Human Gene Module / Chromosome 2 / TBR1

TBR1T-box, brain, 1

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 18
Rare Variants / Common Variants
16 / 1
Aliases
TBR1, TBR-1,  TES-56
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
2q24.2
Associated Disorders
DD/NDD, ADHD, EPS, EP, ASD
Relevance to Autism

De novo variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (Sanders et al. 2012a, 2012b)

Molecular Function

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

Reports related to TBR1 (18 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 Recent recommendation De novo TBR1 mutations in sporadic autism disrupt protein functions. Deriziotis P , et al. (2014) No -
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 -
Rare Variants   (16)
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.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)
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

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

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.

04-01-2017
1

Initial score established: 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]
CNVs associated with TBR1(1 CNVs)
2q24.2 11 Deletion-Duplication 20  /  43
Animal Models associated with TBR1(9 Models)
Tbr1_1_KO_HM Genetic
Tbr1_1_KO_HM_golli-lacZ Genetic
Tbr1_1_KO_HM_tau-lacz Genetic
Tbr1_1_KO_HT Genetic
Tbr1_2_KO_HT_Cycloserine-1 RESCUE-Pharmaceutical
Tbr1_2_KO_HT_Cycloserine-2 RESCUE-Pharmaceutical
Tbr1_2_KO_HT_miRNAs RESCUE-Genetic
Tbr1_3_KO_HT Genetic
Tbr1_3_KO_HT_CQ RESCUE-Genetic
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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