Human Gene Module / Chromosome 5 / NR2F1

NR2F1nuclear receptor subfamily 2 group F member 1

Score
4S
Minimal Evidence, Syndromic Criteria 4.1, Syndromic
Autism Reports / Total Reports
5 / 11
Rare Variants / Common Variants
30 / 0
Aliases
NR2F1, BBOAS,  BBSOAS,  COUP-TFI,  EAR-3,  EAR3,  ERBAL3,  NR2F2,  SVP44,  TCFCOUP1,  TFCOUP1
Associated Syndromes
Bosch-Boonstra-Schaaf optic atrophy syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
5q15
Associated Disorders
EPS, ID, ASD, ADHD, DD/NDD
Relevance to Autism

One of the six patients with Bosch-Boonstra-Schaaf optic atrophy syndrome described in Bosch et al., 2014 presented with autism spectrum disorder with marked obsessive-compulsive behaviors. Evaluation of the clinical features of 20 individuals with novel pathogenic NR2F1 variants demonstrated that, in addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), repetitive behavior (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%) (Chen et al., 2016). De novo probably damaging missense variants in NR2F1 have also been observed in two ASD probands: one from the Simons Simplex Collection (Sanders et al., 2012), the other from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Molecular Function

The protein encoded by this gene is a nuclear hormone receptor and transcriptional regulator that binds to 5'-AGGTCA-3' repeats. Heterozygous mutations in this gene are a cause of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; OMIM 615722), an autosomal dominant disorder characterized by delayed development, moderate intellectual disability, and optic atrophy (Bosch et al., 2014).

Reports related to NR2F1 (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
2 Primary NR2F1 mutations cause optic atrophy with intellectual disability. Bosch DG , et al. (2014) No ID, ASD
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
4 Recent Recommendation The expanding clinical phenotype of Bosch-Boonstra-Schaaf optic atrophy syndrome: 20 new cases and possible genotype-phenotype correlations. Chen CA , et al. (2016) No ID, ASD, epilepsy/seizures, ADHD
5 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
6 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No Multiple congenital anomalies
7 Support Lessons learned from additional research analyses of unsolved clinical exome cases. Eldomery MK , et al. (2017) Yes -
8 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
9 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism. Chen R , et al. (2017) Yes -
10 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
11 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. Jiao Q , et al. (2019) No DD, ID
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 26986877 Chen CA , et al. (2016)
- - copy_number_loss Unknown - - 26986877 Chen CA , et al. (2016)
- - copy_number_loss De novo - - 24462372 Bosch DG , et al. (2014)
- - copy_number_loss Unknown - - 24462372 Bosch DG , et al. (2014)
C>T - stop_gained De novo - Simplex 28344757 Chen R , et al. (2017)
C>G p.Asp177Glu missense_variant De novo - - 28714951 Lim ET , et al. (2017)
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
c.382T>C p.Cys128Arg missense_variant De novo - - 26986877 Chen CA , et al. (2016)
c.403C>A p.Arg135Ser missense_variant De novo - - 26986877 Chen CA , et al. (2016)
c.413G>A p.Cys138Tyr missense_variant De novo - - 26986877 Chen CA , et al. (2016)
c.425G>T p.Arg142Leu missense_variant De novo - - 26986877 Chen CA , et al. (2016)
c.436T>C p.Cys146Arg missense_variant De novo - - 26986877 Chen CA , et al. (2016)
c.463G>A p.Ala155Thr missense_variant De novo - - 26986877 Chen CA , et al. (2016)
c.1103G>A p.Gly368Asp missense_variant De novo - - 26986877 Chen CA , et al. (2016)
c.2T>G p.Met1? initiator_codon_variant De novo - - 26986877 Chen CA , et al. (2016)
c.339C>A p.Ser113Arg missense_variant De novo - - 24462372 Bosch DG , et al. (2014)
c.344G>C p.Arg115Pro missense_variant De novo - - 24462372 Bosch DG , et al. (2014)
c.755T>C p.Leu252Pro missense_variant De novo - - 24462372 Bosch DG , et al. (2014)
c.2T>C p.Met1Thr initiator_codon_variant De novo - - 30945278 Jiao Q , et al. (2019)
c.314G>A p.Gly105Asp missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.328_330del p.Phe110del inframe_deletion De novo - - 26986877 Chen CA , et al. (2016)
c.305C>T p.Thr102Ile missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.314G>A p.Gly105Asp missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
- - copy_number_loss Familial Paternal Multi-generational 26986877 Chen CA , et al. (2016)
c.335G>A p.Arg112Lys missense_variant De novo - Simplex 24462372 Bosch DG , et al. (2014)
c.291delC p.His79HisfsTer22 frameshift_variant De novo - - 26986877 Chen CA , et al. (2016)
c.1211G>A p.Arg404His missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.413G>A p.Cys138Tyr missense_variant De novo - Simplex 28327206 Eldomery MK , et al. (2017)
c.2_4delTGGinsGGA p.Met1? initiator_codon_variant De novo - - 26986877 Chen CA , et al. (2016)
c.103_113delinsCGCCGCCGC p.Gly35ArgfsTer361 frameshift_variant De novo - - 26986877 Chen CA , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
4S

Minimal Evidence, Syndromic

4S

Score Delta: Score remained at 4.4 + S

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

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
4S
icon
4S

Score remained at 4S

Description

Heterozygous mutations in this gene are a cause of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; OMIM 615722), an autosomal dominant disorder characterized by delayed development, moderate intellectual disability, and optic atrophy (Bosch et al., 2014). One of the six patients with Bosch-Boonstra-Schaaf optic atrophy syndrome described in Bosch et al., 2014 presented with autism spectrum disorder with marked obsessive-compulsive behaviors. Evaluation of the clinical features of 20 individuals with novel pathogenic NR2F1 variants demonstrated that, in addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), repetitive behavior (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%) (Chen et al., 2016). De novo probably damaging missense variants in NR2F1 have also been observed in two ASD probands: one from the Simons Simplex Collection (Sanders et al., 2012), the other from the Autism Sequencing Consortium (De Rubeis et al., 2014).

4/1/2017
4S
icon
4S

Score remained at 4S

Description

Heterozygous mutations in this gene are a cause of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; OMIM 615722), an autosomal dominant disorder characterized by delayed development, moderate intellectual disability, and optic atrophy (Bosch et al., 2014). One of the six patients with Bosch-Boonstra-Schaaf optic atrophy syndrome described in Bosch et al., 2014 presented with autism spectrum disorder with marked obsessive-compulsive behaviors. Evaluation of the clinical features of 20 individuals with novel pathogenic NR2F1 variants demonstrated that, in addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), repetitive behavior (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%) (Chen et al., 2016). De novo probably damaging missense variants in NR2F1 have also been observed in two ASD probands: one from the Simons Simplex Collection (Sanders et al., 2012), the other from the Autism Sequencing Consortium (De Rubeis et al., 2014).

10/1/2016
4S
icon
4S

Score remained at 4S

Description

Heterozygous mutations in this gene are a cause of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; OMIM 615722), an autosomal dominant disorder characterized by delayed development, moderate intellectual disability, and optic atrophy (Bosch et al., 2014). One of the six patients with Bosch-Boonstra-Schaaf optic atrophy syndrome described in Bosch et al., 2014 presented with autism spectrum disorder with marked obsessive-compulsive behaviors. Evaluation of the clinical features of 20 individuals with novel pathogenic NR2F1 variants demonstrated that, in addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), repetitive behavior (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%) (Chen et al., 2016). De novo probably damaging missense variants in NR2F1 have also been observed in two ASD probands: one from the Simons Simplex Collection (Sanders et al., 2012), the other from the Autism Sequencing Consortium (De Rubeis et al., 2014).

7/1/2016
4S
icon
4S

Score remained at 4S

Description

Heterozygous mutations in this gene are a cause of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; OMIM 615722), an autosomal dominant disorder characterized by delayed development, moderate intellectual disability, and optic atrophy (Bosch et al., 2014). One of the six patients with Bosch-Boonstra-Schaaf optic atrophy syndrome described in Bosch et al., 2014 presented with autism spectrum disorder with marked obsessive-compulsive behaviors. Evaluation of the clinical features of 20 individuals with novel pathogenic NR2F1 variants demonstrated that, in addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), repetitive behavior (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%) (Chen et al., 2016). De novo probably damaging missense variants in NR2F1 have also been observed in two ASD probands: one from the Simons Simplex Collection (Sanders et al., 2012), the other from the Autism Sequencing Consortium (De Rubeis et al., 2014).

4/1/2016
icon
4S

Increased from to 4S

Description

Heterozygous mutations in this gene are a cause of Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS; OMIM 615722), an autosomal dominant disorder characterized by delayed development, moderate intellectual disability, and optic atrophy (Bosch et al., 2014). One of the six patients with Bosch-Boonstra-Schaaf optic atrophy syndrome described in Bosch et al., 2014 presented with autism spectrum disorder with marked obsessive-compulsive behaviors. Evaluation of the clinical features of 20 individuals with novel pathogenic NR2F1 variants demonstrated that, in addition to visual and cognitive deficits, individuals with BBSOAS manifested hypotonia (75%), seizures (40%), repetitive behavior (40%), autism spectrum disorder (35%), oromotor dysfunction (60%), thinning of the corpus callosum (53%), and hearing defects (20%) (Chen et al., 2016). De novo probably damaging missense variants in NR2F1 have also been observed in two ASD probands: one from the Simons Simplex Collection (Sanders et al., 2012), the other from the Autism Sequencing Consortium (De Rubeis et al., 2014).

Krishnan Probability Score

Score 0.56619311657082

Ranking 1220/25841 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.
Sanders TADA Score

Score 0.40393677506562

Ranking 284/18665 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 0.2346314388017

Ranking 3695/20870 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 NR2F1(1 CNVs)
5q15 17 Deletion-Duplication 27  /  48
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