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Intellectual disability
Gene: TAF4

TAF4 (TATA-box binding protein associated factor 4)
EnsemblGeneIds (GRCh38): ENSG00000130699
EnsemblGeneIds (GRCh37): ENSG00000130699
OMIM: 601796, Gene2Phenotype
TAF4 is in 2 panels

5 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Created: 11 Oct 2023, 9:34 a.m. | Last Modified: 11 Oct 2023, 9:34 a.m.

Panel Version: 5.286

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Created: 11 Oct 2023, 9:34 a.m.
Last Modified: 11 Oct 2023, 9:34 a.m.
Panel version: 5.286

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There is sufficient evidence available to promote this gene to GREEN rating at the next major update.
Created: 22 May 2023, 3:50 p.m. | Last Modified: 22 May 2023, 5:29 p.m.

Panel Version: 5.152

There are eight unrelated cases with intellectual disability (one each with severe, moderate and mild to moderate, while the severity was unknown for others) and an additional case that was intellectually slightly delayed with uneven cognitive profile. In addition, PMID:28191890 reported a child with autism.

This gene has been associated with neurodevelopmental disorder in Gene2Phenotype (with 'limited' rating in the DD panel), but not yet associated with phenotypes in OMIM.
Created: 22 May 2023, 1:42 p.m. | Last Modified: 22 May 2023, 1:42 p.m.

Panel Version: 5.145

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
intellectual disability, MONDO:0001071

Publications

Created: 22 May 2023, 1:42 p.m.
Last Modified: 22 May 2023, 5:29 p.m.
Panel version: 5.145

Konstantinos Varvagiannis (Other)

Green List (high evidence)

In a recent study, Janssen et al (2022 - PMID: 35904126) describe the phenotype of 8 unrelated individuals with de novo pLoF TAF4 variants.

Overlapping features included speech delay (in 7/8), ID (7/8), behavioral abnormalities (6/8), joint laxity (4/8), spine anomalies (3/8), brain MRI abnrmalities (3/5). Mild non-specific/recognizable facial features were observed.

All 8 individuals were investigated with trio-ES/GS and harbored harbored de novo pLoF (nonsense / frameshift) TAF4 variants with no other SNVs/CNVs explaining their phenotype.

TAF4 encodes TATA-binding protein associated factor 4, a subunit of the transcription factor IID complex, which has a central role in transcription initiation.

TAF4 participates in the formation of a subcomplex with TAF12 (TAF4-TAF12 dimerization mediated by the C-terminal domain of TAF4), TAF5, TAF6 and TAF9. As the TFIID complex has 3 main lobes (A,B,C) with the TAF4/5/6/9/12 complex participating in A and B, TFIID contains 2 copies of TAF4.

In gnomAD TAF4 has a pLI score of 1, o/e : 0, LOEUF : 0.08.

Among the 8 different variants reported, 6 are expected to lead to NMD while 2 further localize in the last exon (15/15 - NM_003185.3) leading presumably to a truncated protein. This C-terminal domain is however important for TAF4-TAF12 dimerization essential for the TFIID complex.

Comparison with other disorders caused by mutation in genes encoding other TFIID complex members (incl. TAF1, TAF2, TAF6, TAF13) revealed that all TAF-opathies all share ID as a feature.
Created: 18 Aug 2022, 9:06 a.m. | Last Modified: 18 Aug 2022, 9:06 a.m.

Panel Version: 3.1677

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Delayed speech and language development; Intellectual disability; Behavioral abnormality; Joint laxity; Abnormality of the vertebral column; Abnormality of nervous system morphology; Abnormality of head or neck

Publications

35904126

Created: 18 Aug 2022, 9:06 a.m.
Last Modified: 18 Aug 2022, 9:06 a.m.
Panel version: 3.1677

Eleanor Williams (Genomics England Curator)

Comment on list classification: Promoting this gene from grey to amber. There are 3 cases reported but in one the phenotype is reported as autism, and in the other two there is no information as to the severity. The mouse knockout shows there is an effect of loss of TAF4 but the phenotype is perhaps not specific enough to add weight to rating of this gene for intellectual disability.
Created: 10 Aug 2022, 3:04 p.m. | Last Modified: 10 Aug 2022, 3:04 p.m.

Panel Version: 3.1666

Not associated with a phenotype in OMIM or Gene2Phenotype.

PMID: 33875846 - Bertoli-Avella et al 2021 - identified two de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and one with intellectual disability and one with delayed speech and language development with global developmental delay.

PMID: 28191890 - Kosmicki et al 2017 - report a child with autism with an indel in TAF4 leading to a frameshift. No phenotypic details provided.

PMID: 27026076 - Langer et al 2016 - Taf4a−/− (gene encoding Taf4) mouse embryos survive until E9.5, but show severe growth retardation and specific defects in anterior and ventral patterning and morphogenesis.
Created: 10 Aug 2022, 3 p.m. | Last Modified: 10 Aug 2022, 3 p.m.

Panel Version: 3.1662

This panel reflects the DD panel in the Gene2Phenotype resource. This gene is not currently listed there.
This gene will be copied to the PanelApp Intellectual disability panel (285) and reviewed for inclusion there.
Created: 10 Aug 2022, 2:29 p.m. | Last Modified: 10 Aug 2022, 2:29 p.m.

Panel Version: 2.78

Created: 10 Aug 2022, 2:29 p.m.
Last Modified: 10 Aug 2022, 2:29 p.m.
Copied from panel: DDG2P v2.78

Dmitrijs Rots (Children's Clinical University Hospital)

Green List (high evidence)

From the literature:
"A heterozygous de novo variant (frameshift) was reported in TAF4 by Kosmicki et al., in a patient with autism.36 The gene has no phenotypic association in OMIM (accessed 12 October 2020). Within this study, we identified two additional de novo LoF variants (splicing and nonsense) in two unrelated patients with dysmorphic features and NDD. TAF4 is highly intolerant to LoF as documented in gnomAD (pLi = 1). Expression of TAF4 varies during development and in the processes of cell differentiation; TAF4 is detected in various regions of the human brain, and it is believed to control the differentiation of human neural progenitor cells having a role in the regulation of neural development and brain function.37 The current data suggests that TAF4 haploinsufficiency leads to NDD in humans."
Sources: Literature
Created: 30 Oct 2021, 11:45 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Developmental delay

Publications

33875846

Created: 30 Oct 2021, 11:45 a.m.

Copied from panel: DDG2P v2.78

Details

Mode of Inheritance

MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Sources

Expert Review Green
NHS GMS
Literature

Phenotypes

Intellectual developmental disorder, autosomal dominant 73, OMIM:620450

OMIM

601796

Clinvar variants

Variants in TAF4

Penetrance

unknown

Publications

Panels with this gene

History Filter Activity

11 Oct 2023, Gel status: 3

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: TAF4 were changed from intellectual disability, MONDO:0001071 to Intellectual developmental disorder, autosomal dominant 73, OMIM:620450

11 Oct 2023, Gel status: 3

Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_23_promote_green was removed from gene: TAF4.

11 Oct 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source NHS GMS was added to TAF4. Source Expert Review Green was added to TAF4. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

22 May 2023, Gel status: 2