Human Gene Module / Chromosome 19 / BRD4

BRD4bromodomain containing 4

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
7 / 0
Aliases
BRD4, CAP,  HUNK1,  HUNKI,  MCAP
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
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).

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.

Reports related to BRD4 (4 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
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
- - copy_number_loss De novo NA Simplex 29379197 Olley G , et al. (2018)
c.878A>G p.Asp293Gly missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.1289A>G p.Tyr430Cys missense_variant De novo NA Simplex 29379197 Olley G , et al. (2018)
c.691del p.Asp231ThrfsTer9 frameshift_variant De novo NA Simplex 29379197 Olley G , et al. (2018)
c.651del p.Val218CysfsTer22 inframe_deletion De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.1224delinsCA p.Glu408AspfsTer4 frameshift_variant De novo NA Simplex 29379197 Olley G , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

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: Decreased from 4 to 3

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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]
4/1/2018
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.
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
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).
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.
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