NR4A2-related disorder and intellectual disability

Summary

Published cohorts

These cohorts overlap, because later reviews re-count patients from earlier reports. They must not be summed.

Formally measured cognitive scores in published cases

• WISC-IV Full Scale IQ 65 (Male, 8 years; Liang et al. 2025)
• WISC-IV Full Scale IQ 57 (Female, 7 years; Liang et al. 2025)
• WISC-IV verbal comprehension 63 (1st percentile), working memory 52 (0.1th percentile), overall below −2 SD (Child, 9 years; Ramos et al. 2019)
• IQ 77, required special education to learn basic writing and arithmetic (Male, tested at 7 years; Jesús et al. 2021)

Verbal and language scores fall below non-verbal scores across these reports.

Official disease classification

1. NCBI MedGen. Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism (IDLDP). Concept ID C5677001, MedGen UID 1805453. Reproduces OMIM #619911.https://www.ncbi.nlm.nih.gov/medgen/1805453The official disorder name is "Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism (IDLDP)", OMIM phenotype MIM 619911, gene NR4A2 at 2q24.1. The OMIM-sourced definition, tagged "[from OMIM]", characterises it as "global developmental delay affecting motor, cognitive, and speech domains apparent in early childhood or infancy". The HPO feature list on the same page includes global developmental delay, delayed speech and language development, and mild intellectual disability.
2. OMIM #619911. Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism; IDLDP. Gene NR4A2, OMIM *601828.https://omim.org/entry/619911Phenotype MIM number 619911, gene MIM 601828, autosomal dominant inheritance. This is the citation form a paediatrician or assessor will recognise on sight.
3. ClinGen Gene-Disease Validity. NR4A2 (HGNC:7981), complex neurodevelopmental disorder (MONDO:0100038), autosomal dominant. Intellectual Disability and Autism Gene Curation Expert Panel, approved 5 May 2021 (SOP8).https://search.clinicalgenome.org/kb/genes/HGNC:7981ClinGen classifies the NR4A2 gene-disease relationship as DEFINITIVE, the highest of its six validity tiers. The curating body is named the "Intellectual Disability and Autism Gene Curation Expert Panel". ClinGen's Dosage Sensitivity Working Group separately scores NR4A2 as having sufficient evidence for haploinsufficiency (score 3), curated 27 September 2022.
4. Orphanet. Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome. ORPHA:660017.https://www.orpha.net/en/disease/detail/660017The European reference nosology names the disorder Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome, cross-referenced to OMIM:619911 and MONDO:0859257. Autosomal dominant, onset in infancy or childhood, prevalence under 1 in 1,000,000 with roughly 15 documented families.
5. PanelApp Australia. Panel 250, Intellectual disability syndromic and non-syndromic, v2.43. NR4A2 rated GREEN (confidence level 3), Genetic Health Queensland.https://panelapp-aus.org/panels/250/gene/NR4A2/In Australia's national gene-panel resource, NR4A2 is a Green (diagnostic-grade) gene on the Intellectual disability syndromic and non-syndromic panel, curated by Genetic Health Queensland, for the phenotype Intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, OMIM:619911.
6. Genomics England PanelApp. Intellectual disability panel (Panel 285), v10.60. NHS Genomic Medicine Service.https://panelapp.genomicsengland.co.uk/panels/285/NR4A2 is a GREEN (highest confidence) gene on the NHS national Intellectual disability diagnostic panel, monoallelic autosomal inheritance, listed against OMIM:619911. It is also Green on the Early onset or syndromic epilepsy panel (Panel 402) and appears three times as Green on the currently orderable R27 Paediatric disorders super panel.
7. EMBL-EBI Gene2Phenotype. NR4A2-related developmental disorder, record G2P02861, Developmental Disorders (DDG2P) panel, updated 21 January 2025.https://www.ebi.ac.uk/gene2phenotype/api/lgd/G2P02861/Curated in the Developmental Disorders panel with disease name NR4A2-related developmental disorder, monoallelic autosomal, molecular mechanism loss of function, confidence category STRONG.
8. Gene Curation Coalition (GenCC). NR4A2 (HGNC:7981) submissions: 1 Definitive, 3 Strong.https://search.thegencc.org/genes/HGNC:7981Four independent curating bodies have submitted NR4A2 gene-disease assertions and none is rated below Strong: ClinGen (Definitive), Labcorp Genetics, Gene2Phenotype and PanelApp Australia (Strong), all autosomal dominant.
9. SFARI Gene. NR4A2 human gene record, Simons Foundation Autism Research Initiative.https://gene.sfari.org/database/human-gene/NR4A2NR4A2 holds a SFARI gene score of 1, the top tier, labelled "High Confidence". Genetic category: Rare Single Gene Mutation, Syndromic, Functional. The score rationale cites de novo NR4A2 deletions in unrelated individuals with developmental delay or intellectual disability and language impairment, several also meeting DSM-5 criteria for autism spectrum disorder.
10. NCBI ClinVar. NM_006186.4(NR4A2):c.325dup (p.Gln109fs), Variation ID 985332.https://www.ncbi.nlm.nih.gov/clinvar/variation/985332/ClinVar holds 284 NR4A2 records, of which 73 are pathogenic or likely pathogenic and 24 are frameshift variants. 20 of those 24 frameshift variants are classified Pathogenic, Likely pathogenic, or Pathogenic/Likely pathogenic, submitted under neurodevelopmental disorder conditions. c.325dup itself is classified Pathogenic with multiple submitters and no conflicts.

Primary literature

1. Lévy J, Grotto S, Mignot C, et al. NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder. Clin Genet. 2018 Aug;94(2):264-268.https://pubmed.ncbi.nlm.nih.gov/29770430/Three patients with de novo 2q24.1 deletions involving NR4A2, two of which delete NR4A2 only. The authors report a neurodevelopmental disorder including language impairment, developmental delay, intellectual disability and/or autism spectrum disorder, and attribute it to NR4A2 haploinsufficiency with high penetrance.
2. Reuter MS, Krumbiegel M, Schlüter G, Ekici AB, Reis A, Zweier C. Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment. Am J Med Genet A. 2017 Aug;173(8):2231-2234.https://pubmed.ncbi.nlm.nih.gov/28544326/A patient with a de novo 89 kb deletion covering NR4A2 and no other gene, with severe language impairment and mild intellectual disability. Notes NR4A2 is highly expressed in brain regions critical for speech and language.
3. Kaplanis J, Samocha KE, Wiel L, et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature. 2020;586(7831):757-762.https://pubmed.ncbi.nlm.nih.gov/33057194/A de novo mutation study across 31,058 developmental-disorder parent-offspring trios from the Deciphering Developmental Disorders study, GeneDx and Radboud UMC, identifying 285 significantly associated genes. NR4A2 is one of them, with p = 1.75e-6 across the full cohort and p = 2.64e-7 in the undiagnosed subset.
4. gnomAD v4, Broad Institute. NR4A2 (ENSG00000153234) constraint metrics.https://gnomad.broadinstitute.org/gene/ENSG00000153234NR4A2 is extremely intolerant of loss of function: pLI = 1.00, LOEUF = 0.094, with 1 observed loss-of-function variant against 50.47 expected across the population database.
5. Simons Searchlight. NR4A2-Related Syndrome gene guide, Simons Foundation.https://www.simonssearchlight.org/gene-guide/nr4a2/States that NR4A2-related syndrome is also called intellectual developmental disorder with language impairment and early-onset DOPA-responsive dystonia-parkinsonism, and lists intellectual disability, developmental delay, learning difficulties and speech and language issues among the core symptoms.

The variant NM_006186.4:c.325dup, p.(Gln109ProfsTer3) in the literature

This is a de novo frameshift variant that has been reported previously. The published individual carrying the identical variant was two years old at the time of report, so intellectual disability had not yet been formally assessed in that case. It is a documented precedent, not a prognosis.

1. Singh S, Gupta A, Zech M, et al. De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy. Genet Med. 2020 Aug;22(8):1413-1417. See Patient 6.https://pubmed.ncbi.nlm.nih.gov/32366965/Patient 6 carries c.325dupC, p.Q109Pfs*3, the same variant. That child had global developmental delay across all domains, seizures from six months of age, speech and language impairment, motor delay, severe hypotonia, feeding difficulties, facial dysmorphism and sleep-disordered breathing, with MRI showing pontine hypoplasia and ventriculomegaly. He was two years old at the time of the report, so intellectual disability had not yet been formally assessed and he is not described as carrying an ID diagnosis.
2. NCBI ClinVar. NM_006186.4(NR4A2):c.325dup (p.Gln109fs), Variation ID 985332.https://www.ncbi.nlm.nih.gov/clinvar/variation/985332/Classified Pathogenic, with multiple independent submitters and no conflicting interpretations. It is filed under the broad condition name Neurodevelopmental disorder rather than the full OMIM 619911 name, which is a cataloguing convention and not a different diagnosis.
3. Ramos LLP, Monteiro FP, Sampaio LPB, et al. Clin Case Rep. 2019;7(8):1582-1584; and Wirth T, Mariani LL, Bergant G, et al. Mov Disord. 2020;35(5):880-885.https://pubmed.ncbi.nlm.nih.gov/31428396/Both report patients carrying c.326dupA, one base away, with the same predicted loss-of-function mechanism. Ramos records WISC-IV verbal comprehension of 63 and working memory of 52 at age 9. Wirth states that both of their patients had a history of mild intellectual disability in childhood.

Second diagnosis: 16p11.2 deletion and dual diagnosis

1. Taylor CM, Smith R, Lehman C, et al. 16p11.2 Recurrent Deletion. GeneReviews. 2009 Sep 22 [updated 2021 Oct 28]. University of Washington, Seattle.https://www.ncbi.nlm.nih.gov/books/NBK11167/The standard clinical reference for the roughly 593 kb BP4-BP5 deletion. States that "Most affected individuals do not have intellectual disability (defined as an IQ of <70), but many have below average cognition and learning disabilities in both verbal and nonverbal domains", alongside high base rates of speech, language, motor and seizure involvement.
2. ClinGen Dosage Sensitivity Curation. 16p11.2 recurrent region (proximal, BP4-BP5), ISCA-37400.https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37400Haploinsufficiency score 3, sufficient evidence for haploinsufficiency. Deletions are associated with proximal 16p11.2 microdeletion syndrome, with developmental delay, motor speech and coordination disorders, language disorders and cognitive deficits.
3. Hanson E, Bernier R, Porche K, et al. The cognitive and behavioral phenotype of the 16p11.2 deletion in a clinically ascertained population. Biol Psychiatry. 2015;77(9):785-93.https://pubmed.ncbi.nlm.nih.gov/25064419/85 deletion carriers against 153 familial controls. Over 90% presented with psychiatric and developmental disorders. Expressive and receptive language disorders in 71% of individuals over 3 years. This is the source of the widely quoted downward IQ shift, measured against family members.
4. Posey JE, Harel T, Liu P, et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017;376(1):21-31.https://pubmed.ncbi.nlm.nih.gov/27959697/Of 7,374 consecutive patients referred for clinical exome sequencing, 2,076 received a molecular diagnosis, and 101 of those (4.9%) had diagnoses involving two or more disease loci. Phenotypes in those patients were blended or more complex.
5. Girirajan S, Rosenfeld JA, Coe BP, et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med. 2012;367(14):1321-31.https://pubmed.ncbi.nlm.nih.gov/22970919/Across 2,312 children carrying a copy-number variant associated with intellectual disability, 10.1% carried a second large copy-number variant. Children carrying two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as controls.

Limits of this evidence

• This literature describes the condition, not any individual child. Every figure here is a statement about published patients. What establishes a particular child's cognitive and adaptive level is their own assessment, and nothing substitutes for it.
• It is 93 to 100 per cent, not 100 per cent. The largest pooled cohort (Borden 2025, n=32) reports 93 per cent, so a small number of published patients did not have intellectual disability or developmental delay documented. Claiming universality is the easiest way to lose credibility on a checkable point.
• OMIM itself documents mild presentations, in the same paragraph an assessor will read: severity is highly variable, and less severely affected individuals have only mild deficits. The Simons Searchlight registry rates 48 per cent mild. Quote that variability yourself rather than letting someone else find it.
• The gene cannot predict an individual outcome. Published severity spans mild to severe and Singh et al. 2020 found no apparent genotype-phenotype correlation. Do not use this literature to forecast an IQ, a trajectory, or a support level.
• The evidence base is small because the condition is ultra-rare, with roughly 15 documented families on Orphanet. Quote fractions as published rather than bare percentages, and be ready to say the denominator is small because the disorder is rare, not because the finding is uncertain.
• Do not add the cohorts together. Borden 2025, Gabaldón-Albero 2024 and the Simons Searchlight registry re-count many of the same underlying patients. Cite one headline figure and use the primary papers for individual detail.
• For a 16p11.2 deletion, the defensible claim is that it is an independently sufficient cause of developmental impairment with a large average effect on cognition, language, motor coordination and seizure risk. It is not that it causes intellectual disability on its own. GeneReviews says the opposite in plain terms.
• No published study examines NR4A2 together with 16p11.2, and no study measures support hours or funding tiers in children with two diagnoses against one. The dual-diagnosis literature supports blended and more complex presentations, not a specific funding entitlement.
• NR4A2 also carries a separate, unrelated association with late-onset Parkinson disease susceptibility. Anyone searching the gene name may land on that material, so it is worth pre-empting in a line.
• Panel versions, ClinVar counts and PanelApp ratings change over time. Everything on this page was checked on 27 July 2026.