Human Gene Module / Chromosome 19 / BRD4

BRD4bromodomain containing 4

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 13
Rare Variants / Common Variants
28 / 0
Aliases
BRD4, CAP,  HUNK1,  HUNKI,  MCAP
Associated Syndromes
-
Chromosome Band
19p13.12
Associated Disorders
-
Relevance to Autism

A de novo in-frame deletion variant in the BRD4 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012; functional characterization in Korb et al., 2017 demonstrated that this variant prevented a Brd4-induced increase in spine formation in transfected neurons compared to wild-type Brd4, suggesting a loss-of-function effect. Korb et al., 2017 also demonstrated that Brd4 was upregulated in a mouse model of Fragile X syndrome (FXS), and that inhibition of Brd4 function by the inhibitor JQ1 alleviated many of the phenotypes associated with Fragile X syndrome that were observed in FXS mice. De novo missense variants in BRD4 have also been identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015). Jouret et al., 2022 reported 14 individuals with either point mutations or deletions affecting the BRD4 gene and found that microcephaly, initial global developmental delay, intellectual disability/learning disability, psychiatric disorders, and dysmorphic features were frequently observed phenotypes.

Molecular Function

BRD4 encodes a chromatin reader protein that recognizes and binds acetylated histones and plays a key role in transmission of epigenetic memory across cell divisions and transcription regulation. The protein encoded by the BRD4 gene remains associated with acetylated chromatin throughout the entire cell cycle and provides epigenetic memory for postmitotic G1 gene transcription by preserving acetylated chromatin status and maintaining high-order chromatin structure.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to BRD4 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Recent Recommendation Excess Translation of Epigenetic Regulators Contributes to Fragile X Syndrome and Is Alleviated by Brd4 Inhibition Korb E , et al. (2017) No -
4 Recent Recommendation BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome Olley G , et al. (2018) No Microcephaly, OCD
5 Support - Woodbury-Smith M et al. (2022) Yes -
6 Support - Farrelly LA et al. (2022) No -
7 Support - Jouret G et al. (2022) No Psychiatric disorders (SCZ, OCD), epilepsy/seizure
8 Support - Levchenko O et al. (2022) No -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Spataro N et al. (2023) Yes -
11 Support - Cirnigliaro M et al. (2023) Yes -
12 Support - Noor Smal et al. () No -
13 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 35470444 Jouret G et al. (2022)
- - missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
- - copy_number_loss De novo - Simplex 29379197 Olley G , et al. (2018)
c.1267C>T p.Arg423Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.883A>C p.Thr295Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2272C>A p.Pro758Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2692C>A p.Pro898Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.434A>G p.Asp145Gly missense_variant Unknown - - 35470444 Jouret G et al. (2022)
c.2239C>T p.Gln747Ter stop_gained De novo - - 39039281 Axel Schmidt et al. (2024)
c.3798G>A p.Glu1266%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.703C>T p.Gln235Ter stop_gained De novo - Simplex 35470444 Jouret G et al. (2022)
c.878A>G p.Asp293Gly missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.883A>C p.Thr295Pro missense_variant De novo - Simplex 35470444 Jouret G et al. (2022)
c.1292A>T p.Lys431Met missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1289A>G p.Tyr430Cys missense_variant De novo - Simplex 29379197 Olley G , et al. (2018)
c.1169A>G p.Tyr390Cys missense_variant De novo - Simplex 35470444 Jouret G et al. (2022)
c.1289A>G p.Tyr430Cys missense_variant De novo - Simplex 35470444 Jouret G et al. (2022)
c.662C>T p.Thr221Met missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.137dup p.Pro47AlafsTer8 frameshift_variant De novo - Simplex 35470444 Jouret G et al. (2022)
c.2872dup p.Leu958ProfsTer135 frameshift_variant De novo - Simplex 38965372 Noor Smal et al. ()
c.691del p.Asp231ThrfsTer9 frameshift_variant De novo - Simplex 29379197 Olley G , et al. (2018)
c.691del p.Asp231ThrfsTer9 frameshift_variant De novo - Simplex 35470444 Jouret G et al. (2022)
c.651del p.Val218CysfsTer22 inframe_deletion De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.3169+1G>A - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1224delinsCA p.Glu408AspfsTer4 frameshift_variant De novo - Simplex 29379197 Olley G , et al. (2018)
c.2753_2754insT p.Pro919ThrfsTer174 frameshift_variant De novo - Simplex 35470444 Jouret G et al. (2022)
c.3666_3667insCAGCTTC p.Ser1223GlnfsTer18 frameshift_variant Unknown - Unknown 35887114 Levchenko O et al. (2022)
c.3693_3694insTCGGGAGAAAGAGGAGC p.Arg1232SerfsTer16 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo in-frame deletion variant in the BRD4 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012; functional characterization in Korb et al., 2017 demonstrated that this variant prevented a Brd4-induced increase in spine formation in transfected neurons compared to wild-type Brd4, suggesting a loss-of-function effect. Korb et al., 2017 also demonstrated that Brd4 was upregulated in a mouse model of Fragile X syndrome (FXS), and that inhibition of Brd4 function by the inhibitor JQ1 alleviated many of the phenotypes associated with Fragile X syndrome that were observed in FXS mice. De novo missense variants in BRD4 have also been identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015).

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo in-frame deletion variant in the BRD4 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012; functional characterization in Korb et al., 2017 demonstrated that this variant prevented a Brd4-induced increase in spine formation in transfected neurons compared to wild-type Brd4, suggesting a loss-of-function effect. Korb et al., 2017 also demonstrated that Brd4 was upregulated in a mouse model of Fragile X syndrome (FXS), and that inhibition of Brd4 function by the inhibitor JQ1 alleviated many of the phenotypes associated with Fragile X syndrome that were observed in FXS mice. De novo missense variants in BRD4 have also been identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo in-frame deletion variant in the BRD4 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012; functional characterization in Korb et al., 2017 demonstrated that this variant prevented a Brd4-induced increase in spine formation in transfected neurons compared to wild-type Brd4, suggesting a loss-of-function effect. Korb et al., 2017 also demonstrated that Brd4 was upregulated in a mouse model of Fragile X syndrome (FXS), and that inhibition of Brd4 function by the inhibitor JQ1 alleviated many of the phenotypes associated with Fragile X syndrome that were observed in FXS mice. De novo missense variants in BRD4 have also been identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2017
icon
4

Increased from to 4

Description

A de novo in-frame deletion variant in the BRD4 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012; functional characterization in Korb et al., 2017 demonstrated that this variant prevented a Brd4-induced increase in spine formation in transfected neurons compared to wild-type Brd4, suggesting a loss-of-function effect. Korb et al., 2017 also demonstrated that Brd4 was upregulated in a mouse model of Fragile X syndrome (FXS), and that inhibition of Brd4 function by the inhibitor JQ1 alleviated many of the phenotypes associated with Fragile X syndrome that were observed in FXS mice. De novo missense variants in BRD4 have also been identified in ASD probands from the Simons Simplex Collection (Krumm et al., 2015).

Krishnan Probability Score

Score 0.49648019290963

Ranking 2590/25841 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 0.99999344625469

Ranking 417/18225 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
Sanders TADA Score

Score 0.94899632177504

Ranking 17911/18665 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 0.29928752652742

Ranking 2752/20870 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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