Human Gene Module / Chromosome 15 / RORA

RORARAR-related orphan receptor A

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 18
Rare Variants / Common Variants
18 / 1
Aliases
RORA, RORalpha,  ROR1,  ROR2,  ROR3,  RZRA,  NR1F1,  MGC119326,  MGC119329,  RZR-ALPHA,  DKFZp686M2414,  RORA
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Chromosome Band
15q22.2
Associated Disorders
ASD, EPS, EP
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

Reports related to RORA (18 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 candidat... 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 charac... 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 two 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 Highly Cited Disruption of the nuclear hormone receptor RORalpha in staggerer mice. Hamilton BA , et al. (1996) No -
Rare Variants   (18)
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_loss De novo - - 29656859 Guissart C , et al. (2018)
c.1498C>T p.Arg500Ter stop_gained De novo - - 29656859 Guissart C , et al. (2018)
- p.Ser66TrpfsTer24 copy_number_loss De novo - - 29656859 Guissart C , et al. (2018)
- p.Gln315LeufsTer51 copy_number_gain De novo - - 29656859 Guissart C , et al. (2018)
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.Ser409Arg 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.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.1019delG p.Arg340ProfsTer17 frameshift_variant De novo - - 29656859 Guissart C , et al. (2018)
c.425-1G>A p.Ala142_Leu273del splice_site_variant De novo - - 29656859 Guissart C , et al. (2018)
c.804_805delGT p.Ser269HisfsTer13 frameshift_variant De novo - - 29656859 Guissart C , et al. (2018)
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

S

Score Delta: Decreased from 5 to S

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."

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).

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.
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
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).
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.
CNVs associated with RORA(1 CNVs)
15q22.2 8 Deletion-Duplication 15  /  36
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