KDM6A – Kabuki syndrome 2

KDM6A (HGNC:12637) encodes the X-linked histone H3K27 demethylase UTX and is causally implicated in X-linked Kabuki syndrome type 2 (KS2, MONDO:0010465). KS2 accounts for 5–8% of Kabuki syndrome cases and presents with characteristic facial dysmorphism, intellectual disability, congenital heart defects, growth retardation and skeletal anomalies. Female patients often exhibit milder features compared to males, consistent with dosage effects of the escaping X-linked UTX locus.

Genetic evidence for KDM6A in KS2 is robust. In a comprehensive cohort of 80 unrelated KS2 patients, 61 distinct pathogenic variants (50 truncating, 11 missense) were identified, including de novo and inherited alleles, with clustering of missense variants in the TPR and JmjC domains ([PMID:33674768]). Recurrent variant classes encompass nonsense, frameshift, splice-site and small in-frame deletions. One representative truncating mutation is c.752G>A (p.Trp251Ter), which abolishes JmjC catalytic activity.

Segregation data include 13 maternally inherited and one paternally inherited pathogenic variant, with evidence of skewed X-inactivation modulating expressivity in female carriers. No large multiplex pedigrees have been reported, and the number of additional affected relatives remains limited.

Functional studies confirm a loss-of-function mechanism. Morpholino knockdown of zebrafish kdm6a and kdm6al phenocopies human KS2 craniofacial, cardiac and neurodevelopmental defects, demonstrating UTX’s role in organogenesis ([PMID:25972376]). In patient-derived cell lines, nonsense mutations show efficient gentamicin-mediated readthrough, restoring full-length KDM6A protein and implicating haploinsufficiency as the primary pathogenic mechanism ([PMID:24633898]).

No conflicting reports have challenged the KDM6A–KS2 association. Taken together, the genetic and experimental concordance over multiple independent studies supports a definitive relationship.

Key Take-Home: KDM6A haploinsufficiency causes X-linked Kabuki syndrome type 2; genetic testing for truncating and missense variants in KDM6A informs diagnosis, sex-specific prognosis, and potential therapeutic readthrough strategies.

References

• Genetics in Medicine • 2021 • Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2 PMID:33674768
• Human molecular genetics • 2015 • Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development PMID:25972376
• Human Mutation • 2014 • Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients PMID:24633898

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