intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism

Summary

intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism (MONDO:0859257) is a disease caused by NR4A2 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NR4A2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 58

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism
Mondo ID	MONDO:0859257
OMIM	619911
Orphanet	660017
UMLS	C5677001
MedGen	1805453
GARD	0027148
Is cancer (heuristic)	no

Also known as: NR4A2-related neurodevelopmental syndrome

Data availability: 58 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › dopa-responsive dystonia › autosomal dominant dopa-responsive dystonia › intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism

Related subtypes (1): dystonia 5

Subtypes (1): developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to a NR4A2 point mutation

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

58 retrieved; paginated sample, class counts are floors:

22 uncertain significance, 21 pathogenic, 14 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1693495	NM_006186.4(NR4A2):c.839G>A (p.Cys280Tyr)	NR4A2	Pathogenic	no assertion criteria provided
1693496	NM_006186.4(NR4A2):c.914G>A (p.Cys305Tyr)	NR4A2	Pathogenic	no assertion criteria provided
1693498	NM_006186.4(NR4A2):c.956G>A (p.Arg319Gln)	NR4A2	Pathogenic	no assertion criteria provided
1710386	NM_006186.4(NR4A2):c.698del (p.Pro233fs)	NR4A2	Pathogenic	criteria provided, single submitter
2576541	NM_006186.4(NR4A2):c.591_592del (p.Leu198fs)	NR4A2	Pathogenic	criteria provided, single submitter
3338013	NM_006186.4(NR4A2):c.44_45insA (p.Ser16fs)	NR4A2	Pathogenic	criteria provided, single submitter
3338016	NM_006186.4(NR4A2):c.534del (p.Phe178fs)	NR4A2	Pathogenic	criteria provided, single submitter
3338024	NM_006186.4(NR4A2):c.1159-81_1540+67del	NR4A2	Pathogenic	criteria provided, single submitter
3338025	NM_006186.4(NR4A2):c.1del (p.Met1fs)	NR4A2	Pathogenic	criteria provided, single submitter
3338030	NM_006186.4(NR4A2):c.536del (p.Lys179fs)	NR4A2	Pathogenic	criteria provided, single submitter
3338047	NM_006186.4(NR4A2):c.-2-2del	NR4A2	Pathogenic	criteria provided, single submitter
3338476	NM_006186.4(NR4A2):c.14_15insT (p.Gln5fs)	NR4A2	Pathogenic	criteria provided, single submitter
3338477	NM_006186.4(NR4A2):c.548del (p.Pro183fs)	NR4A2	Pathogenic	criteria provided, single submitter
3338478	NM_006186.4(NR4A2):c.30_31insG (p.Ser11fs)	NR4A2	Pathogenic	criteria provided, single submitter
3773737	NM_006186.4(NR4A2):c.706C>T (p.Gln236Ter)	NR4A2	Pathogenic	criteria provided, single submitter
3893207	NM_006186.4(NR4A2):c.995-1G>A	NR4A2	Pathogenic	criteria provided, single submitter
3912065	NM_006186.4(NR4A2):c.460C>T (p.Gln154Ter)	NR4A2	Pathogenic	criteria provided, single submitter
4082007	NM_006186.4(NR4A2):c.603del (p.Pro201_Met202insTer)	NR4A2	Pathogenic	no assertion criteria provided
4291747	NM_006186.4(NR4A2):c.377C>A (p.Ser126Ter)	NR4A2	Pathogenic	criteria provided, single submitter
4755530	NM_006186.4(NR4A2):c.80C>A (p.Ser27Ter)	NR4A2	Pathogenic	criteria provided, single submitter
985332	NM_006186.4(NR4A2):c.325dup (p.Gln109fs)	NR4A2	Pathogenic	criteria provided, multiple submitters, no conflicts
1321298	NM_006186.4(NR4A2):c.1157_1158insCCTGGACTAGACCAGCCTGGACTATTCCAG (p.Arg386delinsSerLeuAspTer)	NR4A2	Likely pathogenic	criteria provided, single submitter
2443341	NM_006186.4(NR4A2):c.325del (p.Gln109fs)	NR4A2	Likely pathogenic	criteria provided, single submitter
2499614	NM_006186.4(NR4A2):c.863A>G (p.Lys288Arg)	NR4A2	Likely pathogenic	criteria provided, single submitter
2578337	NM_006186.4(NR4A2):c.863A>C (p.Lys288Thr)	NR4A2	Likely pathogenic	criteria provided, single submitter
2582359	NM_006186.4(NR4A2):c.854G>T (p.Gly285Val)	NR4A2	Likely pathogenic	criteria provided, single submitter
2691885	NM_006186.4(NR4A2):c.934C>T (p.Arg312Trp)	NR4A2	Likely pathogenic	criteria provided, single submitter
3065339	NM_006186.4(NR4A2):c.1157G>C (p.Arg386Thr)	NR4A2	Likely pathogenic	criteria provided, single submitter
3066310	NM_006186.4(NR4A2):c.968G>A (p.Cys323Tyr)	NR4A2	Likely pathogenic	criteria provided, single submitter
3068080	NM_006186.4(NR4A2):c.960_961delinsGT (p.Phe320_Gln321delinsLeuTer)	NR4A2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
NR4A2	Strong	Autosomal dominant	intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NR4A2	Orphanet:1617	Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to 2q24 microdeletion
NR4A2	Orphanet:660012	Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to a NR4A2 point mutation
NR4A2	Orphanet:98808	Autosomal dominant dopa-responsive dystonia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NR4A2	HGNC:7981	ENSG00000153234	P43354	Nuclear receptor subfamily 4 group A member 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NR4A2	Nuclear receptor subfamily 4 group A member 2	Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Nuclear receptor	1	385.9×	0.003

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NR4A2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of paranasal sinus	1
mucosa of stomach	1
trachea	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NR4A2	278	ubiquitous	marker	mucosa of paranasal sinus, mucosa of stomach, trachea

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NR4A2	2,418

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NR4A2	P43354	8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SUMOylation of intracellular receptors	1	335.9×	0.005	NR4A2
Nuclear Receptor transcription pathway	1	200.3×	0.005	NR4A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
general adaptation syndrome	1	16852.0×	0.002	NR4A2
habenula development	1	5617.3×	0.002	NR4A2
regulation of respiratory gaseous exchange	1	4213.0×	0.002	NR4A2
cellular response to corticotropin-releasing hormone stimulus	1	4213.0×	0.002	NR4A2
central nervous system projection neuron axonogenesis	1	1872.4×	0.002	NR4A2
dopamine biosynthetic process	1	1872.4×	0.002	NR4A2
regulation of dopamine metabolic process	1	1685.2×	0.002	NR4A2
midbrain dopaminergic neuron differentiation	1	1203.7×	0.003	NR4A2
neuron maturation	1	802.5×	0.004	NR4A2
dopaminergic neuron differentiation	1	624.1×	0.004	NR4A2
central nervous system neuron differentiation	1	601.9×	0.004	NR4A2
negative regulation of apoptotic signaling pathway	1	561.7×	0.004	NR4A2
response to amphetamine	1	495.6×	0.004	NR4A2
adult locomotory behavior	1	300.9×	0.006	NR4A2
DNA-templated transcription	1	224.7×	0.008	NR4A2
post-embryonic development	1	205.5×	0.008	NR4A2
neuron apoptotic process	1	185.2×	0.008	NR4A2
fat cell differentiation	1	181.2×	0.008	NR4A2
cellular response to oxidative stress	1	154.6×	0.009	NR4A2
canonical Wnt signaling pathway	1	153.2×	0.009	NR4A2
neuron migration	1	133.8×	0.010	NR4A2
negative regulation of neuron apoptotic process	1	110.9×	0.011	NR4A2
response to hypoxia	1	95.8×	0.012	NR4A2
transcription by RNA polymerase II	1	70.5×	0.016	NR4A2
negative regulation of transcription by RNA polymerase II	1	17.7×	0.061	NR4A2
positive regulation of transcription by RNA polymerase II	1	14.9×	0.070	NR4A2
regulation of transcription by RNA polymerase II	1	11.7×	0.086	NR4A2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
NR4A2	BEXAROTENE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NR4A2	14	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEXAROTENE	4	NR4A2
MECLOFENAMIC ACID	4	NR4A2
SIMVASTATIN	4	NR4A2
OXAPROZIN	4	NR4A2
PITAVASTATIN	4	NR4A2
PARECOXIB	4	NR4A2
FLUVASTATIN	4	NR4A2
ALPROSTADIL	4	NR4A2
AMODIAQUINE	4	NR4A2
CHLOROQUINE	4	NR4A2
VIDOFLUDIMUS	3	NR4A2
LINOLEIC ACID	2	NR4A2
TECASTEMIZOLE	2	NR4A2
OLEIC ACID	2	NR4A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
NR4A2	274	Binding:273, Functional:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
NR4A2	274

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

14 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)
BEXAROTENE	4	NR4A2
MECLOFENAMIC ACID	4	NR4A2
SIMVASTATIN	4	NR4A2
OXAPROZIN	4	NR4A2
PITAVASTATIN	4	NR4A2
PARECOXIB	4	NR4A2
FLUVASTATIN	4	NR4A2
ALPROSTADIL	4	NR4A2
AMODIAQUINE	4	NR4A2
CHLOROQUINE	4	NR4A2
VIDOFLUDIMUS	3	NR4A2
LINOLEIC ACID	2	NR4A2
TECASTEMIZOLE	2	NR4A2
OLEIC ACID	2	NR4A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	NR4A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.