Human Gene Module / Chromosome 2 / NR4A2

NR4A2nuclear receptor subfamily 4 group A member 2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 11
Rare Variants / Common Variants
19 / 0
EAGLE Score
11.5
Strong Learn More
Aliases
NR4A2, HZF-3,  NOT,  NURR1,  RNR1,  TINUR
Associated Syndromes
-
Chromosome Band
2q24.1
Associated Disorders
ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

De novo deletions encompassing the NR4A2 gene were identified in three unrelated individuals with developmental delay/intellectual disability and language delay/impairment, two of whom also met DSM-5 criteria for a diagnosis of ASD, in Levy et al., 2018; in contrast, no CNVs encompassing this gene were reported in the Database of Genomic Variants (DGV). De novo deletions affecting this gene had previously been identified in individuals with intellectual disability and language delay/impairment (one of whom was also diagnosed with ASD) in three separate reports (Barge-Schaapveld et al., 2013; Leppa et al., 2016; Reuter et al., 2017). A de novo damaging missense variant in the NR4A2 gene was observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012).

Molecular Function

This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcription factor. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NR4A2 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
2 Support Intellectual disability and hemizygous GPD2 mutation Barge-Schaapveld DQ , et al. (2013) No -
3 Support Rare Inherited and De Novo CNVs Reveal Complex Contributions to ASD Risk in Multiplex Families Leppa VM , et al. (2016) Yes -
4 Support Haploinsufficiency of NR4A2 is associated with a neurodevelopmental phenotype with prominent language impairment Reuter MS , et al. (2017) No -
5 Primary NR4A2 haploinsufficiency is associated with intellectual disability and autism spectrum disorder Lvy J , et al. (2018) Yes -
6 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
7 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
8 Recent Recommendation De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy Singh S et al. (2020) No ASD
9 Support - Krgovic D et al. (2022) Yes ID
10 Support - Zhou X et al. (2022) Yes -
11 Support - Suhua Chang et al. () Yes -
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 32366965 Singh S et al. (2020)
- - copy_number_loss De novo - - 28544326 Reuter MS , et al. (2017)
- - copy_number_loss De novo - Simplex 29770430 Lvy J , et al. (2018)
- - copy_number_loss De novo - Simplex 27569545 Leppa VM , et al. (2016)
- - copy_number_loss De novo - - 23554088 Barge-Schaapveld DQ , et al. (2013)
c.571C>T p.Gln191Ter stop_gained De novo - - 35813072 Krgovic D et al. (2022)
c.839G>A p.Cys280Tyr missense_variant De novo - - 32366965 Singh S et al. (2020)
c.857T>C p.Phe286Ser missense_variant De novo - - 32366965 Singh S et al. (2020)
c.1175A>G p.Asp392Gly missense_variant De novo - - 32366965 Singh S et al. (2020)
c.914G>A p.Cys305Tyr missense_variant De novo - Simplex 32366965 Singh S et al. (2020)
c.968G>T p.Cys323Phe missense_variant De novo - Simplex 32366965 Singh S et al. (2020)
c.1576G>T p.Glu526Ter stop_gained Unknown Not maternal - 32366965 Singh S et al. (2020)
c.325dup p.Gln109ProfsTer3 frameshift_variant De novo - - 32366965 Singh S et al. (2020)
c.823T>C p.Tyr275His missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.865-1_865delinsAAAAAGGAGT - splice_site_variant De novo - - 32366965 Singh S et al. (2020)
c.693del p.Phe232SerfsTer69 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.598_599insGTCC p.Val200GlyfsTer83 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.860_864del p.Phe287SerfsTer15 frameshift_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.354_355insGTCC p.Ser119ValfsTer62 frameshift_variant De novo - Simplex 30504930 Guo H , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2020
1
icon
1

Score remained at 1

Description

De novo deletions encompassing the NR4A2 gene were identified in three unrelated individuals with developmental delay/intellectual disability and language delay/impairment, two of whom also met DSM-5 criteria for a diagnosis of ASD, in Levy et al., 2018; in contrast, no CNVs encompassing this gene were reported in the Database of Genomic Variants (DGV). De novo deletions affecting this gene had previously been identified in individuals with intellectual disability and language delay/impairment (one of whom was also diagnosed with ASD) in three separate reports (Barge-Schaapveld et al., 2013; Leppa et al., 2016; Reuter et al., 2017). A de novo damaging missense variant in the NR4A2 gene was observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012).

Reports Added
[De novo variants of NR4A2 are associated with neurodevelopmental disorder and epilepsy2020]
10/1/2019
4
icon
1

Decreased from 4 to 1

New Scoring Scheme
Description

De novo deletions encompassing the NR4A2 gene were identified in three unrelated individuals with developmental delay/intellectual disability and language delay/impairment, two of whom also met DSM-5 criteria for a diagnosis of ASD, in Levy et al., 2018; in contrast, no CNVs encompassing this gene were reported in the Database of Genomic Variants (DGV). De novo deletions affecting this gene had previously been identified in individuals with intellectual disability and language delay/impairment (one of whom was also diagnosed with ASD) in three separate reports (Barge-Schaapveld et al., 2013; Leppa et al., 2016; Reuter et al., 2017). A de novo damaging missense variant in the NR4A2 gene was observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

De novo deletions encompassing the NR4A2 gene were identified in three unrelated individuals with developmental delay/intellectual disability and language delay/impairment, two of whom also met DSM-5 criteria for a diagnosis of ASD, in Levy et al., 2018; in contrast, no CNVs encompassing this gene were reported in the Database of Genomic Variants (DGV). De novo deletions affecting this gene had previously been identified in individuals with intellectual disability and language delay/impairment (one of whom was also diagnosed with ASD) in three separate reports (Barge-Schaapveld et al., 2013; Leppa et al., 2016; Reuter et al., 2017). A de novo damaging missense variant in the NR4A2 gene was observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012).

Reports Added
[Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.2018]
7/1/2018
icon
4

Increased from to 4

Description

De novo deletions encompassing the NR4A2 gene were identified in three unrelated individuals with developmental delay/intellectual disability and language delay/impairment, two of whom also met DSM-5 criteria for a diagnosis of ASD, in Levy et al., 2018; in contrast, no CNVs encompassing this gene were reported in the Database of Genomic Variants (DGV). De novo deletions affecting this gene had previously been identified in individuals with intellectual disability and language delay/impairment (one of whom was also diagnosed with ASD) in three separate reports (Barge-Schaapveld et al., 2013; Leppa et al., 2016; Reuter et al., 2017). A de novo damaging missense variant in the NR4A2 gene was observed in an ASD proband from the Simons Simplex Collection (O'Roak et al., 2012).

Krishnan Probability Score

Score 0.57232097632821

Ranking 713/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99143286550823

Ranking 1744/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.75828136767205

Ranking 1640/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.47752191524009

Ranking 678/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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