Intellectual Disability, X-linked 93 (MRX93 / XLID93; BRWD3-related XLID): Research Report

Target: MONDO:0010393 · Category: Mendelian · Report date: 2026-10-01

About the sources. Abstracts were pulled from PubMed E-utilities through a summarizing fetch tool. The abstracts for PMIDs 17668385, 24462886, 30628072, 31714006 and 36414205 came back in full and look verbatim. A few others were partly paraphrased: 16094372, 15543602, 26323392, 30086552, 38751117 and 40282429. Before any snippet goes into the KB, run just fetch-reference PMID:<id> and copy the quote from references_cache/. Inline quotation marks that the tool added inside some abstracts (e.g. in 37722046 and 25666827) are not part of the source. HPO, GO, CL, UBERON and NCIT IDs below were checked against this repo's cache/*/terms.csv unless marked [lookup needed].

Summary

• The disease. XLID93 is X-linked intellectual disability caused by hemizygous loss-of-function variants in BRWD3 (hgnc:17342, Xq21.1).
• Core features in males. Mild-to-moderate intellectual disability (ID), speech delay, postnatal macrocephaly, obesity and a recognizable face. The face includes a prominent or broad forehead, large or cupped ears, a tall or pointed chin and prognathism.
• "Non-syndromic" is a misnomer. OMIM/MONDO originally filed it as non-syndromic. The case series now describe a reproducible overgrowth–ID (OGID) syndrome.
• Size of the literature. About 45 published individuals (43 males, 2 females) in the 2023 meta-analysis (PMID:36414205). At least 5 females in total by 2026 (PMID:42298746).
• Mechanism (proposed). BRWD3 is a chromatin reader (two bromodomains plus WD40 repeats). It acts as a substrate receptor (DCAF) for the CUL4–DDB1 E3 ubiquitin ligase. Its best-characterized molecular functions come from Drosophila and cell work:
• degrading the H3K4 demethylase KDM5;
• restraining HIRA/YEM-mediated deposition of histone H3.3.
• What is not shown. No human tissue, iPSC or mouse study of the disease mechanism has been found.

1. Disease information

Overview. "In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3… Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability." (PMID:17668385, Field et al., Am J Hum Genet 2007; human clinical)

Identifiers

Synonyms (from the MONDO stub): MRX93; mental retardation, X-linked 93; intellectual developmental disorder, X-linked 93; intellectual disability / mental retardation, X-linked, with macrocephaly; BRWD3 non-syndromic X-linked ID; XMR93 syndrome; XLID-BRWD3-related syndrome.

Data basis. All information is aggregated from case series and case reports. There are no EHR or registry data.

Lump/split note for curators. The stub records entry_type: DISEASE, decided in dismech#12227. MRX93 was declined as a subtype row of Non-Syndromic_X-Linked_Intellectual_Disability because the phenotype is reproducibly syndromic.

2. Etiology

• Cause. Germline, hemizygous (males) loss-of-function variants in BRWD3:
• nonsense, frameshift and canonical-splice variants;
• intragenic or whole-gene deletions.
• Haploinsufficiency (loss of function) is the established mechanism. "Our patient confirms that the haploinsufficiency due to BRWD3 deletion is a causal genetic mechanism" (PMID:38813790; the 586 kb deletion contained only BRWD3).
• Inheritance pattern. "Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo." (PMID:36414205)
• Environmental risk or protective factors and gene–environment interactions. None reported; not applicable.
• Modifiers.
• X-inactivation skewing modifies severity in heterozygous females (PMID:42298746).
• Variant class or position may modify phenotype. Missense variants in the WD40 repeats and bromodomain have been associated with X-linked partial epilepsy without ID (PMID:36514184). This is a single Chinese cohort, all variants maternally inherited, so treat it as an allelic or uncertain association rather than XLID93 itself.

3. Phenotypes

The main frequency sources are: - (a) Grotto 2014, n = 9 (PMID:24462886); - (b) Ostrowski 2019, 17 males (PMID:31714006); - (c) Delanne 2023 meta-analysis, 43 males and 2 females (PMID:36414205).

Key quotes

• (a) "The main symptoms are mild to moderate intellectual disability (n = 9/9) with speech delay (n = 8/8), behavioral disturbances (n = 7/8), macrocephaly (n = 7/9), dysmorphic facial features (n = 9/9)…"
• (b) "Mean head circumference was +2.8 SD… and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype."
• (c) "The most common features in males… included ID (39/39 males), speech delay (24/25 males), postnatal macrocephaly (28/35 males) with prominent forehead (18/25 males) and large ears (14/26 males), and obesity (12/27 males)."

Onset, course and quality of life - Onset is congenital or infantile, recognized through developmental delay. Macrocephaly is postnatal. - The course is static (non-progressive neurodevelopmental). - No quality-of-life instrument data exist. The main burdens are the ID and the behavioral disorder.

Females. Across 5 reported females: developmental delay 60%, neurological signs 60%, OFC above the 95th centile 60%, facial features 40%. Overall they are milder than males, and severity tracks the direction of X-inactivation skewing (PMID:42298746). Most carrier mothers are asymptomatic (PMID:38813790).

4. Genetic and molecular information

Gene and protein. BRWD3 (Xq21.1), formerly BRODL, "bromo domain-containing protein disrupted in leukemia". The protein has eight WD40 repeats and two bromodomains (from the Drosophila ortholog ramshackle, PMID:16904300).

Variant spectrum. Delanne 2023 counted 33 different variants: - Ostrowski 2019 alone reported "17 males with 12 distinct null variants and 2 partial gene deletions" (PMID:31714006). - Specific examples: - p.Tyr1131* (PMID:24462886); - a de novo 74 kb deletion of exons 11–41 (PMID:24462886); - a 586 kb whole-gene deletion (PMID:38813790); - a de novo exon 21–30 deletion in a female (PMID:42298746). - One case has a mosaic variant (PMID:36414205).

Gene–disease validity classification - ClinGen rates BRWD3 Definitive for X-linked syndromic intellectual disability (MONDO:0020119), with loss of function as the mechanism (ClinGen/GenCC). - Under the repo's rules (Gene-Disease Validity Is Copied, Never Assigned), that assertion counts only if MONDO:0020119 is this entry's disease_term, a has_subtypes term, or an exactMatch mapping. Otherwise it is an other_disease case: cite it in notes and do not record it as a gene_disease_validity row without deciding entity identity first. - The CGGV: record is not yet cached in the repo.

Population frequency. Truncating variants are absent from controls: "No truncating variants were found in 520 control X chromosomes" (PMID:17668385). gnomAD constraint was not retrieved [lookup needed].

Copy-number events - Large Xq21.1 contiguous deletions that include BRWD3 cause a broader phenotype. One 5.8 Mb, 14-gene deletion also involved TBX22 and POU3F4, giving cleft palate and deafness (PMID:26323392). - A maternally inherited duplication of only BRWD3 is of uncertain significance (PMID:30086552).

Epigenetic biomarker. A BRWD3 episignature was reported as matched in one test case (PMID:38751117; partly paraphrased, so verify).

Somatic, not relevant to XLID93. BRWD3 was originally found disrupted by t(X;11)(q13;q23) in B-cell CLL (PMID:15543602).

5. Environmental information

Not applicable. There are no environmental, lifestyle or infectious factors.

6. Mechanism and pathophysiology

Ordered causal chain (steps 3–5 are model-system inferences, not shown in human neurons)

1. The lesion. A hemizygous BRWD3 null variant or deletion results in loss of BRWD3 protein. This step is demonstrated: the variants are truncating or deletions, and haploinsufficiency is accepted (PMID:31714006, 38813790).
2. Loss of the CRL4 adaptor. Loss of BRWD3 removes a substrate-specificity factor of the CUL4–DDB1 E3 ligase (Drosophila, PMID:23479607, 37722046).
3. Two chromatin branches.
4. (3a) KDM5 escapes BRWD3/CUL4-dependent K48-polyubiquitination and degradation. This leads to increased H3K4me1 and decreased H3K4me3 at BRWD3-bound sites. Drosophila cells; "depleting KDM5 fully restores altered H3K4me3 levels" (PMID:37722046).
5. (3b) Loss of negative regulation of HIRA/YEM leads to increased H3.3 deposition (Drosophila, PMID:25666827).
6. Transcriptional dysregulation. Steps 3a and 3b result in global transcriptional dysregulation. In fly mutants this causes defects in dendrite morphogenesis and sensory-organ differentiation that are suppressed by inactivating yem or H3.3 (PMID:25666827). This step is in vivo, but invertebrate.
7. Clinical outcome (inferred). Abnormal neuronal differentiation and dendritic morphogenesis are proposed to lead to intellectual disability, speech delay and behavioral disorder. No direct human evidence exists.
8. Growth branch (speculative).
9. BRWD3 sits in growth and proliferation pathways: it was a JAK/STAT-pathway hit in a Drosophila genome-wide RNAi screen (PMID:16094372). The fly gene dBRWD3 is also required for Polycomb-mutant tissue overgrowth (PMID:27588417).
10. DDB1–BRWD3 promotes adipogenic transcription; Ddb1+/- mice resist diet-induced obesity (PMID:34161765).
11. How loss of BRWD3 produces macrocephaly and obesity is unexplained. The adipogenesis data predict the opposite direction for obesity. Record this as a knowledge gap, not an edge.

Suggested terms (all in repo cache) - GO biological process: GO:0016567 protein ubiquitination; GO:0006511 ubiquitin-dependent protein catabolic process; GO:0006338 chromatin remodeling; GO:0006334 nucleosome assembly (for H3.3 deposition); GO:0006355 regulation of DNA-templated transcription; GO:0048813 dendrite morphogenesis; GO:0030182 neuron differentiation; GO:0007420 brain development; GO:0045444 fat cell differentiation. - GO terms not in cache: regulation of histone H3K4 methylation and JAK-STAT signaling [lookup needed]. - CL: CL:0000540 neuron; CL:0000598 pyramidal neuron (speculative); CL:0000136 adipocyte (only for the obesity hypothesis). - GO cellular component: nucleus / chromatin [lookup needed].

Not available: human transcriptomic, proteomic, metabolomic, single-cell or spatial data.

7. Anatomical structures

• Primary: brain (UBERON:0000955) and cerebral cortex (UBERON:0000956), presumed. No consistent MRI lesion has been reported.
• Secondary: skull and craniofacial structures (UBERON:0003129 skull), adipose tissue (UBERON:0001013), skeleton (spine, feet), testis/scrotum (cryptorchidism).
• Subcellular: nucleus and chromatin.
• Laterality: bilateral or systemic.

8. Temporal development

• Onset: congenital; delay is recognized in infancy or early childhood. Macrocephaly is postnatal (PMID:36414205), and obesity emerges in childhood.
• Course: non-progressive and lifelong. Index patients range up to adulthood (a 20-year-old in PMID:24462886).
• Stages, remission and natural history: no stages, no remission, no formal natural-history study.
• Critical period: early childhood, for speech and developmental intervention.

9. Inheritance and population

• Inheritance: X-linked recessive (HP:0001419) with occasional affected heterozygous females. Females are affected through skewed X-inactivation, and in one case through a de novo exon deletion (PMID:42298746, 36414205).
• Penetrance: apparently complete in hemizygous males. Heterozygous females are mostly unaffected (PMID:38813790).
• Expressivity: variable (ID mild versus moderate; macrocephaly in about 80% and obesity in about 44% of males).
• De novo rate: 9 of 28 variants with segregation data (32%). No anticipation, founder effect or consanguinity role.
• Germline mosaicism: not reported. One somatic-mosaic male is reported (PMID:36414205).
• Prevalence: unknown, about 45–50 published cases. Use measure_type: CASES_IN_LITERATURE, prevalence_class: ULTRA_RARE or NOT_YET_DOCUMENTED.
• Sex ratio: overwhelmingly male. Reports are worldwide: UK, Australia, USA, France, Spain, China.

10. Diagnostics

• Testing route: genotype-first. "BRWD3-related phenotypes are largely non-specific… A genotype-first approach, however, allows for the more efficient diagnosis" (PMID:36414205).
• Exome or genome sequencing; NCIT:C101295 Whole Exome Sequencing (in cache).
• XLID or overgrowth gene panels.
• Chromosomal microarray or array-CGH for deletions (PMID:24462886, 38813790).
• Exon-level CNV confirmation by qPCR (PMID:42298746).
• Females: X-inactivation testing is recommended (PMID:42298746).
• Episignature: DNA methylation analysis may help resolve VUS (PMID:38751117).
• Not diagnostic: no specific laboratory biomarker, imaging feature or electrophysiology finding.
• Differential diagnosis (OGID / macrocephaly-ID):
• PTEN hamartoma tumor syndrome;
• Sotos syndrome (NSD1);
• PPP2R5D-related disorder;
• fragile X syndrome (FMR1);
• Simpson-Golabi-Behmel syndrome;
• other XLID with macrocephaly.
• PMID:31714006 says BRWD3 should be in the OGID differential. In one macrocephaly-ASD panel cohort, PTEN and PPP2R5D dominated the diagnostic yield (PMID:40282429).
• Screening: no newborn screening. Cascade carrier testing of female relatives is indicated.

11. Outcome and prognosis

• Life expectancy: no reduction has been reported, and there are no mortality data.
• Morbidity: lifelong ID, behavioral disorders, and obesity-related comorbidity risk (inferred).
• Epilepsy: uncommon in males (about 10%) and drug-responsive in the allelic IPE cohort (PMID:36514184).
• Prognostic factors: severity of ID; in females, the direction of X-inactivation skewing (PMID:42298746).

12. Treatment

There is no disease-specific or targeted therapy, and no clinical trials were identified. Management is supportive:

Pharmacogenomic, gene, cell and RNA therapies: none.

13. Prevention

• Primary prevention: none.
• Genetic counseling and cascade testing: counsel families and test at-risk female relatives. A carrier mother has a 50% risk of an affected son. Prenatal diagnosis and PGT are available once the familial variant is known (PMID:38813790, 42298746).
• Tertiary prevention: weight management, and surveillance for seizures, behavior and scoliosis.

14. Other species

• No naturally occurring animal disease is known; no OMIA entry was found.
• Orthologs exist: Drosophila ramshackle / dBRWD3 (CG31132) and mouse Brwd3. [NCBI Gene IDs lookup needed]
• One donkey GWAS reports BRWD3 among body-size candidate genes (PMID:36926587; title only, weak).

15. Model organisms

Curation recommendations for the dismech entry

1. Phenotypes: use the cache-verified HP IDs above, with frequencies from PMID:36414205 and 31714006. Look up the ID mild/moderate terms and broad hand before binding them.
2. Pathophysiology:
3. Root node: BRWD3 loss of function (functional_impact_category: LOSS_OF_FUNCTION, hemizygous germline).
4. Two chromatin nodes: KDM5 accumulation / H3K4 methylation imbalance, and excess H3.3 deposition. Cite these as MODEL_ORGANISM / IN_VITRO with directness: INDIRECT.
5. A neuronal differentiation / dendrite node, leading to the ID phenotypes.
6. Leave macrocephaly and obesity mechanisms as a KNOWLEDGE_GAP discussion rather than edges.
7. Genetic: CAUSATIVE with hgnc:17342. Handle ClinGen per the other_disease rule: the assertion is against MONDO:0020119.
8. Allelic epilepsy (PMID:36514184): consider a notes caveat or a REFUTE/NO_EVIDENCE-style item rather than a subtype.
9. Prevalence: CASES_IN_LITERATURE, about 45 individuals (PMID:36414205).

Sources

• PubMed records: 17668385, 24462886, 30628072, 31714006, 36414205, 42298746, 38813790, 36514184, 37722046, 34161765, 25666827, 27588417, 23479607, 16904300, 16094372, 15543602, 26323392, 30086552, 38751117, 40282429
• HGNC BRWD3 REST record
• ClinGen Syndromic Disorders GCEP (PMC11601709)
• GenCC BRWD3 submission
• PanelApp Australia BRWD3
• DOID:0112045 (GlyCosmos)
• MalaCards MRX93
• NORD entry
• Southampton eprint of Ostrowski 2019

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

1 of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

• PMID:17668385: "In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3… Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability."
• closest text in source: "In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain-containing protein"
• PMID:36414205 (abstract only): "BRWD3-related phenotypes are largely non-specific… A genotype-first approach, however, allows for the more efficient diagnosis"
• closest text in source: "A genotype-first approach, however, allows for the more efficient diagnosis of the BRWD3-related nonsyndromic ID"

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• DOID:0112045 (4 mentions) - the report calls it "GlyCosmos"; DOID calls it non-syndromic X-linked intellectual disability 93
• HP:0000256 (1 mention) - the report calls it "Macrocephaly (postnatal; mean OFC +2.8 SD)"; HP calls it Macrocephaly
• HP:0001513 (1 mention) - the report calls it "Obesity (mean BMI +2.0 SD)"; HP calls it Obesity

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

• HP:0001382 (1 mention) - the report calls it "Joint hypermobility (small joints)"; HP calls it Joint hypermobility
• UBERON:0000955 (1 mention) - the report calls it "Primary: brain"; UBERON calls it brain**
• NCIT:C15302 (1 mention) - the report calls it "Physical therapy (hypotonia)"; NCIT calls it Physical Therapy