Human Gene Module/ Chromosome 10 /TCF7L2
TCF7L2Transcription factor 7-like 2 (T-cell specific, HMG-box)
SFARI Gene Score
1Autism Reports / Total Reports
10 / 14Rare Variants / Common Variants
37 / 0EAGLE Score
2.1Aliases
TCF7L2, RP11-357H24.1, TCF-4, TCF4Associated Syndromes
-Chromosome Band
10q25.2-q25.3Associated Disorders
DD/NDD, ADHD, ID, ASDGenetic Category
Rare Single Gene Mutation, Syndromic, FunctionalRelevance 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
SFARI Genomic Platforms
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.666C>T | p.Ala222= | synonymous_variant | Unknown | - | - | 35205252 | Woodbury-Smith M et al. (2022) | |
| c.1804G>T | p.Glu602Ter | stop_gained | Familial | Paternal | Simplex | 30564305 | Guo H , et al. (2018) | |
| 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 at1
criteria met
See SFARI Gene'scoring criteriaWe 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
1
Decreased from2 to1
4/1/2021
2
2
Decreased from2 to2
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).
10/1/2020
2
2
Decreased from2 to2
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).
1/1/2020
2
2
Decreased from2 to2
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).
10/1/2019
3
2
Decreased from3 to2
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
3
Decreased from3 to3
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).
10/1/2014
3
Increased from to3
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
Score0.49128103738989
Ranking5670/25841 scored genes
[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learningapproach on a human brain-specific gene network. The method was first presented in NatNeurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessedin 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 atasd.princeton.edu.
ExAC Score
Score0.98960502908944
Ranking1818/18225 scored genes
[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that hasbeen widely used to estimate 'constraint' on mutation for individual genes. It was introduced byLek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found atexac.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 ofpLI scores see:ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cleaned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score
Score0.0013288470924657
Ranking20/18665 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
Score12
Ranking164/461 scored genes
[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all availableASD-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 Autism7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 fromthat paper.
Zhang D Score
Score-0.2514913543757
Ranking16402/20870 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 withevidence from cell-type- specific gene expression in the mouse brain (specifically translationalprofiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes withpositive D scores are more likely to be associated with autism risk, with higher-confidence geneshaving 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 insupplementary table 2 from that paper.
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 |