KMT2D – Kabuki syndrome

KMT2D encodes a histone H3K4 methyltransferase that is critical for transcriptional activation at enhancer elements. Kabuki syndrome (MONDO:0016512) is an autosomal dominant, multisystem developmental disorder defined by characteristic facial features, intellectual disability, growth retardation, and congenital anomalies. Heterozygous loss-of-function variants in KMT2D underlie the majority of Kabuki syndrome cases, establishing a definitive gene–disease relationship.

1 ClinGen Clinical Validity

The association between KMT2D and Kabuki syndrome is classified as Definitive based on identification of >300 unrelated patients with de novo or segregating variants (208 in a cohort of 347, multi-family segregation) (PMID:27302555), concordant functional data in patient cells and animal models, and replication over >10 years.

2 Genetic Evidence

Kabuki syndrome is inherited in an autosomal dominant manner, with most cases due to de novo heterozygous variants. Segregation has been observed in at least one pedigree involving a mother and two affected children (2 additional relatives) carrying KMT2D p.Gln3575His (PMID:27991736). Across case reports and series, >208 probands harbored KMT2D mutations, including nonsense, frameshift, splice site, missense, and deep intronic variants. The variant spectrum is dominated by truncating alleles, but over 30 missense changes cluster in functional domains. A recurrent founder or hotspot allele has not been described. Reported carrier frequencies in population databases are negligible.

Example variant: c.9820C>T (p.Gln3274Ter)

3 Functional / Experimental Evidence

Experimental studies demonstrate that KMT2D haploinsufficiency impairs global H3K4 monomethylation and disrupts enhancer activation, leading to altered gene expression in neural crest and B-cell lineages. Knockdown of kmt2d in zebrafish recapitulates craniofacial, cardiac, and neural defects seen in Kabuki syndrome (PMID:25972376). Patient fibroblasts show reduced KMT2D protein levels, altered expression of developmental target genes, and impaired histone methylation, supporting haploinsufficiency as the pathogenic mechanism (PMID:24633898).

4 Conflicting Evidence

No robust studies have disputed the link between KMT2D variants and Kabuki syndrome. Rare missense alleles of uncertain significance are occasionally reported in healthy individuals but are distinguished by lack of functional or segregation support.

5 Integrated Conclusion

De novo and inherited heterozygous variants in KMT2D cause autosomal dominant Kabuki syndrome, with strong genetic evidence (multiple unrelated probands, family segregation) and concordant functional studies demonstrating loss of methyltransferase activity and downstream developmental gene dysregulation. The broad phenotypic spectrum—from classic craniofacial features to immunodeficiency—reflects KMT2D’s role in chromatin modification across tissues. Further deep-sequencing and model organism studies continue to expand variant interpretation but exceed ClinGen scoring limits.

Key Take-home: KMT2D haploinsufficiency is definitively linked to autosomal dominant Kabuki syndrome, providing a reliable target for genetic diagnosis and potential epigenetic therapies.

References

• Human mutation | 2016 | Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2 PMID:27302555
• The Journal of allergy and clinical immunology | 2016 | Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome PMID:26194542
• Human molecular genetics | 2015 | Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients PMID:24633898
• Human molecular genetics | 2015 | Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development PMID:25972376
• American journal of medical genetics. Part A | 2017 | KMT2D p.Gln3575His segregating in a family with autosomal dominant choanal atresia strengthens the Kabuki/CHARGE connection PMID:27991736

Evidence Based Scoring (AI generated)