Dystonia 28, childhood-onset

Summary

Dystonia 28, childhood-onset (MONDO:0015004) is a disease caused by KMT2B (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: KMT2B (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 130
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		160	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0007325	Generalized dystonia	Very frequent (80-99%)
HP:0033049	Globus pallidus hypointensity on susceptibility-weighted imaging	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0012758	Neurodevelopmental delay	Frequent (30-79%)
HP:0031959	Leg dystonia	Frequent (30-79%)
HP:0000276	Long face	Occasional (5-29%)
HP:0000414	Bulbous nose	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000821	Hypothyroidism	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0001618	Dysphonia	Occasional (5-29%)
HP:0002425	Anarthria	Occasional (5-29%)
HP:0004209	Clinodactyly of the 5th finger	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007256	Abnormal pyramidal sign	Occasional (5-29%)
HP:0012048	Oromandibular dystonia	Occasional (5-29%)
HP:0031960	Arm dystonia	Occasional (5-29%)
HP:0011968	Feeding difficulties	Excluded (0%)
HP:0000486	Strabismus	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 28, childhood-onset
Mondo ID	MONDO:0015004
EFO	EFO:0009301
OMIM	617284
Orphanet	589618
DOID	DOID:0060936
UMLS	C4310633
MedGen	934600
GARD	0022359
Is cancer (heuristic)	no

Also known as: dystonia 28, childhood-onset · dystonia 28, childhood-onset; DYT28 · dystonic disorder caused by mutation in KMT2B · DYT28 · KMT2B dystonic disorder

Data availability: 130 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › dystonia 28, childhood-onset

Related subtypes (23): lymphatic malformation 5, Woodhouse-Sakati syndrome, severe motor and intellectual disabilities-sensorineural deafness-dystonia syndrome, torsion dystonia 7, developmental malformations-deafness-dystonia syndrome, dopa-responsive dystonia due to sepiapterin reductase deficiency, ataxia - oculomotor apraxia type 4, striatonigral degeneration, childhood-onset, dystonia, childhood-onset, with optic atrophy and basal ganglia abnormalities, isolated dystonia, combined dystonia, dystonia 30, dystonia 31, dystonia 32, dystonia 33, dystonia 34, myoclonic, dystonia 35, childhood-onset, familial idiopathic torsion dystonia, dystonia, focal, task-specific, dystonia 37, early-onset, with striatal lesions, dystonia 22, juvenile-onset, dystonia 22, adult-onset, autosomal dominant dopa-responsive dystonia

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

130 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 25 likely pathogenic, 25 conflicting classifications of pathogenicity, 23 pathogenic, 7 benign, 4 benign/likely benign, 4 likely benign, 3 not provided, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172540	NM_014727.3(KMT2B):c.7614del (p.Thr2539fs)	KMT2B	Pathogenic	criteria provided, single submitter
1297015	NM_014727.3(KMT2B):c.6413dup (p.Ala2139fs)	KMT2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1525972	NM_014727.3(KMT2B):c.5073C>T (p.Gly1691=)	KMT2B	Pathogenic	criteria provided, single submitter
1685914	NM_014727.3(KMT2B):c.683del (p.Ala228fs)	KMT2B	Pathogenic	criteria provided, single submitter
1687549	NM_014727.3(KMT2B):c.5230_5233del (p.Ser1744fs)	KMT2B	Pathogenic	criteria provided, multiple submitters, no conflicts
1708481	NM_014727.3(KMT2B):c.5741_5748dup (p.Ser1917fs)	KMT2B	Pathogenic	criteria provided, single submitter
1803994	NM_014727.3(KMT2B):c.7012del (p.Asp2338fs)	KMT2B	Pathogenic	criteria provided, single submitter
2577441	NM_014727.3(KMT2B):c.5060dup (p.Asp1687fs)	KMT2B	Pathogenic	no assertion criteria provided
3066001	NM_014727.3(KMT2B):c.610C>T (p.Gln204Ter)	KMT2B	Pathogenic	no assertion criteria provided
3381835	NM_014727.3(KMT2B):c.4090del (p.Val1364fs)	KMT2B	Pathogenic	criteria provided, single submitter
374870	NM_014727.3(KMT2B):c.6406del (p.Leu2136fs)	KMT2B	Pathogenic	criteria provided, single submitter
374871	NM_014727.3(KMT2B):c.1633C>T (p.Arg545Ter)	KMT2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374872	NM_014727.3(KMT2B):c.7050-2A>G	KMT2B	Pathogenic	criteria provided, single submitter
374874	NM_014727.3(KMT2B):c.402dup (p.Ser135fs)	KMT2B	Pathogenic	no assertion criteria provided
374875	NM_014727.3(KMT2B):c.1690C>T (p.Arg564Ter)	KMT2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
450816	NM_014727.3(KMT2B):c.12_24dup (p.Ser9fs)	KMT2B	Pathogenic	criteria provided, multiple submitters, no conflicts
488539	NM_014727.3(KMT2B):c.521dup (p.Thr176fs)	KMT2B	Pathogenic	criteria provided, multiple submitters, no conflicts
523817	NM_014727.3(KMT2B):c.5113C>T (p.Arg1705Ter)	KMT2B	Pathogenic	criteria provided, multiple submitters, no conflicts
807435	NM_014727.3(KMT2B):c.424C>T (p.Arg142Ter)	KMT2B	Pathogenic	criteria provided, multiple submitters, no conflicts
807438	NM_014727.3(KMT2B):c.4549C>T (p.Arg1517Ter)	KMT2B	Pathogenic	criteria provided, single submitter
817423	NM_014727.3(KMT2B):c.15_24dup (p.Ser9fs)	KMT2B	Pathogenic	criteria provided, multiple submitters, no conflicts
817932	NM_014727.3(KMT2B):c.648_649insA (p.Arg217fs)	KMT2B	Pathogenic	criteria provided, single submitter
870575	NM_014727.3(KMT2B):c.118del (p.Ala40fs)	KMT2B	Pathogenic	criteria provided, single submitter
976707	NM_014727.3(KMT2B):c.3335-9_3363del	KMT2B	Pathogenic	criteria provided, single submitter
988727	NM_014727.3(KMT2B):c.3596dup (p.Met1202fs)	KMT2B	Pathogenic	no assertion criteria provided
1065339	NM_014727.3(KMT2B):c.4109_4110dup (p.Leu1371fs)	KMT2B	Likely pathogenic	criteria provided, single submitter
1184467	NM_014727.3(KMT2B):c.7348C>T (p.Arg2450Ter)	KMT2B	Likely pathogenic	no assertion criteria provided
1320082	NM_014727.3(KMT2B):c.7984C>T (p.Arg2662Trp)	KMT2B	Likely pathogenic	criteria provided, single submitter
1679290	NM_014727.3(KMT2B):c.7470C>A (p.Phe2490Leu)	KMT2B	Likely pathogenic	criteria provided, single submitter
1700217	NM_014727.3(KMT2B):c.7921G>A (p.Ala2641Thr)	KMT2B	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
KMT2B	Definitive	Autosomal dominant	dystonia 28, childhood-onset	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KMT2B	Orphanet:528084	Non-specific syndromic intellectual disability
KMT2B	Orphanet:589618	Dystonia 28
ENPP1	Orphanet:289176	Autosomal recessive hypophosphatemic rickets
ENPP1	Orphanet:324561	Hypopigmentation-punctate palmoplantar keratoderma syndrome
ENPP1	Orphanet:51608	Generalized arterial calcification of infancy
ENPP1	Orphanet:758	Pseudoxanthoma elasticum

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KMT2B	HGNC:15840	ENSG00000272333	Q9UMN6	Histone-lysine N-methyltransferase 2B	gencc,clinvar
ENPP1	HGNC:3356	ENSG00000197594	P22413	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KMT2B	Histone-lysine N-methyltransferase 2B	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism.
ENPP1	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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	42.0×	0.047
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KMT2B	Transcription factor	no		SET_dom, Znf_PHD, Znf_CXXC
ENPP1	Phosphatase	yes	3.6.1.9	Somatomedin_B_dom, Endo_G_ENPP1-like_dom, Phosphodiest/P_Trfase

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left testis	1
lower esophagus mucosa	1
right testis	1
cartilage tissue	1
decidua	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KMT2B	269	ubiquitous	marker	right testis, left testis, lower esophagus mucosa
ENPP1	227	ubiquitous	marker	tibia, decidua, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KMT2B	2,639
ENPP1	1,911

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ENPP1	P22413	7
KMT2B	Q9UMN6	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin B2 (riboflavin) metabolism	1	815.7×	0.018	ENPP1
Vitamin B5 (pantothenate) metabolism	1	380.7×	0.020	ENPP1
Formation of WDR5-containing histone-modifying complexes	1	132.8×	0.028	KMT2B
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.028	KMT2B
PKMTs methylate histone lysines	1	80.4×	0.028	KMT2B
Epigenetic regulation by WDR5-containing histone modifying complexes	1	77.2×	0.028	KMT2B
Transcriptional regulation by RUNX1	1	73.2×	0.028	KMT2B
Formation of the beta-catenin:TCF transactivating complex	1	60.1×	0.028	KMT2B
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	60.1×	0.028	KMT2B
Chromatin organization	1	40.8×	0.035	KMT2B
Chromatin modifying enzymes	1	36.1×	0.035	KMT2B
Epigenetic regulation of gene expression	1	35.7×	0.035	KMT2B
RNA Polymerase II Transcription	1	11.3×	0.100	KMT2B
Gene expression (Transcription)	1	8.9×	0.117	KMT2B
Generic Transcription Pathway	1	7.5×	0.128	KMT2B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete negative regulation of hh target transcription factor activity	1	8426.0×	0.003	ENPP1
inorganic diphosphate transport	1	4213.0×	0.003	ENPP1
nucleoside triphosphate catabolic process	1	1685.2×	0.004	ENPP1
nucleic acid metabolic process	1	1404.3×	0.004	ENPP1
negative regulation of glycogen biosynthetic process	1	1053.2×	0.004	ENPP1
intracellular phosphate ion homeostasis	1	766.0×	0.004	ENPP1
negative regulation of D-glucose import across plasma membrane	1	601.9×	0.004	ENPP1
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	561.7×	0.004	ENPP1
phosphate ion homeostasis	1	526.6×	0.004	ENPP1
phosphate-containing compound metabolic process	1	495.6×	0.004	ENPP1
response to ATP	1	495.6×	0.004	ENPP1
negative regulation of bone mineralization	1	468.1×	0.004	ENPP1
melanocyte differentiation	1	401.2×	0.005	ENPP1
regulation of bone mineralization	1	366.4×	0.005	ENPP1
ATP metabolic process	1	234.1×	0.007	ENPP1
negative regulation of insulin receptor signaling pathway	1	187.2×	0.008	ENPP1
generation of precursor metabolites and energy	1	172.0×	0.009	ENPP1
negative regulation of fat cell differentiation	1	156.0×	0.009	ENPP1
bone mineralization	1	135.9×	0.010	ENPP1
methylation	1	85.1×	0.014	KMT2B
cellular response to insulin stimulus	1	85.1×	0.014	ENPP1
negative regulation of cell growth	1	72.0×	0.016	ENPP1
gene expression	1	39.9×	0.027	ENPP1
immune response	1	23.5×	0.044	ENPP1
positive regulation of DNA-templated transcription	1	14.0×	0.070	KMT2B

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ENPP1	1	3
KMT2B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	ENPP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ENPP1	167	Binding:154, ADMET:13
KMT2B	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENPP1	3.6.1.9	nucleotide diphosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ENPP1	167

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
SURAMIN	3	ENPP1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ENPP1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KMT2B

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
KMT2B	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.