Kabuki syndrome: genes and variants

Genes linked to Kabuki syndrome

• KMT2D: Histone-lysine N-methyltransferase 2D

  It deposits enhancer-associated H3K4 methylation and coordinates developmental gene expression through chromatin regulatory complexes. Heterozygous loss-of-function variants are a major cause of Kabuki syndrome, and somatic mutations are common in several lymphomas and solid tumors.

  34 disease-causing and 1,602 uncertain variants in KMT2D are linked to Kabuki syndrome.

• KDM6A: Lysine-specific demethylase 6A

  It removes repressive H3K27 methylation and also contributes to chromatin regulation through demethylase-independent interactions. Germline loss-of-function variants cause Kabuki syndrome type 2, while somatic alterations occur in multiple cancers.

  14 disease-causing and 355 uncertain variants in KDM6A are linked to Kabuki syndrome.

Weakly linked (only a few uncertain records): KMT2A.

Where Kabuki syndrome variants cluster

• KMT2D C2HC pre-PHD-type 2 (positions 5029–5069): 5 of 34 disease-causing changes, 19.9× more than its size predicts.
• KDM6A JmjC (positions 1095–1258): 8 of 14 disease-causing changes, 4.9× more than its size predicts.
• KMT2D PHD-type 5 (positions 1427–1477): 4 of 34 disease-causing changes, 12.8× more than its size predicts.
• KMT2D SET (positions 5397–5513): 5 of 34 disease-causing changes, 7.0× more than its size predicts.
• KMT2D PHD-type 4 (positions 1377–1430): 3 of 34 disease-causing changes, 9.1× more than its size predicts.

Known disease-causing variants in Kabuki syndrome

Which prediction tools work for Kabuki syndrome

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MutPred2: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 88 out of 100
• CATVariant: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• MetaLR: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• EVE: 83 out of 100
• SIFT: 77 out of 100

Same protein, different disease

• Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome is also caused by KMT2D variants; they fall partly in the same places as the Kabuki syndrome variants (6 disease-causing).

Diseases related to Kabuki syndrome

• Tremor, hereditary essential, 4, also linked to KDM6A
• Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome, also linked to KMT2D
• Medulloblastoma, also linked to KMT2D

Frequently asked questions

Which genes are linked to Kabuki syndrome?

In CATVariant, Kabuki syndrome is linked to 2 analyzed proteins: KMT2D (Histone-lysine N-methyltransferase 2D) and KDM6A (Lysine-specific demethylase 6A).

How many genetic variants are linked to Kabuki syndrome?

3,071 variants: 48 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,958 are of uncertain significance or have conflicting reports.

Which uncertain variants in Kabuki syndrome look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Kabuki syndrome?

Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.89, based on 18 disease-causing and 169 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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