Human Gene Module / Chromosome 15 / RORA

RORARAR-related orphan receptor A

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
8 / 26
Rare Variants / Common Variants
25 / 1
Aliases
RORA, RORalpha,  ROR1,  ROR2,  ROR3,  RZRA,  NR1F1,  MGC119326,  MGC119329,  RZR-ALPHA,  DKFZp686M2414,  RORA
Associated Syndromes
-
Chromosome Band
15q22.2
Associated Disorders
ASD, EP, EPS
Relevance to Autism

Immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (Nguyen et al., 2010).

Molecular Function

A member of the nuclear hormone-receptor superfamily

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Zebrafish
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RORA (26 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways Gold DA , et al. (2003) No -
2 Highly Cited A functional genomics strategy reveals Rora as a component of the mammalian circadian clock Sato TK , et al. (2004) No -
3 Recent Recommendation The nuclear receptor ROR(alpha) exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes Journiac N , et al. (2009) No -
4 Recent Recommendation RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer Lee JM , et al. (2010) No -
5 Recent Recommendation Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha Wang Y , et al. (2010) No -
6 Primary Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidate gene, RORA, whose protein product is reduced in autistic brain Nguyen A , et al. (2010) Yes -
7 Recent Recommendation Induction of early Purkinje cell dendritic differentiation by thyroid hormone requires ROR? Boukhtouche F , et al. (2010) No -
8 Recent Recommendation Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene Crumbley C , et al. (2010) No -
9 Recent Recommendation Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism Sarachana T , et al. (2011) No -
10 Recent Recommendation Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder Sarachana T and Hu VW (2013) No -
11 Recent Recommendation Mature Purkinje cells require the retinoic acid-related orphan receptor-? (ROR?) to maintain climbing fiber mono-innervation and other adult characteristics Chen XR , et al. (2013) No -
12 Recent Recommendation A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137 Devanna P and Vernes SC (2014) No -
13 Recent Recommendation Overlapping microdeletions involving 15q22.2 narrow the critical region for intellectual disability to NARG2 and RORA Yamamoto T , et al. (2014) No Epilepsy/seizures, autistic features
14 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
15 Positive Association Retinoic acid-related orphan receptor alpha (RORA) variants are associated with autism spectrum disorder Sayad A , et al. (2017) Yes -
16 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No Epilepsy, ataxia
17 Recent Recommendation Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia Guissart C , et al. (2018) No ASD, cerebellar ataxia
18 Support - Yu H et al. (2022) Yes -
19 Support - Xiao L et al. (2022) No -
20 Support - Zhou X et al. (2022) Yes -
21 Support - Cirnigliaro M et al. (2023) Yes -
22 Support - Sanchis-Juan A et al. (2023) No -
23 Support - Lowther C et al. (2023) Yes -
24 Support - Jia Q et al. (2023) Yes -
25 Support - Axel Schmidt et al. (2024) No -
26 Highly Cited Disruption of the nuclear hormone receptor RORalpha in staggerer mice Hamilton BA , et al. (1996) No -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 24525055 Yamamoto T , et al. (2014)
- - copy_number_loss Unknown - - 24525055 Yamamoto T , et al. (2014)
- - copy_number_gain De novo - - 29656859 Guissart C , et al. (2018)
- - copy_number_loss De novo - - 29656859 Guissart C , et al. (2018)
- - copy_number_loss De novo - Simplex 37595579 Lowther C et al. (2023)
c.137G>A p.Ser46Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1498C>T p.Leu500= stop_gained De novo - - 29656859 Guissart C , et al. (2018)
c.517C>G p.Arg173Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1248G>T p.Gly416%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.269G>C p.Cys90Ser missense_variant Unknown - - 29656859 Guissart C , et al. (2018)
c.275G>C p.Gly92Ala missense_variant De novo - - 29656859 Guissart C , et al. (2018)
c.281A>G p.Lys94Arg missense_variant De novo - - 29656859 Guissart C , et al. (2018)
c.1225A>C p.Asn409His missense_variant De novo - - 29656859 Guissart C , et al. (2018)
c.1385G>A p.Arg462Gln missense_variant De novo - - 29656859 Guissart C , et al. (2018)
c.1484G>A p.Arg495Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.393_395del p.Arg132del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.1118del p.Arg373ProfsTer17 frameshift_variant De novo - - 28708303 Chrot E , et al. (2017)
- - copy_number_loss Familial Paternal Multi-generational 24525055 Yamamoto T , et al. (2014)
- - copy_number_loss Familial Maternal Multi-generational 29656859 Guissart C , et al. (2018)
c.997del p.Ile333LeufsTer11 frameshift_variant De novo - - 29656859 Guissart C , et al. (2018)
c.1396C>A p.Arg466Ser missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.425-1G>A p.Ala142_Leu273del splice_site_variant De novo - - 29656859 Guissart C , et al. (2018)
c.781_782del p.Ile261GlnfsTer10 frameshift_variant De novo - - 29656859 Guissart C , et al. (2018)
c.966_975dup p.Glu326IlefsTer20 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.100_103del p.Ser34ProfsTer19 frameshift_variant Familial Maternal Multiplex (monozygotic twins) 37506195 Cirnigliaro M et al. (2023)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.166+54254G>A;c.-328+54254G>A - intron_variant - - - 28608249 Sayad A , et al. (2017)
SFARI Gene score
S

Syndromic

Immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (Nguyen et al., 2010). A major isoform of RORA protein in human brain, RORA1, was shown by ChIP analysis in human neuronal cells to be recruited to the promoter regions of over 2,500 genes, with subsequent gene ontology analysis showing statistically significant enrichment in biological processes relevant to ASD (Sarachana and Hu, 2013). In the same report, RORA1 was confirmed to bind to the promoter regions of several ASD candidate genes whose expression levels were reduced in RORA1-repressed human neuronal cells and in ASD prefrontal cortex tissues. De novo and inherited 15q22.2 deletions involving the RORA gene were identified in five individuals from DECIPHER presenting with intellectual disability, epilepsy, and, in one case, autistic features (Yamamoto et al., 2014). Overrepresentation of the T allele of the RORA SNP rs4774388 was observed in a cohort of 518 Iranian ASD patients compared to 472 controls in Sayad et al., 2017; the rs4774388-TT genotype was also significantly higher in ASD patients compared with controls and was associated with ASD risk in a dominant inheritance model in this report. The phenotypes observed in 16 individuals from 13 families with dominant RORA mutations in Guissart et al., 2018 included developmental delay/intellectual disability (15/16), seizures (11/16), ASD (5/16), and cerebellar ataxia (4/16).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (Nguyen et al., 2010). A major isoform of RORA protein in human brain, RORA1, was shown by ChIP analysis in human neuronal cells to be recruited to the promoter regions of over 2,500 genes, with subsequent gene ontology analysis showing statistically significant enrichment in biological processes relevant to ASD (Sarachana and Hu, 2013). In the same report, RORA1 was confirmed to bind to the promoter regions of several ASD candidate genes whose expression levels were reduced in RORA1-repressed human neuronal cells and in ASD prefrontal cortex tissues. De novo and inherited 15q22.2 deletions involving the RORA gene were identified in five individuals from DECIPHER presenting with intellectual disability, epilepsy, and, in one case, autistic features (Yamamoto et al., 2014). Overrepresentation of the T allele of the RORA SNP rs4774388 was observed in a cohort of 518 Iranian ASD patients compared to 472 controls in Sayad et al., 2017; the rs4774388-TT genotype was also significantly higher in ASD patients compared with controls and was associated with ASD risk in a dominant inheritance model in this report. The phenotypes observed in 16 individuals from 13 families with dominant RORA mutations in Guissart et al., 2018 included developmental delay/intellectual disability (15/16), seizures (11/16), ASD (5/16), and cerebellar ataxia (4/16).

Reports Added
[New Scoring Scheme]
7/1/2018
5
icon
S

Decreased from 5 to S

Description

Immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (Nguyen et al., 2010). A major isoform of RORA protein in human brain, RORA1, was shown by ChIP analysis in human neuronal cells to be recruited to the promoter regions of over 2,500 genes, with subsequent gene ontology analysis showing statistically significant enrichment in biological processes relevant to ASD (Sarachana and Hu, 2013). In the same report, RORA1 was confirmed to bind to the promoter regions of several ASD candidate genes whose expression levels were reduced in RORA1-repressed human neuronal cells and in ASD prefrontal cortex tissues. De novo and inherited 15q22.2 deletions involving the RORA gene were identified in five individuals from DECIPHER presenting with intellectual disability, epilepsy, and, in one case, autistic features (Yamamoto et al., 2014). Overrepresentation of the T allele of the RORA SNP rs4774388 was observed in a cohort of 518 Iranian ASD patients compared to 472 controls in Sayad et al., 2017; the rs4774388-TT genotype was also significantly higher in ASD patients compared with controls and was associated with ASD risk in a dominant inheritance model in this report. The phenotypes observed in 16 individuals from 13 families with dominant RORA mutations in Guissart et al., 2018 included developmental delay/intellectual disability (15/16), seizures (11/16), ASD (5/16), and cerebellar ataxia (4/16).

7/1/2017
5
icon
5

Decreased from 5 to 5

Description

While there are no apparent human genetic studies on the RORA gene, immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (PMID 20375269).

Reports Added
[Retinoic acid-related orphan receptor alpha (RORA) variants are associated with autism spectrum disorder.2017] [Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
1/1/2016
5
icon
5

Decreased from 5 to 5

Description

While there are no apparent human genetic studies on the RORA gene, immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (PMID 20375269).

Reports Added
[Global methylation profiling of lymphoblastoid cell lines reveals epigenetic contributions to autism spectrum disorders and a novel autism candidat...2010] [Overlapping microdeletions involving 15q22.2 narrow the critical region for intellectual disability to NARG2 and RORA.2014] [Disruption of the nuclear hormone receptor RORalpha in staggerer mice.1996] [RORalpha coordinates reciprocal signaling in cerebellar development through sonic hedgehog and calcium-dependent pathways.2003] [A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.2004] [The nuclear receptor ROR(alpha) exerts a bi-directional regulation of IL-6 in resting and reactive astrocytes.2009] [RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer.2010] [Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha.2010] [Induction of early Purkinje cell dendritic differentiation by thyroid hormone requires ROR.2010] [Characterization of the core mammalian clock component, NPAS2, as a REV-ERBalpha/RORalpha target gene.2010] [Sex hormones in autism: androgens and estrogens differentially and reciprocally regulate RORA, a novel candidate gene for autism.2011] [Genome-wide identification of transcriptional targets of RORA reveals direct regulation of multiple genes associated with autism spectrum disorder.2013] [Mature Purkinje cells require the retinoic acid-related orphan receptor- (ROR) to maintain climbing fiber mono-innervation and other adult charac...2013] [A direct molecular link between the autism candidate gene RORa and the schizophrenia candidate MIR137.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

While there are no apparent human genetic studies on the RORA gene, immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (PMID 20375269).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

While there are no apparent human genetic studies on the RORA gene, immunohistochemical analyses of tissue arrays containing slices of the cerebellum and frontal cortex of autistic and age- and sex-matched control subjects revealed decreased expression of RORA in the autistic brain (PMID 20375269).

Krishnan Probability Score

Score 0.48981494308819

Ranking 6355/25841 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 0.95319654970805

Ranking 2627/18225 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 0.76929695341897

Ranking 1765/18665 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 0.23829250980896

Ranking 3646/20870 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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