Human Gene Module / Chromosome 10 / TCF7L2

TCF7L2Transcription factor 7-like 2 (T-cell specific, HMG-box)

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
10 / 14
Rare Variants / Common Variants
37 / 0
EAGLE Score
2.1
Limited Learn More
Aliases
TCF7L2, RP11-357H24.1,  TCF-4,  TCF4
Associated Syndromes
-
Chromosome Band
10q25.2-q25.3
Associated Disorders
DD/NDD, ADHD, ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768). 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 TCF7L2 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Dias et al., 2021 reported 11 individuals with de novo TCF7L2 variants presenting with a syndromic neurodevelopmental disorder; autism spectrum disorder was reported in four of these individuals.

Molecular Function

This gene encodes a high mobility group (HMG) box-containing transcription factor that plays a key role in the Wnt signaling pathway. The protein has been implicated in blood glucose homeostasis. Genetic variants of this gene are associated with increased risk of type 2 diabetes (Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]).

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 TCF7L2 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
4 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
5 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
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 Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes DD, ID
8 Recent Recommendation - Dias C et al. (2021) No ASD, ADHD, ID
9 Support - Woodbury-Smith M et al. (2022) Yes -
10 Recent Recommendation - Qi H et al. (2023) Yes -
11 Support - Wang J et al. (2023) Yes -
12 Support - Tuncay IO et al. (2023) Yes -
13 Support - Lukasz Mateusz Szewczyk et al. (2024) Yes -
14 Support - Siavash Fazel Darbandi et al. () Yes -
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1219C>T p.Arg407Ter stop_gained De novo - - 28135719 et al. (2017)
c.1319-636G>A - missense_variant De novo - - 33004838 Wang T et al. (2020)
c.451-1G>C - splice_site_variant De novo - - 33004838 Wang T et al. (2020)
c.881C>T p.Pro294Leu missense_variant De novo - - 28135719 et al. (2017)
c.1144C>T p.Gln382Ter stop_gained De novo - - 34003604 Dias C et al. (2021)
c.490G>A p.Gly164Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.526C>T p.Arg176Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.836C>T p.Pro279Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.866C>T p.Ser289Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1097C>A p.Ala366Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1211G>A p.Arg404Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1243C>G p.Pro415Ala missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1412G>T p.Arg471Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1643C>A p.Ser548Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1694C>A p.Ser565Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1763C>T p.Ser588Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1143C>G p.Asn381Lys missense_variant De novo - - 34003604 Dias C et al. (2021)
c.1268A>G p.Tyr423Cys missense_variant De novo - - 34003604 Dias C et al. (2021)
c.553-1G>A - splice_site_variant De novo - Simplex 34003604 Dias C et al. (2021)
c.875+1G>C - splice_site_variant De novo - Simplex 34003604 Dias C et al. (2021)
c.1269T>G p.Tyr423Ter stop_gained De novo - Simplex 34003604 Dias C et al. (2021)
c.685+1G>A - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1001+1G>A - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.971C>T p.Ser324Phe missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.595C>G p.Pro199Ala missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1143C>G p.Asn381Lys missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1427A>G p.Glu476Gly missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1142A>C p.Asn381Thr missense_variant De novo - Simplex 34003604 Dias C et al. (2021)
c.1250G>T p.Trp417Leu missense_variant De novo - Simplex 34003604 Dias C et al. (2021)
c.1267T>C p.Tyr423His missense_variant De novo - Simplex 34003604 Dias C et al. (2021)
c.552+49423C>T - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.787del p.Gln263SerfsTer22 frameshift_variant De novo - - 34003604 Dias C et al. (2021)
c.1804G>T p.Glu602Ter stop_gained Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.666C>T p.Ala222%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.536C>A p.Ser179Ter missense_variant Familial Both parents - 37492102 Tuncay IO et al. (2023)
c.660dup p.Pro221ThrfsTer107 frameshift_variant De novo - Simplex 34003604 Dias C et al. (2021)
c.1219C>T p.Arg407Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

4/1/2022
2
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1

Decreased from 2 to 1

4/1/2021
2
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2

Decreased from 2 to 2

Description

Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[De novo variants in TCF7L2 are associated with a syndromic neurodevelopmental disorder2021]
10/1/2020
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Prevalence and architecture of de novo mutations in developmental disorders2017] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[New Scoring Scheme]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants in the TCF7L2 gene (both splice-site) were identified in ASD probands from the Simons Simplex Collection (PMID 25363768).

Krishnan Probability Score

Score 0.49128103738989

Ranking 5670/25841 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 0.98960502908944

Ranking 1818/18225 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 0.0013288470924657

Ranking 20/18665 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 12

Ranking 164/461 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 -0.2514913543757

Ranking 16402/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Sp5 Sp5 transcription factor Rat DNA Binding 296510 A0A0G2JUC1
Wnt10a wingless-type MMTV integration site family, member 10A Rat DNA Binding 316527 D3ZRW5
Zfp24 zinc finger protein 24 Rat DNA Binding 360204 Q7TNK3
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