Human Gene Module / Chromosome 22 / TBX1

TBX1T-box 1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 7
Rare Variants / Common Variants
4 / 0
Aliases
TBX1, CAFS,  CTHM,  DGCR,  DGS,  DORV,  TBX1C,  TGA,  VCFS
Associated Syndromes
DiGeorge syndrome
Chromosome Band
22q11.21
Associated Disorders
ASD
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, a rare mutation in the TBX1 gene has been identified with 22q11 deletion syndrome (22q11DS) (Paylor et al., 2006).

Molecular Function

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS), a common congenital disorder characterized by neural-crest-related developmental defects, has been associated with deletions of chromosome 22q11.2, where this gene has been mapped. Several alternatively spliced transcript variants encoding different isoforms have been described for this gene.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TBX1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Role of TBX1 in human del22q11.2 syndrome Yagi H , et al. (2003) No -
2 Primary Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome Paylor R , et al. (2006) No AS
3 Support Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions Zweier C , et al. (2007) No -
4 Support Tbx1: identification of a 22q11.2 gene as a risk factor for autism spectrum disorder in a mouse model Hiramoto T , et al. (2011) No -
5 Support Structure and function of neonatal social communication in a genetic mouse model of autism Takahashi T , et al. (2015) No -
6 Support - Zhou X et al. (2022) Yes -
7 Support - Balasar et al. (2023) No -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.590C>T p.Ala197Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1263C>G p.His421Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1168G>T p.Gly390Cys missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
- - frameshift_variant Familial Maternal Multi-generational 16684884 Paylor R , et al. (2006)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

TBX1 lies within the 22q11.21 chromosomal locus; heterozygous deletions in this region are responsible for 22q11.21 deletion syndromes (DiGeorge syndrome and Velocardiofacial syndrome), whereas heterozygous duplications in the same region are a significant risk factor for autism spectrum disorder and other neurodevelopmental and neuropsychiatric disorders. Several studies have demonstrated that haploinsufficiency of the TBX1 gene is responsible for many of the malformations associated with 22q11.21 deletion syndrome, and that variants in this gene can also cause this syndrome (Yagi et al., 2003; Paylor et al., 2006; Zweier et al., 2007). In particular, Paylor et al. 2006 reported a family in which the phenotypic features of 22q11.21 deletion syndrome segregated with an inactivating mutation in the TBX1 gene; one of three family members with this mutation had Asperger syndrome. TBX1 mouse models have also been shown to recapitulate features of autism spectrum disorder (Hiramoto et al., 2011; Takahashi et al., 2016).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

TBX1 lies within the 22q11.21 chromosomal locus; heterozygous deletions in this region are responsible for 22q11.21 deletion syndromes (DiGeorge syndrome and Velocardiofacial syndrome), whereas heterozygous duplications in the same region are a significant risk factor for autism spectrum disorder and other neurodevelopmental and neuropsychiatric disorders. Several studies have demonstrated that haploinsufficiency of the TBX1 gene is responsible for many of the malformations associated with 22q11.21 deletion syndrome, and that variants in this gene can also cause this syndrome (Yagi et al., 2003; Paylor et al., 2006; Zweier et al., 2007). In particular, Paylor et al. 2006 reported a family in which the phenotypic features of 22q11.21 deletion syndrome segregated with an inactivating mutation in the TBX1 gene; one of three family members with this mutation had Asperger syndrome. TBX1 mouse models have also been shown to recapitulate features of autism spectrum disorder (Hiramoto et al., 2011; Takahashi et al., 2016).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
S

Decreased from 4 to S

Description

TBX1 lies within the 22q11.21 chromosomal locus; heterozygous deletions in this region are responsible for 22q11.21 deletion syndromes (DiGeorge syndrome and Velocardiofacial syndrome), whereas heterozygous duplications in the same region are a significant risk factor for autism spectrum disorder and other neurodevelopmental and neuropsychiatric disorders. Several studies have demonstrated that haploinsufficiency of the TBX1 gene is responsible for many of the malformations associated with 22q11.21 deletion syndrome, and that variants in this gene can also cause this syndrome (Yagi et al., 2003; Paylor et al., 2006; Zweier et al., 2007). In particular, Paylor et al. 2006 reported a family in which the phenotypic features of 22q11.21 deletion syndrome segregated with an inactivating mutation in the TBX1 gene; one of three family members with this mutation had Asperger syndrome. TBX1 mouse models have also been shown to recapitulate features of autism spectrum disorder (Hiramoto et al., 2011; Takahashi et al., 2016).

4/1/2019
4
icon
4

Decreased from 4 to 4

Description

Paylor et al. (2006) reports a family in which the phenotypic features of 22q11 deletion syndrome segregate with an inactivating mutation of TBX1. One family member (of three with the mutation) has Asperger syndrome, an autistic spectrum disorder.

Reports Added
[Role of TBX1 in human del22q11.2 syndrome.2003] [Human TBX1 missense mutations cause gain of function resulting in the same phenotype as 22q11.2 deletions.2007] [Tbx1: identification of a 22q11.2 gene as a risk factor for autism spectrum disorder in a mouse model.2011] [Structure and function of neonatal social communication in a genetic mouse model of autism.2015]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Paylor et al. (2006) reports a family in which the phenotypic features of 22q11 deletion syndrome segregate with an inactivating mutation of TBX1. One family member (of three with the mutation) has Asperger syndrome, an autistic spectrum disorder.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Paylor et al. (2006) reports a family in which the phenotypic features of 22q11 deletion syndrome segregate with an inactivating mutation of TBX1. One family member (of three with the mutation) has Asperger syndrome, an autistic spectrum disorder.

Krishnan Probability Score

Score 0.50100699646015

Ranking 2049/25841 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 0.98339678776606

Ranking 2029/18225 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 0.93257894456532

Ranking 12020/18665 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
Larsen Cumulative Evidence Score

Score 5

Ranking 294/461 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.
Original Source
Zhang D Score

Score -0.10957809252152

Ranking 12703/20870 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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