Kabuki syndrome 2

Summary

Kabuki syndrome 2 (MONDO:0010465) is a disease caused by KDM6A (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: KDM6A (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 955

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Kabuki syndrome 2
Mondo ID	MONDO:0010465
OMIM	300867
UMLS	C3275495
MedGen	477126
GARD	0015270
Is cancer (heuristic)	no

Also known as: KABUK2 · Kabuki syndrome 2 · Kabuki syndrome 2, X-linked dominant · Kabuki syndrome type 2

Data availability: 955 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Kabuki syndrome › Kabuki syndrome 2

Related subtypes (1): Kabuki syndrome 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

233 uncertain significance, 209 likely benign, 49 benign, 36 pathogenic, 31 conflicting classifications of pathogenicity, 22 benign/likely benign, 17 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2426670	NC_000023.10:g.(?43515590)(44970656_?)del	DUSP21	Pathogenic	criteria provided, single submitter
1067136	NM_001291415.2(KDM6A):c.2858+1G>A	KDM6A	Pathogenic	criteria provided, single submitter
1071021	NC_000023.10:g.(?44894176)(44896934_?)del	KDM6A	Pathogenic	criteria provided, single submitter
1071579	NM_001291415.2(KDM6A):c.565-1G>A	KDM6A	Pathogenic	criteria provided, single submitter
1071788	NM_001291415.2(KDM6A):c.348C>A (p.Tyr116Ter)	KDM6A	Pathogenic	criteria provided, single submitter
1324613	NM_001291415.2(KDM6A):c.3793C>T (p.Arg1265Ter)	KDM6A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1360596	NM_001291415.2(KDM6A):c.2284C>T (p.Gln762Ter)	KDM6A	Pathogenic	criteria provided, single submitter
1452097	NM_001291415.2(KDM6A):c.1177C>T (p.Arg393Ter)	KDM6A	Pathogenic	criteria provided, single submitter
1454641	NM_001291415.2(KDM6A):c.2858+2T>C	KDM6A	Pathogenic	criteria provided, single submitter
1459416	NM_001291415.2(KDM6A):c.3384del (p.Gly1129fs)	KDM6A	Pathogenic	criteria provided, single submitter
1471961	NM_001291415.2(KDM6A):c.225+1G>A	KDM6A	Pathogenic	criteria provided, single submitter
1684286	NM_001291415.2(KDM6A):c.2597_2598del (p.Ser866fs)	KDM6A	Pathogenic	criteria provided, multiple submitters, no conflicts
1708049	NM_001291415.2(KDM6A):c.3494dup (p.Ser1166fs)	KDM6A	Pathogenic	criteria provided, single submitter
1805035	NM_001291415.2(KDM6A):c.2379dup (p.Ala794fs)	KDM6A	Pathogenic	criteria provided, single submitter
1805249	NM_001291415.2(KDM6A):c.1164del (p.Ala389fs)	KDM6A	Pathogenic	criteria provided, single submitter
1878500	NM_001291415.2(KDM6A):c.4243C>T (p.Arg1415Ter)	KDM6A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
190247	NM_001291415.2(KDM6A):c.2671_2674del (p.Asn891fs)	KDM6A	Pathogenic	criteria provided, single submitter
2091420	NM_001291415.2(KDM6A):c.1537C>T (p.Gln513Ter)	KDM6A	Pathogenic	criteria provided, single submitter
2097180	NM_001291415.2(KDM6A):c.444G>A (p.Trp148Ter)	KDM6A	Pathogenic	criteria provided, single submitter
211254	NM_001291415.2(KDM6A):c.1699del (p.Val567fs)	KDM6A	Pathogenic	criteria provided, single submitter
2133290	NM_001291415.2(KDM6A):c.349C>T (p.Gln117Ter)	KDM6A	Pathogenic	criteria provided, single submitter
216950	NM_001291415.2(KDM6A):c.3991C>T (p.Arg1331Ter)	KDM6A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2426671	NC_000023.10:g.(?44941801)(44945244_?)del	KDM6A	Pathogenic	criteria provided, single submitter
2426672	NC_000023.10:g.(?44820509)(44896954_?)del	KDM6A	Pathogenic	criteria provided, single submitter
2436899	NM_001291415.2(KDM6A):c.3300+1del	KDM6A	Pathogenic	criteria provided, single submitter
2442333	NM_001291415.2(KDM6A):c.357C>G (p.Tyr119Ter)	KDM6A	Pathogenic	no assertion criteria provided
2442335	NM_001291415.2(KDM6A):c.197del (p.Gly66fs)	KDM6A	Pathogenic	no assertion criteria provided
2442336	NM_001291415.2(KDM6A):c.722_723dup (p.Lys242Ter)	KDM6A	Pathogenic	no assertion criteria provided
2500339	NM_001291415.2(KDM6A):c.3773_3776dup (p.Tyr1260fs)	KDM6A	Pathogenic	criteria provided, single submitter
2504605	NM_001291415.2(KDM6A):c.816T>G (p.Tyr272Ter)	KDM6A	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
KDM6A	Definitive	X-linked	Kabuki syndrome 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KDM6A	Orphanet:2322	Kabuki syndrome
EXOSC9	Orphanet:2254	Pontocerebellar hypoplasia type 1

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KDM6A	HGNC:12637	ENSG00000147050	O15550	Lysine-specific demethylase 6A	gencc,clinvar
CHST7	HGNC:13817	ENSG00000147119	Q9NS84	Carbohydrate sulfotransferase 7	clinvar
DUSP21	HGNC:20476	ENSG00000189037	Q9H596	Dual specificity protein phosphatase 21	clinvar
DIPK2B	HGNC:25866	ENSG00000147113	Q9H7Y0	Divergent protein kinase domain 2B	clinvar
EXOSC9	HGNC:9137	ENSG00000123737	Q06265	Exosome complex component RRP45	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KDM6A	Lysine-specific demethylase 6A	Histone demethylase that specifically demethylates ‘Lys-27’ of histone H3, thereby playing a central role in histone code.
CHST7	Carbohydrate sulfotransferase 7	Sulfotransferase that utilizes 3’-phospho-5’-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the transfer of sulfate to position 6 of non-reducing N-acetylglucosamine (GlcNAc) residues.
DUSP21	Dual specificity protein phosphatase 21	Protein phosphatase component of the sperm flagellar doublet microtubules.
EXOSC9	Exosome complex component RRP45	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.8

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	16.8×	0.117
Enzyme (other)	2	4.8×	0.117
Kinase	1	5.5×	0.224
Scaffold/PPI	1	3.5×	0.258

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KDM6A	Enzyme (other)	yes	1.14.11.68	JmjC_dom, TPR-like_helical_dom_sf, TPR_rpt
CHST7	Enzyme (other)	yes	2.8.2.17	Sulfotransferase_dom, Carbohydrate_sulfotransferase, P-loop_NTPase
DUSP21	Phosphatase	yes		Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, Tyr_Pase_AS
DIPK2B	Kinase	yes		DIPK2A/B, FAM69_kinase_dom
EXOSC9	Scaffold/PPI	no		ExoRNase_PH_dom1, ExoRNase_PH_dom2, Ribosomal_Su5_D2-typ_SF

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	2
bone marrow cell	1
decidua	1
left ovary	1
right ovary	1
male germ cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
sperm	1
apex of heart	1
omental fat pad	1
peritoneum	1
calcaneal tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KDM6A	286	ubiquitous	yes	secondary oocyte, oocyte, bone marrow cell
CHST7	186	ubiquitous	marker	decidua, left ovary, right ovary
DUSP21	23	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, sperm, male germ cell
DIPK2B	190	broad	marker	omental fat pad, peritoneum, apex of heart
EXOSC9	285	ubiquitous	marker	secondary oocyte, oocyte, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KDM6A	8,825
EXOSC9	2,532
DUSP21	951
CHST7	607
DIPK2B	272

Intra-cohort edges

A	B	Sources
DIPK2B	DUSP21	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EXOSC9	Q06265	8
KDM6A	O15550	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DUSP21	Q9H596	92.15
DIPK2B	Q9H7Y0	84.17
CHST7	Q9NS84	80.60

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 5 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
mRNA decay by 3’ to 5’ exoribonuclease	1	237.9×	0.021	EXOSC9
Maternal to zygotic transition (MZT)	1	237.9×	0.021	KDM6A
Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA	1	211.5×	0.021	EXOSC9
Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA	1	211.5×	0.021	EXOSC9
KSRP (KHSRP) binds and destabilizes mRNA	1	211.5×	0.021	EXOSC9
CS-GAG biosynthesis	1	181.3×	0.021	CHST7
Activation of HOX genes during differentiation	1	146.4×	0.021	KDM6A
ATF4 activates genes in response to endoplasmic reticulum stress	1	135.9×	0.021	EXOSC9
Nuclear RNA decay	1	102.9×	0.025	EXOSC9
Formation of WDR5-containing histone-modifying complexes	1	88.5×	0.026	KDM6A
HDMs demethylate histones	1	76.1×	0.027	KDM6A
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	71.8×	0.027	KDM6A
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	65.6×	0.027	KDM6A
Chromatin modifications during the maternal to zygotic transition (MZT)	1	54.4×	0.030	KDM6A
Epigenetic regulation by WDR5-containing histone modifying complexes	1	51.4×	0.030	KDM6A
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	30.4×	0.046	KDM6A
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	27.6×	0.046	KDM6A
Chromatin organization	1	27.2×	0.046	KDM6A
Chromatin modifying enzymes	1	24.1×	0.048	KDM6A
Epigenetic regulation of gene expression	1	23.8×	0.048	KDM6A
Major pathway of rRNA processing in the nucleolus and cytosol	1	20.6×	0.052	EXOSC9
Gene expression (Transcription)	1	6.0×	0.166	KDM6A
Developmental Biology	1	4.8×	0.194	KDM6A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
polysaccharide metabolic process	1	1404.3×	0.006	CHST7
U1 snRNA 3’-end processing	1	1404.3×	0.006	EXOSC9
U5 snRNA 3’-end processing	1	1404.3×	0.006	EXOSC9
exonucleolytic trimming to generate mature 3’-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	1	601.9×	0.007	EXOSC9
nuclear polyadenylation-dependent rRNA catabolic process	1	601.9×	0.007	EXOSC9
TRAMP-dependent tRNA surveillance pathway	1	601.9×	0.007	EXOSC9
U4 snRNA 3’-end processing	1	526.6×	0.007	EXOSC9
nuclear mRNA surveillance	1	468.1×	0.007	EXOSC9
N-acetylglucosamine metabolic process	1	300.9×	0.009	CHST7
sulfur compound metabolic process	1	280.9×	0.009	CHST7
rRNA catabolic process	1	247.8×	0.009	EXOSC9
peptidyl-tyrosine dephosphorylation	1	221.7×	0.009	DUSP21
nuclear-transcribed mRNA catabolic process	1	191.5×	0.010	EXOSC9
chondroitin sulfate proteoglycan biosynthetic process	1	156.0×	0.011	CHST7
mRNA catabolic process	1	123.9×	0.013	EXOSC9
RNA catabolic process	1	113.9×	0.014	EXOSC9
RNA processing	1	54.7×	0.027	EXOSC9
positive regulation of cell growth	1	45.8×	0.030	EXOSC9
rRNA processing	1	35.4×	0.037	EXOSC9
flagellated sperm motility	1	29.3×	0.042	DUSP21
regulation of gene expression	1	20.9×	0.056	KDM6A
heart development	1	19.7×	0.057	KDM6A
chromatin remodeling	1	18.2×	0.058	KDM6A
immune response	1	11.8×	0.086	EXOSC9
positive regulation of transcription by RNA polymerase II	1	3.7×	0.243	EXOSC9

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 3

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KDM6A	DEFERIPRONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KDM6A	1	4
EXOSC9	1	2
CHST7	0	0
DUSP21	0	0
DIPK2B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DEFERIPRONE	4	KDM6A
MOLIBRESIB	2	EXOSC9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KDM6A	40	Binding:36, Functional:4
EXOSC9	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDM6A	1.14.11.68	[histone H3]-trimethyl-L-lysine27 demethylase
CHST7	2.8.2.17	chondroitin 6-sulfotransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
DEFERIPRONE	4	KDM6A
MOLIBRESIB	2	EXOSC9

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KDM6A
B	Phased (≥1) drug, not yet approved	1	EXOSC9
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	3	CHST7, DUSP21, DIPK2B
E	Difficult family or no structure, no drug	0

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CHST7	0	—
DUSP21	0	—
DIPK2B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.