Human Gene Module / Chromosome X / BRWD3

BRWD3bromodomain and WD repeat domain containing 3

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 10
Rare Variants / Common Variants
25 / 0
Aliases
BRWD3, BRODL,  MRX93
Associated Syndromes
-
Chromosome Band
Xq21.1
Associated Disorders
ASD
Relevance to Autism

Variants in the BRWD3 gene are responsible for a form of X-linked intellectual disability associated with macrocephaly (Field et al., 2007; Tatton-Brown et al., 2017). A review of 17 males with 12 distinct null variants and 2 partial gene deletions in BRWD3 demonstrated that behavioral issues were present in 75% of patients, with ASD observed in 3 patients and shyness in social situations observed in another 3 patients (Ostrowski et al., 2019).

Molecular Function

The protein encoded by this gene contains a bromodomain and several WD repeats. It is thought to have a chromatin-modifying function, and may thus play a role in transcription.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to BRWD3 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly Field M , et al. (2007) No Macrocephaly
2 Support Mutations in Epigenetic Regulation Genes Are a Major Cause of Overgrowth with Intellectual Disability Tatton-Brown K , et al. (2017) No Macrocephaly
3 Recent Recommendation Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients Ostrowski PJ , et al. (2019) No ASD
4 Support - Hildebrand MS et al. (2020) No ASD, ADD, DD, ID
5 Support - Bruno LP et al. (2021) No -
6 Support - Wang Q et al. (2022) No -
7 Support - Carvalho LML et al. (2022) No -
8 Support - Hu C et al. (2022) Yes -
9 Support - Zhou X et al. (2022) Yes -
10 Support - Hosneara Akter et al. () No -
Rare Variants   (25)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 31714006 Ostrowski PJ , et al. (2019)
c.91-4T>C - splice_region_variant Unknown - - 35741772 Hu C et al. (2022)
c.766C>T p.Pro256Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3340G>A p.Glu1114Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2368C>T p.Gln790Ter stop_gained Unknown - - 31714006 Ostrowski PJ , et al. (2019)
c.451C>T p.Gln151Ter stop_gained Unknown - - 28475857 Tatton-Brown K , et al. (2017)
c.3718C>T p.Arg1240Ter stop_gained De novo - Multiplex 35266334 Wang Q et al. (2022)
c.3121A>C p.Asn1041His missense_variant Unknown - - 39342494 Hosneara Akter et al. ()
c.3977G>A p.Arg1326Gln missense_variant De novo - Simplex 34948243 Bruno LP et al. (2021)
c.451C>T p.Gln151Ter stop_gained Familial Maternal - 31714006 Ostrowski PJ , et al. (2019)
c.3976C>T p.Arg1326Ter stop_gained Familial Maternal - 31714006 Ostrowski PJ , et al. (2019)
c.568C>T p.Arg190Ter stop_gained Familial Maternal - 28475857 Tatton-Brown K , et al. (2017)
c.3602G>A p.Arg1201Lys splice_site_variant Unknown - - 28475857 Tatton-Brown K , et al. (2017)
c.2824A>G p.Met942Val missense_variant Familial Maternal - 32345733 Hildebrand MS et al. (2020)
c.2312dup p.Tyr771Ter frameshift_variant Unknown - Simplex 28475857 Tatton-Brown K , et al. (2017)
c.696T>A p.Tyr232Ter stop_gained Familial Maternal Multiplex 31714006 Ostrowski PJ , et al. (2019)
c.4487C>A p.Ser1496Ter stop_gained Familial Maternal Multiplex 31714006 Ostrowski PJ , et al. (2019)
c.696T>A p.Tyr232Ter stop_gained Familial Maternal Multiplex 28475857 Tatton-Brown K , et al. (2017)
c.3325+1G>T - splice_site_variant Familial Maternal Multi-generational 17668385 Field M , et al. (2007)
c.682dup p.Met228AsnfsTer4 frameshift_variant Familial Maternal Multiplex 17668385 Field M , et al. (2007)
c.3697_3699del p.Ile1233del inframe_deletion Familial Maternal Simplex 35597848 Carvalho LML et al. (2022)
c.2062_2064delinsCCAT p.Met688ProfsTer2 frameshift_variant Unknown - - 28475857 Tatton-Brown K , et al. (2017)
c.4601A>G p.His1534Arg missense_variant Familial Maternal Multi-generational 17668385 Field M , et al. (2007)
c.171del p.Phe57LeufsTer27 frameshift_variant Familial Maternal Simplex 31714006 Ostrowski PJ , et al. (2019)
c.447_451del p.Arg150IlefsTer5 frameshift_variant Familial Maternal Simplex 28475857 Tatton-Brown K , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Variants in the BRWD3 gene are responsible for a form of X-linked intellectual disability associated with macrocephaly (Field et al., 2007; Tatton-Brown et al., 2017). A review of 17 males with 12 distinct null variants and 2 partial gene deletions in BRWD3 demonstrated that behavioral issues were present in 75% of patients, with ASD observed in 3 patients and shyness in social situations observed in another 3 patients (Ostrowski et al., 2019).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

10/1/2019
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S

Score remained at S

New Scoring Scheme
Description

Variants in the BRWD3 gene are responsible for a form of X-linked intellectual disability associated with macrocephaly (Field et al., 2007; Tatton-Brown et al., 2017). A review of 17 males with 12 distinct null variants and 2 partial gene deletions in BRWD3 demonstrated that behavioral issues were present in 75% of patients, with ASD observed in 3 patients and shyness in social situations observed in another 3 patients (Ostrowski et al., 2019).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.47658345223711

Ranking 8477/25841 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 0.9999999959889

Ranking 121/18225 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 0.94666799007083

Ranking 16963/18665 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 0.17778071379027

Ranking 4645/20870 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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