BRWD3

Chr XXLR

bromodomain and WD repeat domain containing 3

Also known as: BRODL, DCAF20, MRX93, XLID93

NCBI Gene: 254065ENSG00000165288UniProt: Q6RI45

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. Mutations in this gene are associated with a spectrum of cognitive disabilities and X-linked macrocephaly. This gene is also associated with translocations in patients with B-cell chronic lymphocytic leukemia. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked 93MIM #300659
XLR
290
ClinVar variants
36
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— BRWD3
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Gene-Disease Validity (ClinGen)
X-linked syndromic intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
36 Pathogenic / Likely Pathogenic· 138 VUS of 290 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.08LOEUF
pLI 1.000
Z-score 7.83
OE 0.03 (0.01–0.08)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
4.27Z-score
OE missense 0.54 (0.49–0.59)
369 obs / 682.9 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.03 (0.01–0.08)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.54 (0.49–0.59)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08
0≤1.21.6
LoF obs/exp: 2 / 75.4Missense obs/exp: 369 / 682.9Syn Z: -0.90

ClinVar Variant Classifications

290 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic7
VUS138
Likely Benign87
Benign24
Conflicting5
29
Pathogenic
7
Likely Pathogenic
138
VUS
87
Likely Benign
24
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
2
21
0
29
Likely Pathogenic
3
0
4
0
7
VUS
0
122
14
2
138
Likely Benign
0
12
25
50
87
Benign
1
5
12
6
24
Conflicting
—5
Total101417658290

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

BRWD3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

BRWD3-related intellectual developmental disorder

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked 93

MIM #300659

Molecular basis of disorder known

X-linked recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway.
Delanne J et al.·Eur J Med Genet
2023Review
Whole-genome sequencing identifies new candidate genes for nonobstructive azoospermia.
Malcher A et al.·Andrology
2022
DNA methylation analysis in patients with neurodevelopmental disorders improves variant interpretation and reveals complexity.
Trajkova S et al.·HGG Adv
2024Cohort
Variants in BRWD3 associated with X-linked partial epilepsy without intellectual disability.
Tian MQ et al.·CNS Neurosci Ther
2023
Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.
L'Erario FF et al.·Genes (Basel)
2025
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.·Am J Med Genet C Semin Med Genet
2019Cohort
MRX93 syndrome (BRWD3 gene): five new patients with novel mutations.
Tenorio J et al.·Clin Genet
2019Case report
Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly.
Grotto S et al.·Eur J Med Genet
2014Cohort
Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3.
Chen WY et al.·EMBO Rep
2015
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools