Human Gene Module / Chromosome 4 / NR3C2

NR3C2Nuclear receptor subfamily 3, group C, member 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
11 / 12
Rare Variants / Common Variants
22 / 0
Aliases
NR3C2, MCR,  MLR,  MRVIT, NR3C2
Associated Syndromes
-
Chromosome Band
4q31.23
Associated Disorders
-
Relevance to Autism

This gene was identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

Molecular Function

This gene encodes the mineralocorticoid receptor, which mediates aldosterone actions on salt and water balance within restricted target cells. The protein functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements in order to transactivate target genes. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NR3C2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Recent Recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA Turner TN et al. (2016) Yes -
4 Support Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations Zhou WZ , et al. (2019) Yes -
5 Recent Recommendation Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
6 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
7 Support Three Brothers With Autism Carry a Stop-Gain Mutation in the HPA-Axis Gene NR3C2 Cukier HN , et al. (2020) Yes -
8 Support - Rodin RE et al. (2021) Yes -
9 Support - Mahjani B et al. (2021) Yes -
10 Support - Singh T et al. (2022) No -
11 Support - Zhou X et al. (2022) Yes -
12 Support - Hu C et al. (2023) Yes -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - intergenic_variant De novo - Simplex 26749308 Turner TN et al. (2016)
c.1954C>T p.Arg652Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.1609C>T p.Arg537Ter stop_gained De novo - - 30763456 Zhou WZ , et al. (2019)
TC>T - frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2799+1G>A - splice_site_variant Familial Maternal - 37007974 Hu C et al. (2023)
- - copy_number_loss Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2543T>A p.Leu848Gln missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.2642-14T>C - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.867del p.Asn289LysfsTer5 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2800-2_2813delinsGACCA - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.2453C>A p.Ser818Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2093C>T p.Pro698Leu missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
G>A p.Gln919Ter stop_gained Familial Maternal Multiplex 32064789 Cukier HN , et al. (2020)
c.899C>G p.Pro300Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2058G>A p.Glu686= missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2233A>G p.Ile745Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.970A>G p.Ser324Gly missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.889G>T p.Val297Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2099C>T p.Pro700Leu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
ENST00000610940:c.1397C>T - missense_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.2686del p.Arg896GlyfsTer8 frameshift_variant Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
ENSG00000151623:ENST00000511528:exon7:c.G2666A:p.G889D,ENSG00000151623:ENST00000512865:exon7:c.G2303 - missense_variant De novo - - 33432195 Rodin RE et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
2S
icon
1

Decreased from 2S to 1

1/1/2021
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). Transmitted variants in the NR3C2 gene were observed in three multiplex ASD families from the iHART cohort in Ruzzo et al., 2019; phenotypic characterization of probands from these three families found striking phenotypic similarities defining a new syndromic form of ASD characterized by metacarpal hypoplasia, a high arched palate, sensory hypersensitivity, and abnormal prosody. Furthermore, Ruzzo et al., 2019 demonstrated that nr3c2 mutant zebrafish exhibited impaired social preference behavior and disrupted sleep at night.

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
1/1/2020
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). Transmitted variants in the NR3C2 gene were observed in three multiplex ASD families from the iHART cohort in Ruzzo et al., 2019; phenotypic characterization of probands from these three families found striking phenotypic similarities defining a new syndromic form of ASD characterized by metacarpal hypoplasia, a high arched palate, sensory hypersensitivity, and abnormal prosody. Furthermore, Ruzzo et al., 2019 demonstrated that nr3c2 mutant zebrafish exhibited impaired social preference behavior and disrupted sleep at night.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Three Brothers With Autism Carry a Stop-Gain Mutation in the HPA-Axis Gene NR3C2.2020]
10/1/2019
3S
icon
2S

Decreased from 3S to 2S

New Scoring Scheme
Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). Transmitted variants in the NR3C2 gene were observed in three multiplex ASD families from the iHART cohort in Ruzzo et al., 2019; phenotypic characterization of probands from these three families found striking phenotypic similarities defining a new syndromic form of ASD characterized by metacarpal hypoplasia, a high arched palate, sensory hypersensitivity, and abnormal prosody. Furthermore, Ruzzo et al., 2019 demonstrated that nr3c2 mutant zebrafish exhibited impaired social preference behavior and disrupted sleep at night.

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3S

Decreased from 3 to 3S

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). Transmitted variants in the NR3C2 gene were observed in three multiplex ASD families from the iHART cohort in Ruzzo et al., 2019; phenotypic characterization of probands from these three families found striking phenotypic similarities defining a new syndromic form of ASD characterized by metacarpal hypoplasia, a high arched palate, sensory hypersensitivity, and abnormal prosody. Furthermore, Ruzzo et al., 2019 demonstrated that nr3c2 mutant zebrafish exhibited impaired social preference behavior and disrupted sleep at night.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

Reports Added
[Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype c...2019]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA2016]
4/1/2015
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015]
10/1/2014
icon
3

Increased from to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in the NR3C2 gene in unrelated ASD probands from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified NR3C2 as a gene meeting high statistical significance with a 0.05

Krishnan Probability Score

Score 0.52096192556707

Ranking 1684/25841 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 0.92508855260719

Ranking 2974/18225 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 0.13647980116871

Ranking 80/18665 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
Larsen Cumulative Evidence Score

Score 21

Ranking 99/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.16773734411906

Ranking 4842/20870 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
Submit New Gene

Report an Error