Human Gene Module / Chromosome 20 / TAF4

TAF4TATA-box binding protein associated factor 4

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
16 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
20q13.33
Associated Disorders
-
Relevance to Autism

TAF4 was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were three de novo loss-of-function variants. An additional de novo missense variant in TAF4 was identified in an ASD proband from the Simons Simplex Collection (Werling et al., 2018). Janssen et al., 2022 presented a cohort of eight individuals with de novo putative loss-of-function variants in TAF4 and expressing phenotypes consistent with a neurodevelopmental syndrome, including speech delay, intellectual disability, behavioral abnormalities, and facial dysmorphisms; autism spectrum disorder was reported in one of these individuals, while autistic features were reported in two others.

Molecular Function

Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates these activities is transcription factor IID (TFIID), which binds to the core promoter to position the polymerase properly, serves as the scaffold for assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of evolutionarily conserved proteins known as TBP-associated factors or TAFs. TAFs may participate in basal transcription, serve as coactivators, function in promoter recognition or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. This gene encodes one of the larger subunits of TFIID that has been shown to potentiate transcriptional activation by retinoic acid, thyroid hormone and vitamin D3 receptors. In addition, this subunit interacts with the transcription factor CREB, which has a gluta

External Links
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Reports related to TAF4 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder Werling DM et al. (2018) Yes -
3 Recent Recommendation - Janssen BDE et al. (2022) No ASD or autistic features
4 Primary - Zhou X et al. (2022) Yes -
5 Support - More RP et al. (2023) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1960G>A p.Val654Met missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2549C>G p.Ala850Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1348C>T p.Gln450Ter stop_gained De novo - - 35904126 Janssen BDE et al. (2022)
c.2029C>T p.Gln677Ter stop_gained De novo - - 35904126 Janssen BDE et al. (2022)
c.2185C>T p.Gln729Ter stop_gained De novo - - 35904126 Janssen BDE et al. (2022)
c.2719C>T p.Gln907Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.2570_2571del p.Ser857Ter stop_gained De novo - - 35904126 Janssen BDE et al. (2022)
c.2971del p.Met991CysfsTer9 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.370G>C p.Ala124Pro missense_variant De novo - Multiplex 36702863 More RP et al. (2023)
c.900C>T p.Pro300%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1484C>G p.Pro495Arg missense_variant De novo - Simplex 29700473 Werling DM et al. (2018)
c.2453dup p.Asn818LysfsTer2 frameshift_variant De novo - - 35904126 Janssen BDE et al. (2022)
c.2664del p.Lys888AsnfsTer4 frameshift_variant De novo - - 35904126 Janssen BDE et al. (2022)
c.2375del p.Pro792LeufsTer3 frameshift_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3101_3102del p.Pro1034ArgfsTer36 frameshift_variant De novo - - 35904126 Janssen BDE et al. (2022)
c.3096_3097insCGAC p.Gly1033ArgfsTer39 frameshift_variant De novo - - 35904126 Janssen BDE et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
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.

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."

1/1/2023
S
icon
2S

Increased from S to 2S

Krishnan Probability Score

Score 0.51719247883425

Ranking 1734/25841 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 0.99948708567313

Ranking 939/18225 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
Iossifov Probability Score

Score 0.894

Ranking 153/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.30305354926673

Ranking 182/18665 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
Zhang D Score

Score 0.20672059661918

Ranking 4167/20870 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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