Human Gene Module / Chromosome 22 / TCF20

TCF20Transcription factor 20 (AR1)

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
4 / 11
Rare Variants / Common Variants
71 / 0
Aliases
TCF20, RP4-669P10.13-001,  AR1,  SPBP,  TCF-20
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
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 (11 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 -
9 Recent Recommendation Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature. Torti E , et al. (2019) No ASD or autistic features
10 Recent Recommendation De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impai... Vetrini F , et al. (2019) No ASD
11 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
Rare Variants   (71)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 30819258 Vetrini F , et al. (2019)
- - inversion De novo NA Multiplex 25228304 Babbs C , et al. (2014)
- - copy_number_loss De novo NA - 30819258 Vetrini F , et al. (2019)
G>A - stop_gained De novo NA Simplex 28263302 C Yuen RK et al. (2017)
c.697C>T p.Gln233Ter stop_gained De novo NA - 30739909 Torti E , et al. (2019)
c.5655+1G>A - splice_site_variant Unknown - - 30819258 Vetrini F , et al. (2019)
c.2155C>T p.Arg719Ter stop_gained De novo NA - 30739909 Torti E , et al. (2019)
c.2594C>G p.Ser865Ter stop_gained De novo NA - 30739909 Torti E , et al. (2019)
c.4774C>T p.Gln1592Ter stop_gained De novo NA - 30739909 Torti E , et al. (2019)
c.4786C>T p.Arg1596Ter stop_gained De novo NA - 30739909 Torti E , et al. (2019)
c.3027T>A p.Tyr1009Ter stop_gained Unknown - - 30819258 Vetrini F , et al. (2019)
c.3027T>A p.Tyr1009Ter stop_gained De novo NA - 30819258 Vetrini F , et al. (2019)
c.3805C>T p.Gln1269Ter stop_gained De novo NA - 30819258 Vetrini F , et al. (2019)
c.5719C>T p.Arg1907Ter stop_gained De novo NA - 30819258 Vetrini F , et al. (2019)
c.385C>T p.Gln129Ter stop_gained De novo NA - 27479843 Lelieveld SH et al. (2016)
c.2497C>T p.Gln833Ter stop_gained De novo NA - 27479843 Lelieveld SH et al. (2016)
c.5725C>T p.His1909Tyr missense_variant De novo NA - 30739909 Torti E , et al. (2019)
c.5129A>G p.Lys1710Arg missense_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.955C>T p.Gln319Ter stop_gained De novo NA Simplex 27436265 Schfgen J , et al. (2016)
c.2224C>T p.Arg742Ter stop_gained De novo NA Multiplex 30739909 Torti E , et al. (2019)
c.1960C>T p.Gln654Ter stop_gained Unknown Not maternal - 30739909 Torti E , et al. (2019)
c.2883C>G p.Tyr961Ter stop_gained Unknown Not maternal - 30739909 Torti E , et al. (2019)
c.988C>T p.Gln330Ter stop_gained Unknown Not maternal - 30819258 Vetrini F , et al. (2019)
c.364dup p.Gln122ProfsTer12 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.622del p.Leu208TyrfsTer19 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.1707del p.Arg570AspfsTer37 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.3486dup p.Cys1163LeufsTer5 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.3605dup p.Pro1203SerfsTer15 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.3760dup p.Arg1254LysfsTer14 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.4943del p.Thr1648LysfsTer13 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.5352del p.Arg1785GlyfsTer97 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.594dup p.Gly199TrpfsTer56 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.1520del p.Pro507LeufsTer5 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.5537del p.Pro1846LeufsTer36 frameshift_variant Unknown - - 30819258 Vetrini F , et al. (2019)
c.4894del p.Tyr1632ThrfsTer6 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.5430dup p.Ala1811SerfsTer4 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.2260C>T p.Gln754Ter stop_gained Familial Maternal Simplex 30819258 Vetrini F , et al. (2019)
c.932_933del p.Gln311ArgfsTer22 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.3379del p.Gln1127SerfsTer10 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.4231dup p.Glu1411GlyfsTer33 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.4549dup p.Asp1517GlyfsTer30 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.5570dup p.Cys1858LeufsTer58 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.2088_2089del p.Glu697AlafsTer2 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.4741_4742del p.Arg1581AlafsTer30 frameshift_variant Unknown - - 30739909 Torti E , et al. (2019)
c.1208T>A p.Val403Glu missense_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.1810_1811del p.Val604TrpfsTer21 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
c.5385_5386del p.Cys1795TrpfsTer14 frameshift_variant De novo NA - 30739909 Torti E , et al. (2019)
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.2327_2328del p.Gln776ArgfsTer5 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.5652_5653del p.Glu1884AspfsTer31 frameshift_variant Unknown - - 30819258 Vetrini F , et al. (2019)
c.889_890del p.Met297GlufsTer4 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.3518del p.Lys1173ArgfsTer5 frameshift_variant De novo NA Simplex 25228304 Babbs C , et al. (2014)
c.4670C>T p.Pro1557Leu missense_variant Familial Paternal Multiplex 25228304 Babbs C , et al. (2014)
c.1534A>G p.Lys512Glu missense_variant De novo NA Extended multiplex 25228304 Babbs C , et al. (2014)
c.5385_5386del p.Cys1795TrpfsTer14 frameshift_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.3633_3634insGT p.Tyr1212ValfsTer13 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.5511_5512insGC p.Leu1838AlafsTer45 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.5529_5530insTG p.Glu1844TrpfsTer39 frameshift_variant De novo NA - 30819258 Vetrini F , et al. (2019)
c.3837del p.Asp1280IlefsTer71 frameshift_variant De novo NA Simplex 27436265 Schfgen J , et al. (2016)
c.3889_3890insT p.Asn1297IlefsTer17 frameshift_variant De novo NA - 28333917 Vissers LE , et al. (2017)
c.5164_5173del p.Gly1722IlefsTer157 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.5719C>T p.Arg1907Ter stop_gained De novo NA - 25533962 Deciphering Developmental Disorders Study (2014)
c.3605dup p.Pro1203SerfsTer15 frameshift_variant Unknown Not maternal - 30819258 Vetrini F , et al. (2019)
c.2512_2515del p.Asp838IlefsTer9 frameshift_variant Unknown Not maternal - 30739909 Torti E , et al. (2019)
c.3943_3944del p.Asp1315PhefsTer10 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.3292_3293insT p.Lys1098IlefsTer33 frameshift_variant De novo NA Simplex 31981491 Satterstrom FK et al. (2020)
c.311_312insCACC p.Gln105ThrfsTer30 frameshift_variant Familial Maternal Simplex 30819258 Vetrini F , et al. (2019)
c.3803_3804del p.Arg1268ThrfsTer9 frameshift_variant Unknown Not maternal Multiplex 30739909 Torti E , et al. (2019)
c.2685del p.Arg896GlyfsTer9 frameshift_variant Familial Maternal Multi-generational 30819258 Vetrini F , et al. (2019)
c.5732del p.Pro1911ArgfsTer17 frameshift_variant Familial Paternal Multi-generational 30819258 Vetrini F , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%).

Score Delta: Score remained at 2S

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.

1/1/2020
2S
icon
2S

Score remained at 2S

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. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%).

10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
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. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%).

Reports Added
[New Scoring Scheme]
1/1/2019
2
icon
2S

Decreased from 2 to 2S

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. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%).

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.
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