Human Gene Module / Chromosome 9 / RORB

RORBRAR related orphan receptor B

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
7 / 15
Rare Variants / Common Variants
56 / 0
EAGLE Score
8.25
Moderate Learn More
Aliases
RORB, EIG15,  NR1F2,  ROR-BETA,  RZR-BETA,  RZRB,  bA133M9.1
Associated Syndromes
9q21.13 microdeletion syndrome
Chromosome Band
9q21.13
Associated Disorders
ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

A de novo missense variant in the RORB gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), while two de novo likely-gene disruptive variants in this gene were observed in ASD probands from the Autism Sequencing Consortium (Satterstrom et al., 2020). Subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in Satterstrom et al., 2020 identified RORB as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified RORB as a gene reaching exome-wide significance (P < 2.5E-06). Mutations in the RORB gene are responsible for susceptibility to idiopathic generalized epilepsy-15 (EIG15; OMIM 618357); Rudolf et al., 2016 found that two individuals from a cohort of patients with RORB-associated epilepsy also presented with autism spectrum disorder. Boudry-Labis et al., 2013 had previously shown that RORB was one of four genes within the minimal region of overlap in 9q21.13 microdeletion syndrome, a disorder characterized by developmental delay, epilepsy, behavioral abnormalities (including autistic features), and dysmorphic features. Rorb-knockout mice were found to display motor, olfactory, behavioral, and circadian phenotypes (Masana et al., 2007).

Molecular Function

The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It is a DNA-binding protein that can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, and to help regulate the expression of some genes involved in circadian rhythm.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RORB (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORbeta knockout Masana MI , et al. (2007) No -
2 Support ROR? induces barrel-like neuronal clusters in the developing neocortex Jabaudon D , et al. (2011) No -
3 Support A novel microdeletion syndrome at 9q21.13 characterised by mental retardation, speech delay, epilepsy and characteristic facial features Boudry-Labis E , et al. (2013) No -
4 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy Rudolf G , et al. (2016) No ASD
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 - Sadleir LG et al. (2020) No DD, ID, learning difficulties
8 Support Cortical ROR? is required for layer 4 transcriptional identity and barrel integrity Clark EA et al. (2020) No -
9 Support - Mahjani B et al. (2021) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Yuan B et al. (2023) Yes -
12 Support - Murray GC et al. (2023) No -
13 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
14 Recent Recommendation - et al. () No ASD or autistic features, ADHD
15 Support - et al. () Yes Somatosensory behaviors
Rare Variants   (56)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 38165337 et al. ()
- - copy_number_loss Unknown - - 38165337 et al. ()
- - copy_number_loss Unknown Not maternal - 38165337 et al. ()
- - copy_number_loss De novo - - 27352968 Rudolf G , et al. (2016)
- - copy_number_loss Unknown - - 27352968 Rudolf G , et al. (2016)
c.640C>T p.Arg214Ter stop_gained De novo - - 38165337 et al. ()
c.751C>T p.Gln251Ter stop_gained De novo - - 38165337 et al. ()
c.1114C>T p.Arg372Ter stop_gained De novo - - 38165337 et al. ()
c.86G>T p.Gly29Val missense_variant Unknown - - 38165337 et al. ()
c.99C>A p.Tyr33Ter missense_variant De novo - - 38165337 et al. ()
- - translocation De novo - Simplex 27352968 Rudolf G , et al. (2016)
c.207G>C p.Lys69Asn missense_variant De novo - - 38165337 et al. ()
c.817G>T p.Val273Leu missense_variant De novo - - 38165337 et al. ()
c.896G>A p.Cys299Tyr missense_variant De novo - - 38165337 et al. ()
c.926G>A p.Gly309Asp missense_variant De novo - - 38165337 et al. ()
c.935A>G p.Glu312Gly missense_variant De novo - - 38165337 et al. ()
c.971A>G p.Tyr324Cys missense_variant De novo - - 38165337 et al. ()
- - copy_number_loss De novo - Simplex 27352968 Rudolf G , et al. (2016)
c.759G>A p.Lys253= splice_region_variant De novo - - 38165337 et al. ()
c.423T>G p.Tyr141Ter stop_gained Familial Maternal - 38165337 et al. ()
c.659_661del p.Met220del inframe_deletion De novo - - 38165337 et al. ()
c.1074_1076del p.Lys358del inframe_deletion De novo - - 38165337 et al. ()
c.1114C>T p.Arg372Ter stop_gained De novo - - 36881370 Yuan B et al. (2023)
c.777G>A p.Trp259Ter stop_gained Unknown Not maternal - 38165337 et al. ()
c.208T>C p.Cys70Arg missense_variant Familial Maternal - 38165337 et al. ()
c.344C>G p.Ala115Gly missense_variant Familial Paternal - 38165337 et al. ()
c.926G>A p.Gly309Asp missense_variant Familial Paternal - 38165337 et al. ()
c.357dup p.Gln120AlafsTer19 frameshift_variant De novo - - 38165337 et al. ()
c.1066G>A p.Glu356Lys missense_variant Familial Maternal - 38165337 et al. ()
c.784T>C p.Cys262Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1016T>C p.Val339Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1162A>T p.Ile388Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1268A>T p.Lys423Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.237_238dup p.Lys80ArgfsTer6 splice_site_variant Unknown - - 38165337 et al. ()
c.218T>C p.Leu73Pro missense_variant De novo - - 27352968 Rudolf G , et al. (2016)
c.465dup p.His156AlafsTer4 stop_gained Unknown Not paternal - 38165337 et al. ()
c.920A>G p.Lys307Arg missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.959G>A p.Arg320His missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1162dup p.Glu388GlyfsTer27 frameshift_variant Familial Maternal - 38165337 et al. ()
c.1292del p.Cys431SerfsTer18 frameshift_variant Familial Maternal - 38165337 et al. ()
c.1322_1324delinsGG p.Phe441TrpfsTer8 frameshift_variant De novo - - 38165337 et al. ()
c.314del p.Tyr105LeufsTer37 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1249_1251del p.Thr417del inframe_deletion De novo - - 27352968 Rudolf G , et al. (2016)
c.64T>G p.Tyr22Asp missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1114C>T p.Arg372Ter stop_gained De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.654_655insTC p.Thr219SerfsTer3 frameshift_variant Familial Maternal - 38165337 et al. ()
c.202C>T p.Gln68Ter stop_gained Familial Paternal Multiplex 37543562 Sheth F et al. (2023)
c.342_343insAA p.Leu115AsnfsTer28 frameshift_variant Familial Paternal - 38165337 et al. ()
c.1074_1076del p.Lys358del inframe_deletion Familial Paternal Multiplex 38165337 et al. ()
c.1162dup p.Glu388GlyfsTer27 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1162A>T p.Ile388Phe missense_variant Familial Paternal Simplex 32162308 Sadleir LG et al. (2020)
c.777G>T p.Trp259Cys missense_variant Familial Paternal Multiplex 32162308 Sadleir LG et al. (2020)
c.111C>G p.Ser37Arg missense_variant Familial - Extended multiplex 32162308 Sadleir LG et al. (2020)
c.196C>T p.Arg66Ter stop_gained Familial Maternal Multi-generational 27352968 Rudolf G , et al. (2016)
c.816_817dup p.Val273AlafsTer9 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.96_237del p.His32GlnfsTer6 frameshift_variant Familial Maternal Simplex 32162308 Sadleir LG et al. (2020)
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."

7/1/2020
1
icon
1

Score remained at 1

Description

Mutations in the RORB gene are responsible for susceptibility to idiopathic generalized epilepsy-15 (EIG15; OMIM 618357); Rudolf et al., 2016 found that two individuals from a cohort of patients with RORB-associated epilepsy also presented with autism spectrum disorder. Boudry-Labis et al., 2013 had previously shown that RORB was one of four genes within the minimal region of overlap in 9q21.13 microdeletion syndrome, a disorder characterized by developmental delay, epilepsy, behavioral abnormalities (including autistic features), and dysmorphic features. A de novo missense variant in the RORB gene has also been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rorb-knockout mice were found to display motor, olfactory, behavioral, and circadian phenotypes (Masana et al., 2007).

Reports Added
[Cortical RORβ is required for layer 4 transcriptional identity and barrel integrity2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Mutations in the RORB gene are responsible for susceptibility to idiopathic generalized epilepsy-15 (EIG15; OMIM 618357); Rudolf et al., 2016 found that two individuals from a cohort of patients with RORB-associated epilepsy also presented with autism spectrum disorder. Boudry-Labis et al., 2013 had previously shown that RORB was one of four genes within the minimal region of overlap in 9q21.13 microdeletion syndrome, a disorder characterized by developmental delay, epilepsy, behavioral abnormalities (including autistic features), and dysmorphic features. A de novo missense variant in the RORB gene has also been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rorb-knockout mice were found to display motor, olfactory, behavioral, and circadian phenotypes (Masana et al., 2007).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
icon
1

Increased from to 1

New Scoring Scheme
Description

Mutations in the RORB gene are responsible for susceptibility to idiopathic generalized epilepsy-15 (EIG15; OMIM 618357); Rudolf et al., 2016 found that two individuals from a cohort of patients with RORB-associated epilepsy also presented with autism spectrum disorder. Boudry-Labis et al., 2013 had previously shown that RORB was one of four genes within the minimal region of overlap in 9q21.13 microdeletion syndrome, a disorder characterized by developmental delay, epilepsy, behavioral abnormalities (including autistic features), and dysmorphic features. A de novo missense variant in the RORB gene has also been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Rorb-knockout mice were found to display motor, olfactory, behavioral, and circadian phenotypes (Masana et al., 2007).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.61050839261948

Ranking 225/25841 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 0.99855170070759

Ranking 1170/18225 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 0.7282154403737

Ranking 1359/18665 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 0.099653061575431

Ranking 6146/20870 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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