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BRWD3
bromodomain and WD repeat domain containing 3
BRWD3 is located on the long (q) arm of chromosome X, at band Xq21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
BRWD3 (bromodomain and WD repeat domain containing 3) is located on the X chromosome and encodes a large protein of 1,802 amino acids. The BRWD3 protein contains multiple structural domains that facilitate binding to chromatin, the complex of DNA and proteins that packages genetic material in cells. This gene is clinically significant in the context of neurodevelopmental disorders. Pathogenic changes in BRWD3 follow an X-linked inheritance pattern, meaning that males who carry a single variant copy are typically more severely affected than females, who possess two X chromosomes and may have milder or variable features. BRWD3 appears on several UK NHS Genomic Medicine Service gene panels related to intellectual disability and developmental disorders, reflecting its recognised role in clinical genomics.
What the gene does
The BRWD3 protein functions as a chromatin-binding regulator that influences how genes are switched on or off during development. Bromodomains recognise specific chemical modifications on histone proteins, which are the structural scaffolds around which DNA wraps. By binding to these modified histones, BRWD3 is thought to participate in the recruitment or stabilisation of protein complexes that control gene expression. The WD repeat domains form a propeller-like structure that typically mediates protein-protein interactions, allowing BRWD3 to serve as a platform for assembling multi-component regulatory machinery. Research suggests that BRWD3 may contribute to maintaining appropriate gene expression programmes during brain development, though the precise molecular pathways remain under investigation. Disruption of this regulatory function is believed to underlie the neurodevelopmental features observed when the gene is altered.
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Chromosome location
BRWD3 is located on the long arm of the X chromosome at position Xq21.1. This chromosomal region has been mapped through cytogenetic and molecular studies, and the gene's position on the X chromosome accounts for its X-linked inheritance pattern. The genomic structure and transcript organisation of BRWD3 have been characterised, revealing a complex gene capable of encoding a substantial protein product.
Protein structure
The BRWD3 protein is organised into distinct functional regions. The N-terminal portion contains eight WD repeats (WD 1 through WD 8, spanning approximately amino acids 170 to 542), which typically fold into a beta-propeller structure that facilitates interaction with other proteins. The protein also contains two bromodomains: Bromo 1 (amino acids 1138 to 1245) and Bromo 2 (amino acids 1300 to 1430). These bromodomains are specialised modules that recognise acetylated lysine residues on histone tails, enabling BRWD3 to bind chromatin in a modification-dependent manner. Interspersed throughout the sequence are several disordered regions (amino acids 768 to 910, 1262 to 1292, 1326 to 1361, 1438 to 1500, and 1520 to 1725), which may confer flexibility and allow the protein to adopt multiple conformations or interact dynamically with regulatory partners.
Key variants
Pathogenic variants in BRWD3 have been identified in individuals with neurodevelopmental conditions, particularly intellectual disability. Because BRWD3 is located on the X chromosome, males who inherit a variant typically express the associated phenotype, while carrier females may show variable features depending on X-inactivation patterns. Variants include missense changes, truncating mutations, and deletions that disrupt the protein's ability to interact with chromatin or regulatory complexes.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.2248C>T | p.Arg750Ter | Pathogenic | ★★☆☆ | not provided |
c.3413G>A | p.Trp1138Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neurodevelopmental disorder |
c.3718C>T | p.Arg1240Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability, X-linked 93 |
c.5080C>T | p.Arg1694Ter | Pathogenic | ★★☆☆ | not provided |
c.665_666del | p.Ser222fs | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability, X-linked 93 |
c.1897C>T | p.Gln633Ter | Pathogenic | ★☆☆☆ | Intellectual disability, X-linked 93 |
c.2620C>T | p.Gln874Ter | Pathogenic | ★☆☆☆ | Intellectual disability, X-linked 93 |
c.3119del | p.Tyr1040fs | Pathogenic | ★☆☆☆ | Intellectual disability, X-linked 93 |
c.3254_3255insAGGA | p.Tyr1085Ter | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
c.4225A>T | p.Lys1409Ter | Pathogenic | ★☆☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
BRWD3-related conditions primarily involve intellectual disability and developmental delay. Males with pathogenic BRWD3 variants may present with cognitive impairment, speech and language difficulties, and behavioural features. The severity and range of features can vary, and female carriers may exhibit milder manifestations or remain asymptomatic. The neurodevelopmental impact is thought to arise from disrupted gene regulation during critical periods of brain development.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic BRWD3 variants typically follow x-linked inheritance.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
UK clinical status
BRWD3 is included on several UK NHS Genomic Medicine Service gene panels. It appears on the Intellectual disability panel (rated green, R29 eligibility), the DDG2P panel (green), and the Beckwith-Wiedemann syndrome and other congenital overgrowth disorders panel (green). A green rating indicates that there is strong evidence linking variants in this gene to the associated conditions, and testing may be considered in appropriate clinical contexts. Referrals for genetic testing through the NHS typically require assessment by a clinical genetics service or relevant specialist.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the BRWD3 gene do?
BRWD3 encodes a protein that binds to chromatin and helps regulate gene expression. It contains bromodomains that recognise chemical marks on histones and WD repeats that facilitate protein interactions, together enabling the protein to influence which genes are active during development.
How is BRWD3-related intellectual disability inherited?
BRWD3-related conditions follow an X-linked inheritance pattern. Males who inherit a pathogenic variant are typically more severely affected, while females who carry one variant copy may have milder features or be unaffected due to the presence of a second, functional X chromosome.
Is BRWD3 tested on the NHS in the UK?
Yes, BRWD3 is included on NHS gene panels for intellectual disability and developmental disorders. Testing is usually accessed through referral to clinical genetics services, where a specialist will assess whether genetic testing is appropriate based on clinical features and family history.