Human Gene Module / Chromosome 2 / TBR1

TBR1T-box, brain, 1

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 20
Rare Variants / Common Variants
25 / 1
Aliases
TBR1, TBR-1,  TES-56
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
2q24.2
Associated Disorders
ASD, ADHD, EPS, DD/NDD
Relevance to Autism

A number of mutations in the TBR1 gene have been identified in multiple individuals with ASD as described below. Two de novo loss-of-function variants and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis in Deriziotis et al., 2014 demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984).

Molecular Function

Probable transcriptional regulator involved in developmental processes that is required for normal brain development.

Reports related to TBR1 (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2. Hsueh YP , et al. (2000) No -
2 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
3 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
4 Support Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions. Traylor RN , et al. (2012) No Epilepsy (2 cases), PDD (1 case), ADHD (1 case)
5 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
6 Recent Recommendation Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Huang TN , et al. (2014) No -
7 Support TBR1 is the candidate gene for intellectual disability in patients with a 2q24.2 interstitial deletion. Palumbo O , et al. (2014) No -
8 Support De novo TBR1 mutations in sporadic autism disrupt protein functions. Deriziotis P , et al. (2014) Yes -
9 Recent recommendation Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain. Chuang HC , et al. (2014) No -
10 Support De novo mutations in moderate or severe intellectual disability. Hamdan FF , et al. (2014) No Autistic features
11 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
12 Recent recommendation T-Brain-1 - A Potential Master Regulator in Autism Spectrum Disorders. Chuang HC , et al. (2015) No -
13 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
14 Recent recommendation TBR1 regulates autism risk genes in the developing neocortex. Notwell JH , et al. (2016) No -
15 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
16 Positive association Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction. Bagshaw AT , et al. (2017) No -
17 Support Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with... Huang TN and Hsueh YP (2017) No -
18 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) No -
19 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) Yes -
20 Support The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum. McDermott JH , et al. (2017) Yes -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
del(C) p.Ala136ProfsTer80 frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1120A>C p.Asn374His missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
- - copy_number_loss Unknown - - 23112752 Traylor RN , et al. (2012)
- - copy_number_loss De novo - - 23112752 Traylor RN , et al. (2012)
- - copy_number_loss De novo - - 23112752 Traylor RN , et al. (2012)
- - copy_number_loss Unknown - - 23112752 Traylor RN , et al. (2012)
c.682A>G p.Lys228Glu missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
ins(C) p.Ser351Ter frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
- - copy_number_loss De novo - Simplex 24458984 Palumbo O , et al. (2014)
C>G p.Gln178Glu missense_variant Familial Paternal Simplex 25232744 Deriziotis P , et al. (2014)
C>G p.Gln178Glu missense_variant Familial Paternal Simplex 25232744 Deriziotis P , et al. (2014)
A>G p.Gln418Arg missense_variant Familial Maternal Simplex 25232744 Deriziotis P , et al. (2014)
C>G p.Pro542Arg missense_variant Familial Paternal Simplex 25232744 Deriziotis P , et al. (2014)
c.811T>C p.Trp271Arg missense_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.813G>T p.Trp271Cys missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1120A>T p.Asn374Tyr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.91G>C p.Glu31Gln missense_variant Familial Paternal Unknown 25363760 De Rubeis S , et al. (2014)
c.1066G>A p.Val356Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1635_1644dup p.Ser549fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1588_1594dupGGCTGCA p.Thr532Argfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.765T>A p.Asp255Glu missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.765T>A p.Asp255Glu missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.766G>T p.Val256Leu missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.946G>T p.Gly316Ter stop_gained De novo - Simplex 29288087 McDermott JH , et al. (2017)
c.932T>C p.Leu311Pro missense_variant De novo - - 29288087 McDermott JH , et al. (2017)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - microsatellite - - - 28158988 Bagshaw AT , et al. (2017)
SFARI Gene score
1

High Confidence

1

Score Delta: Score remained at 1.1

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.

4/1/2018
7/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

4/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain.2014] [TBR1 regulates autism risk genes in the developing neocortex.2016] [Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction.2017] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.2014] [Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions.2012] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo mutations in moderate or severe intellectual disability.2014] [Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.2000] [Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with...2017] [T-Brain-1 - A Potential Master Regulator in Autism Spectrum Disorders.2015] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [De novo TBR1 mutations in sporadic autism disrupt protein functions.2014] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [TBR1 is the candidate gene for intellectual disability in patients with a 2q24.2 interstitial deletion.2014] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012]
1/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

7/1/2016
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

1/1/2016
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

1/1/2015
1
icon
1

Score remained at 1

Description

Two de novo LGD variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

10/1/2014
2
icon
1

Decreased from 2 to 1

Description

Two de novo LGD variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Two de novo LGD variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

In a screen of 44 genes in 2,446 ASD probands, PMID 23160955 reported 2 de novo LGD in TBR1

Krishnan Probability Score

Score 0.61171905614202

Ranking 193/25841 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 0.99358803746459

Ranking 1629/18225 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
Iossifov Probability Score

Score 0.976

Ranking 47/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.00015371128216179

Ranking 14/18665 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).
Larsen Cumulative Evidence Score

Score 78

Ranking 15/461 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.
Zhang D Score

Score 0.43844562288918

Ranking 1046/20870 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 TBR1(1 CNVs)
2q24.2 14 Deletion-Duplication 26  /  49
Animal Models associated with TBR1(12 Models)
Tbr1_1_KO_HM 4 Genetic Mus musculus
Tbr1_1_KO_HM_golli-lacZ 1 Genetic Mus musculus
Tbr1_1_KO_HM_tau-lacz 1 Genetic Mus musculus
Tbr1_1_KO_HT 2 Genetic Mus musculus
Tbr1_1_KO_HT_Cycloserine-2 1 RESCUE-Pharmaceutical Mus musculus
Tbr1_1_KO_HT_miRNAs 1 RESCUE-Genetic Mus musculus
Tbr1_2_KO_HT_Cycloserine-1 1 RESCUE-Pharmaceutical Mus musculus
Tbr1_2_KO_HT_Cycloserine-2 RESCUE-Pharmaceutical Mus musculus
Tbr1_2_KO_HT_miRNAs RESCUE-Genetic Mus musculus
Tbr1_3_KO_HT 1 Genetic Mus musculus
Tbr1_3_KO_HT_Clioquinone 1 RESCUE-Genetic Mus musculus
Tbr1_3_KO_HT_CQ RESCUE-Genetic Mus musculus
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Cd200 CD200 antigen Mouse Direct Regulation 17470 O54901
Il7r interleukin 7 receptor Mouse Direct Regulation 16197 P16872
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