assays confirm haploinsufficiency |