Human Gene Module / Chromosome 22 / TCF20

TCF20Transcription factor 20 (AR1)

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 8
Rare Variants / Common Variants
16 / 0
Aliases
TCF20, RP4-669P10.13-001,  AR1,  SPBP,  TCF-20
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
22q13.2
Associated Disorders
ASD
Relevance to Autism

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD.

Molecular Function

Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression. It stimulates the activity of various transcriptional activators such as JUN, SP1, PAX6 and ETS1, suggesting a function as a coactivator.

Reports related to TCF20 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder. Babbs C , et al. (2014) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Johnson MR , et al. (2015) No -
4 Support De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth. Schfgen J , et al. (2016) No ASD
5 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
6 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
7 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
8 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion De novo - Multiplex 25228304 Babbs C , et al. (2014)
c.1534A>G p.Lys512Glu missense_variant De novo - Extended multiplex 25228304 Babbs C , et al. (2014)
c.4670C>T p.Pro1557Leu missense_variant Familial Maternal Simplex 25228304 Babbs C , et al. (2014)
c.4670C>T p.Pro1557Leu missense_variant Familial Paternal Simplex 25228304 Babbs C , et al. (2014)
c.4670C>T p.Pro1557Leu missense_variant Familial Paternal Multiplex 25228304 Babbs C , et al. (2014)
c.3518delA p.Lys1173ArgfsTer5 frameshift_variant De novo - Simplex 25228304 Babbs C , et al. (2014)
c.5719C>T p.Arg1907Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.955C>T p.Gln319Ter stop_gained De novo - Simplex 27436265 Schfgen J , et al. (2016)
c.3837del p.Asp1280IlefsTer71 frameshift_variant De novo - Simplex 27436265 Schfgen J , et al. (2016)
c.5164_5173del p.Gly1722fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.385C>T p.Gln129Ter stop_gained De novo - - 27479843 Lelieveld SH , et al. (2016)
c.2497C>T p.Gln833Ter stop_gained De novo - - 27479843 Lelieveld SH , et al. (2016)
c.889_890del p.Met297fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
G>A - stop_gained De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.3889_3890insT p.Asn1297fs frameshift_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.5385_5386delTG p.Cys1795Trpfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

2

Strong Candidate

See all Category 2 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.

4/1/2017
3
icon
2

Decreased from 3 to 2

Description

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD. Another de novo LoF variant in TCF20 was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017

7/1/2016
icon
3

Increased from to 3

Description

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD.

Krishnan Probability Score

Score 0.49542793257762

Ranking 2978/25841 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 0.99997793427612

Ranking 517/18225 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
Sanders TADA Score

Score 0.93819201144901

Ranking 13779/18665 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 17.5

Ranking 118/461 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 0.49115183504

Ranking 582/20870 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 TCF20(1 CNVs)
22q13.2 15 Deletion-Duplication 27  /  110
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