Intellectual Disability X-linked 93

Mendelian MONDO:0010393 Pathograph 10 Show in embeddings browser hereditary disease X-linked intellectual disability

Intellectual disability, X-linked 93 (MRX93, XLID93) is the X-linked neurodevelopmental disorder caused by loss-of-function variants in BRWD3, a bromodomain and WD40-repeat protein encoded at Xq21.1. Affected individuals are overwhelmingly hemizygous males carrying stop-gain, frameshift or canonical splice variants or partial or whole-gene deletions, most often inherited from an unaffected carrier mother and less often de novo. Although MONDO files it under non-syndromic X-linked intellectual disability, the published series describe a recognisable syndrome: mild-to-moderate intellectual disability with speech delay, postnatal macrocephaly (mean head circumference about +2.8 SD), a tendency to obesity, behavioural difficulties (aggression, attention deficit, autism spectrum features, shyness), and a shared face with a prominent or broad forehead, large or cupped ears, a tall or pointed chin, prognathism and prominent supraorbital ridges. Because of the macrocephaly and mild tall stature it is now discussed within the overgrowth-intellectual disability (OGID) group. The molecular mechanism in human neurons is not established. BRWD3 is a substrate receptor of the CUL4-DDB1 (CRL4) E3 ubiquitin ligase and a chromatin reader; in Drosophila cells it targets the H3K4 demethylase KDM5 for degradation, and fly dBRWD3 mutants accumulate histone H3.3 through HIRA/Yemanuclein, with transcriptome and dendrite defects that are suppressed by reducing H3.3 deposition. dBRWD3 was also identified as a positive regulator of JAK/STAT signalling in a Drosophila RNAi screen. None of these links has been tested in a mammalian model of the disease, and the route from BRWD3 loss to macrocephaly and obesity is unexplained.

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Inheritance
6
Pathophys.
24
Phenotypes
2
Gaps
10
Pathograph
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Genes
4
Medical Actions
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Models
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Deep Research
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Inheritance

1
X-linked recessive HP:0001419
Hemizygous BRWD3 null variants or deletions in males. In the largest single series every sequence variant with inheritance data (12 patients) was maternally inherited, while both partial gene deletions arose de novo; across the pooled literature 19 of 28 variants with segregation data came from unaffected mothers and 9 were de novo, so a negative family history does not exclude the diagnosis. Carrier females are usually unaffected, and in the founding family the three tested carriers preferentially inactivated the mutant X. A small number of affected heterozygous females have been reported, all milder than males and with skewed X inactivation in each one tested.
X-linked recessive inheritance
Show evidence (4 references)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Inheritance data were available for 12 patients with sequence variants; all were maternally inherited."
Maternal transmission of every sequence variant with segregation data in the 17-male series.
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo."
Pooled segregation across the literature, showing both carrier-mother transmission and de novo occurrence.
PMID:17668385 SUPPORT PRIMARY RESULT Human Clinical
"In all three carriers, it is the chromosome carrying the BRWD3 c.3325+1G→T mutation that is preferentially inactivated (data not shown)."
Skewed inactivation of the mutant X in unaffected carrier females of the founding family.
+ 1 more reference
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Discussions and Knowledge Gaps

2
How does loss of BRWD3 produce macrocephaly and a tendency to obesity?
KNOWLEDGE GAP brwd3_macrocephaly_obesity_mechanism
Attached to
phenotypes#Macrocephaly phenotypes#Obesity pathophysiology#Neuronal Transcriptional Dysregulation pathophysiology#Impaired Dendrite Morphogenesis
The growth phenotype is what makes this disorder recognisable, and nothing explains it. The only proposed route is the fly H3.3/chromatin mechanism, which its proponents state as a possibility. The obesity is harder still: in mouse adipogenesis work, DDB1 binds BRWD3 to recruit it to acetylated histones and promote the adipogenic transcriptional cascade, and Ddb1 heterozygous mice resist diet-induced obesity, which would predict that losing BRWD3 reduces rather than increases adiposity. Whether the human obesity is central (hypothalamic), a consequence of reduced activity, or an adipocyte-autonomous effect of a different BRWD3 function is untested.
Show evidence (2 references)
PMID:34161765 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity."
The mammalian BRWD3 adipogenesis finding whose direction does not obviously fit the human obesity phenotype.
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"However, further work is required to investigate this and establish the specific mechanism by which BRWD3 haploinsufficiency leads to overgrowth and intellectual disability."
The human series' authors state that the mechanism is not established.
Do the Drosophila BRWD3 mechanisms (KDM5 degradation, restraint of H3.3 deposition, JAK/STAT regulation) operate in human or mouse neurons, and does any of them account for the human phenotype?
HUMAN MODEL MISMATCH brwd3_no_mammalian_model
Attached to
pathophysiology#KDM5 Stabilization and H3K4 Methylation Imbalance pathophysiology#Excess Histone H3.3 Deposition pathophysiology#Reduced JAK-STAT Pathway Signaling animal_models#Drosophila melanogaster
Every mechanistic node below BRWD3 loss comes from Drosophila mutants or Drosophila cultured cells. The fly null is a developmental lethal with eye and dendrite phenotypes, whereas hemizygous human loss is viable and causes mild-to-moderate intellectual disability with overgrowth, so the two may not share the limiting pathway. A mammalian Brwd3 knockout, or patient iPSC neurons measuring KDM5 levels, H3K4me3, H3.3 occupancy and dendrite morphology, would test whether any of the fly mechanisms carries over.
Proposed experiments
Mammalian Brwd3 knockout phenotyping
brwd3_mammalian_knockout
Generate a hemizygous Brwd3 null mouse and measure brain and body growth, adiposity, learning and behaviour, together with neuronal KDM5 protein levels, H3K4me3 and H3.3 occupancy, and dendrite morphology.
Decision criterion
Macrocephaly or adiposity with altered KDM5, H3K4me3 or H3.3 in neurons would support the fly-derived nodes; normal chromatin readouts despite a phenotype would refute them as the limiting mechanism.
Would support
pathophysiology#KDM5 Stabilization and H3K4 Methylation Imbalance pathophysiology#Excess Histone H3.3 Deposition
Patient iPSC-derived neuron chromatin and morphology study
brwd3_patient_ipsc_neurons
Derive cortical neurons from iPSCs of hemizygous BRWD3-null patients and isogenic corrected controls; measure KDM5 protein stability, H3K4me3 and H3K4me1 profiles, H3.3 deposition, transcriptome, and dendrite arborization.
Decision criterion
KDM5 stabilisation or H3.3 excess in patient neurons that is reversed by correction would support carry-over of the fly mechanisms to human neurons.
Would support
pathophysiology#KDM5 Stabilization and H3K4 Methylation Imbalance pathophysiology#Excess Histone H3.3 Deposition pathophysiology#Impaired Dendrite Morphogenesis
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Other
"Relatively little is known about the biology of the BRWD3 phenotype, and to our knowledge, there have been no reports of knockout models or functional studies in mammalian models."
Absence of mammalian functional work as of the largest series.
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Pathophysiology

6
BRWD3 Loss of Function
The initiating lesion. Reported pathogenic alleles are stop-gain, frameshift and canonical splice variants and partial or whole-gene deletions, predicted to abolish BRWD3 function. A 586 kb Xq21.1 deletion whose only disease-associated gene is BRWD3 reproduces the phenotype, which supports loss of function as sufficient to cause the disorder. BRWD3 contains eight N-terminal WD40 repeats and two C-terminal bromodomains. Its best-characterised molecular activity is as a substrate-recognition subunit of the CUL4-DDB1-ROC1 (CRL4) E3 ubiquitin ligase, shown biochemically for Drosophila BRWD3 with human CRL4 components; the molecular function binding records that activity as lost.
BRWD3 hgnc:17342 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BRWD3 (hgnc:17342). hgnc:17342 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: null (stop-gain, frameshift, canonical splice, partial or whole-gene deletion) variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: LOSS_OF_FUNCTION
CRL4 ubiquitin ligase substrate receptor activity GO:1990756 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased CRL4 ubiquitin ligase substrate receptor activity, annotated with ubiquitin-like ligase-substrate adaptor activity (GO:1990756). GO:1990756 is a molecular function from the Gene Ontology.
Downstream
KDM5 Stabilization and H3K4 Methylation Imbalance Shown in Drosophila cultured cells: BRWD3 depletion stabilises KDM5 and shifts H3K4 methylation. Not tested in human or mammalian neurons.
Excess Histone H3.3 Deposition Shown in Drosophila dBRWD3 mutants, where H3.3 levels rise. Not tested in a mammalian system.
Reduced JAK-STAT Pathway Signaling Based on a Drosophila genome-wide RNAi screen hit and fly in vivo epistasis, where dBRWD3 is required for JAK/STAT pathway activity; how dBRWD3 acts on the pathway was not determined. Whether BRWD3 loss alters JAK-STAT signalling in human cells relevant to this disorder is unknown.
Show evidence (6 references)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"The 12 BRWD3 sequence variants included six stop-gain, four frameshift and two canonical splice site variants (predicted to disrupt normal splicing), which were predicted to result in haploinsufficiency of a gene which exhibits a high degree of loss-of-function constraint (pLI 1.00,..."
The allele spectrum of the largest series is entirely null, in a constrained gene.
PMID:38813790 SUPPORT PRIMARY RESULT Human Clinical
"Our patient confirms that the haploinsufficiency due to BRWD3 deletion is a causal genetic mechanism of the BRWD3-related syndromic X-linked intellectual disability."
A whole-gene deletion produces the same syndrome, supporting loss of function as the mechanism.
PMID:17668385 SUPPORT PRIMARY RESULT In Vitro
"Analysis of cDNA isolated from a lymphoblastoid cell line derived from III-6 demonstrates that this mutation leads to complete skipping of exon 29 and the introduction of a premature stop codon"
Transcript analysis in patient cells confirming that a splice allele truncates the protein.
+ 3 more references
KDM5 Stabilization and H3K4 Methylation Imbalance
In Drosophila cultured cells BRWD3 binds the H3K4 demethylase KDM5 (Lid), co-localises with it genome-wide, and promotes its K48-linked polyubiquitination and Cul4-dependent degradation. BRWD3 depletion raises H3K4me1 and lowers H3K4me3, and depleting KDM5 restores H3K4me3, placing KDM5 accumulation between BRWD3 loss and the methylation change. This is the best-characterised BRWD3 substrate relevant to chromatin, but it has not been examined in human cells or neurons.
CRL4-BRWD3-dependent KDM5 degradation GO:0006511 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased CRL4-BRWD3-dependent KDM5 degradation, annotated with ubiquitin-dependent protein catabolic process (GO:0006511). GO:0006511 is a biological process from the Gene Ontology.
KDM5 histone H3K4 demethylase activity GO:0034647 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased KDM5 histone H3K4 demethylase activity, annotated with histone H3K4me/H3K4me2/H3K4me3 demethylase activity (GO:0034647). GO:0034647 is a molecular function from the Gene Ontology.
Show evidence (2 references)
PMID:37722046 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4."
KDM5 as a CRL4-BRWD3 substrate. INDIRECT because the work is in Drosophila cultured cells, not human tissue.
PMID:37722046 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion."
Epistasis placing KDM5 accumulation upstream of the H3K4 methylation change.
Excess Histone H3.3 Deposition
Drosophila dBRWD3 negatively regulates replication-independent deposition of the histone variant H3.3 by HIRA and its chaperone Yemanuclein (the fly orthologue of Ubinuclein1). In dBRWD3 mutants H3.3 levels rise, and inactivating yem or H3.3 suppresses the global transcriptome changes and the developmental defects, which places excess H3.3 deposition causally between dBRWD3 loss and the downstream phenotypes in the fly.
HIRA/YEM-mediated H3.3 nucleosome assembly GO:0006334 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased HIRA/YEM-mediated H3.3 nucleosome assembly, annotated with nucleosome assembly (GO:0006334). GO:0006334 is a biological process from the Gene Ontology.
Animal models
Drosophila dBRWD3 mutant Drosophila melanogaster recapitulates
Downstream
Neuronal Transcriptional Dysregulation Shown in Drosophila: reducing yem or H3.3 suppresses the global transcriptome changes of dBRWD3 mutants.
Impaired Dendrite Morphogenesis Shown in Drosophila: increased H3.3 in dBRWD3 mutants disrupts dendritic morphogenesis, and reducing yem or H3.3 suppresses the developmental defects.
Show evidence (2 references)
PMID:25666827 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
Excess H3.3 after dBRWD3 loss. INDIRECT because the evidence is from Drosophila.
PMID:25666827 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations."
Genetic suppression placing H3.3 deposition upstream of the transcriptional and developmental defects.
Neuronal Transcriptional Dysregulation
The proposed molecular consequence of BRWD3 loss. In Drosophila dBRWD3 mutants, excess H3.3 disrupts gene expression genome-wide. The authors of the largest human series propose this chromatin-level effect on transcription as a possible mechanism for the overgrowth-intellectual disability phenotype, while noting that no mammalian knockout or functional study exists.
regulation of transcription GO:0006355 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of transcription, annotated with regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology.
Downstream
Intellectual Disability Proposed. The link from chromatin-driven transcriptional change in flies to human cognitive impairment is an inference by analogy; no human or mammalian neuronal data exist.
Macrocephaly Speculative. The human series' authors suggest the H3.3/chromatin mechanism as a possible basis for the overgrowth component, without data on brain growth.
Show evidence (3 references)
PMID:25666827 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations."
Global transcriptome changes in the fly model, dependent on H3.3 deposition.
PMID:31714006 SUPPORT INDIRECT BACKGROUND Model Organism
"However, a possible mechanism of pathogenesis of the OGID phenotype is suggested by experiments in Drosophila, which found that loss of the BRWD3 homologue leads to increased histone H3.3 levels and wide-ranging effects on gene transcription mediated through histone-dependent chromatin regulation"
The human series' authors propose the fly chromatin mechanism for the human phenotype, explicitly as a possibility.
PMID:31714006 NO_EVIDENCE PRIMARY RESULT Other
"Relatively little is known about the biology of the BRWD3 phenotype, and to our knowledge, there have been no reports of knockout models or functional studies in mammalian models."
Records that no mammalian evidence bears on this node; the chain rests on Drosophila work.
Impaired Dendrite Morphogenesis
In Drosophila dBRWD3 mutants, increased H3.3 disrupts dendritic morphogenesis and sensory organ differentiation. This is the only neuronal morphology readout for BRWD3 loss; it has not been examined in mammalian neurons.
dendrite morphogenesis GO:0048813 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dendrite morphogenesis (GO:0048813). GO:0048813 is a biological process from the Gene Ontology.
Animal models
Drosophila dBRWD3 mutant Drosophila melanogaster partially recapitulates
Downstream
Intellectual Disability Proposed by analogy. Dendrite defects in fly sensory neurons are taken as a cellular correlate of cognitive impairment; no human or mammalian neuronal data exist.
Show evidence (1 reference)
PMID:25666827 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
Dendritic morphogenesis defects in the fly model.
Reduced JAK-STAT Pathway Signaling
A genome-wide RNAi screen in Drosophila haemocyte-like cells identified dBRWD3 as required for JAK/STAT pathway activity, and in vivo disruption of dBRWD3 suppressed leukaemia-like blood cell tumours driven by the pathway. The relevance of this to the neurodevelopmental disorder is not established; the node is recorded because BRWD3 was first characterised through it and it is the signalling pathway most often cited for the gene, but no edge to a clinical feature is asserted.
JAK-STAT signaling GO:0007259 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased JAK-STAT signaling, annotated with cell surface receptor signaling pathway via JAK-STAT (GO:0007259). GO:0007259 is a biological process from the Gene Ontology.
Show evidence (3 references)
PMID:16094372 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"In addition to multiple human disease gene homologues, we have found the tyrosine phosphatase Ptp61F and the Drosophila homologue of BRWD3, a bromo-domain-containing protein disrupted in leukaemia."
dBRWD3 identified as a JAK/STAT pathway component in a cell-based RNAi screen.
PMID:16094372 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Moreover, in vivo analysis demonstrates that disrupted dBRWD3 and overexpressed Ptp61F function as suppressors of leukaemia-like blood cell tumours."
In vivo fly evidence that dBRWD3 loss dampens a JAK/STAT-driven phenotype.
PMID:31714006 SUPPORT INDIRECT BACKGROUND In Vitro
"BRWD3 was initially described as a putative transcription factor, and the Drosophila homologue was found to be a positive regulator of the JAK/STAT pathway"
The human series summarises dBRWD3 as a positive JAK/STAT regulator.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Intellectual Disability X-linked 93 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

24
Ear 2
Macrotia FREQUENT HP:0000400 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large ears, annotated with Macrotia (HP:0000400). HP:0000400 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"The most common features in males (excluding one patient with a mosaic variant) 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)."
Large ears in 14 of 26 males (54%).
Cupped Ear HP:0000378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cupped ear (HP:0000378). HP:0000378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17668385 SUPPORT PRIMARY RESULT Human Clinical
"Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability."
Large cupped ears in the founding families.
Eye 1
Deeply Set Eye HP:0000490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep-set eyes, annotated with Deeply set eye (HP:0000490). HP:0000490 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24462886 SUPPORT PRIMARY RESULT Human Clinical
"dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6)"
Deep-set eyes among the dysmorphic features.
PMID:38813790 SUPPORT PRIMARY RESULT Human Clinical
"Phenotype with facial dysmorphic features: wide forehead, deep set eyes, bulbous nose, prominent ears and pointed chin."
Deep-set eyes in a male with a BRWD3 deletion.
Genitourinary 1
Cryptorchidism OCCASIONAL HP:0000028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cryptorchidism (HP:0000028). HP:0000028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Clinical features reported in multiple patients included cryptorchidism (5/17, 29%), neonatal hypotonia (4/17, 24%), and small joint hypermobility (4/17, 24%)."
Cryptorchidism in 5 of 17 males (29%).
Head and Neck 6
Macrocephaly VERY_FREQUENT HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postnatal macrocephaly, annotated with Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"The most common features in males (excluding one patient with a mosaic variant) 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)."
Postnatal macrocephaly in 28 of 35 males (80%).
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Macrocephaly (head circumference ≥ +2 SD) was reported in 12/17 (71%), of whom 3/17 (18%) had extreme macrocephaly (> +4 SD)."
Macrocephaly frequency and range in the 17-male series.
Prominent Forehead FREQUENT HP:0011220 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent forehead (HP:0011220). HP:0011220 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"The most common features in males (excluding one patient with a mosaic variant) 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)."
Prominent forehead in 18 of 25 males (72%).
Tall Chin HP:0400000 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tall chin (HP:0400000). HP:0400000 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Shared facial features included a tall chin with associated horizontal skin crease, prognathism, broad forehead, and prominent supraorbital ridge (Figure 1C)."
Tall chin as a shared facial feature.
Pointed Chin HP:0000307 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pointed chin (HP:0000307). HP:0000307 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24462886 SUPPORT PRIMARY RESULT Human Clinical
"dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6)"
Pointed chin among the dysmorphic features in a nine-patient comparison.
Mandibular Prognathia HP:0000303 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prognathism, annotated with Mandibular prognathia (HP:0000303). HP:0000303 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Shared facial features included a tall chin with associated horizontal skin crease, prognathism, broad forehead, and prominent supraorbital ridge (Figure 1C)."
Prognathism as a shared facial feature.
Prominent Supraorbital Ridges HP:0000336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Prominent supraorbital ridge, annotated with Prominent supraorbital ridges (HP:0000336). HP:0000336 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Shared facial features included a tall chin with associated horizontal skin crease, prognathism, broad forehead, and prominent supraorbital ridge (Figure 1C)."
Prominent supraorbital ridge as a shared facial feature.
Limbs 2
Pes Planus HP:0001763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes planus (HP:0001763). HP:0001763 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24462886 SUPPORT PRIMARY RESULT Human Clinical
"skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus"
Skeletal findings including pes planus across the patients assessed.
Broad Foot HP:0001769 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad feet, annotated with Broad foot (HP:0001769). HP:0001769 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24462886 SUPPORT PRIMARY RESULT Human Clinical
"dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6)"
Broad hands and feet in 6 of 6 patients assessed.
Musculoskeletal 3
Neonatal Hypotonia OCCASIONAL HP:0001319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal hypotonia (HP:0001319). HP:0001319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Clinical features reported in multiple patients included cryptorchidism (5/17, 29%), neonatal hypotonia (4/17, 24%), and small joint hypermobility (4/17, 24%)."
Neonatal hypotonia in 4 of 17 males (24%).
Small Joint Hypermobility OCCASIONAL HP:0430046 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small joint hypermobility (HP:0430046). HP:0430046 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Clinical features reported in multiple patients included cryptorchidism (5/17, 29%), neonatal hypotonia (4/17, 24%), and small joint hypermobility (4/17, 24%)."
Small joint hypermobility in 4 of 17 males (24%).
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24462886 SUPPORT PRIMARY RESULT Human Clinical
"skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus"
Scoliosis among the skeletal findings.
Nervous System 7
Intellectual Disability OBLIGATE HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild to moderate intellectual disability, annotated with Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"The most common features in males (excluding one patient with a mosaic variant) 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)."
Intellectual disability in 39 of 39 males across the pooled literature.
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%)."
Universal intellectual disability, mild or moderate, in the largest single series.
PMID:30628072 SUPPORT PRIMARY RESULT Human Clinical
"The main features of these patients include ID, macrocephaly and dysmorphic facial features."
An independent five-patient series with the same core features.
Delayed Speech and Language Development VERY_FREQUENT HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"The most common features in males (excluding one patient with a mosaic variant) 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)."
Speech delay in 24 of 25 males (96%).
PMID:17668385 SUPPORT PRIMARY RESULT Human Clinical
"A disproportionate delay in language skills has been documented in both families."
Language delay out of proportion to other domains in the founding families.
Aggressive Behavior FREQUENT HP:0000718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aggressive behavior (HP:0000718). HP:0000718 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Patients presented with combinations of aggressive behavior (6/16, 38%), attention deficit/hyperactivity disorder (4/16, 25%), and autistic spectrum disorder (3/16, 19%)."
Aggressive behaviour in 6 of 16 males (38%).
Attention Deficit Hyperactivity Disorder OCCASIONAL HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Patients presented with combinations of aggressive behavior (6/16, 38%), attention deficit/hyperactivity disorder (4/16, 25%), and autistic spectrum disorder (3/16, 19%)."
ADHD in 4 of 16 males (25%).
Autistic Behavior OCCASIONAL HP:0000729 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism spectrum disorder, annotated with Autistic behavior (HP:0000729). HP:0000729 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Patients presented with combinations of aggressive behavior (6/16, 38%), attention deficit/hyperactivity disorder (4/16, 25%), and autistic spectrum disorder (3/16, 19%)."
Autism spectrum disorder in 3 of 16 males (19%).
Excessive Shyness OCCASIONAL HP:0100962 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Shyness in social situations, annotated with Excessive shyness (HP:0100962). HP:0100962 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"Shyness in social situations was commonly reported (3/16, 19%)."
Shyness in 3 of 16 males (19%).
Seizure OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males."
Epilepsy in 4 of 41 males (about 10%) and in both affected females.
Growth 2
Obesity FREQUENT HP:0001513 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Obesity (HP:0001513). HP:0001513 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"The most common features in males (excluding one patient with a mosaic variant) 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)."
Obesity in 12 of 27 males (44%).
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"The mean BMI was +2.0 SD. Nine of 17 (53%) patients had a BMI ≥ +2 SD."
BMI at or above +2 SD in 9 of 17 males.
Tall Stature OCCASIONAL HP:0000098 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tall stature (HP:0000098). HP:0000098 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"The mean height was +1.3 SD. Only four (24%) patients had a height ≥ +2 SD."
Tall stature in 4 of 17 males (24%).
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"In addition, although tall stature (above +2 SD) is an infrequent finding in the BRWD3 phenotype, other OGID syndromes including Sotos syndrome (OMIM 117550), Tatton-Brown-Rahman syndrome (OMIM 615879), Weaver syndrome (OMIM 277590), and the CHD8 overgrowth syndrome (OMIM 615032) can present..."
Tall stature is infrequent, and its absence does not separate this disorder from other OGID syndromes.
🧬

Genetic Associations

1
BRWD3
Gene: BRWD3 hgnc:17342 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is BRWD3 (hgnc:17342). hgnc:17342 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:17668385 SUPPORT PRIMARY RESULT Human Clinical
"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."
The founding gene discovery in two XLID families.
PMID:17668385 SUPPORT PRIMARY RESULT Human Clinical
"No truncating variants were found in 520 control X chromosomes."
Absence of truncating variants in controls.
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions."
The largest single series, all null alleles or deletions.
+ 2 more references
💊

Medical Actions

4
Developmental and Therapy Support
Action: physiotherapy within developmental supportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physiotherapy within developmental support, annotated with Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
No disease-specific therapy exists. The largest series found no medical association requiring ongoing surveillance and recommends support for cognitive and motor development, with physiotherapy or occupational therapy for small joint hypermobility.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"However, we propose that patients receive support to optimize their cognitive and motor development, and may require physiotherapy and/or occupational therapy input for small joint hypermobility."
The management recommendation of the largest series.
Occupational Therapy
Action: Occupational therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Occupational therapy (NCIT:C121351). NCIT:C121351 is a clinical intervention from the NCI Thesaurus. Ontology label: Occupational Therapy NCIT:C121351
Platform: Behavioral / lifestyle
Occupational therapy for small joint hypermobility and fine-motor difficulties, as recommended by the largest series.
Show evidence (1 reference)
PMID:31714006 SUPPORT PRIMARY RESULT Human Clinical
"However, we propose that patients receive support to optimize their cognitive and motor development, and may require physiotherapy and/or occupational therapy input for small joint hypermobility."
Occupational therapy is part of the proposed management.
Speech and Language Therapy
Action: Speech language therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Speech language therapy (NCIT:C159273). NCIT:C159273 is a clinical intervention from the NCI Thesaurus. Ontology label: Speech Language Therapy NCIT:C159273
Platform: Behavioral / lifestyle
Speech delay is present in nearly all affected males, and speech and language therapy is part of the developmental support the series recommend. No source evaluates it in this disease specifically.
Show evidence (1 reference)
PMID:36414205 SUPPORT INDIRECT Human Clinical
"The most common features in males (excluding one patient with a mosaic variant) included ID (39/39 males), speech delay (24/25 males)"
Speech delay in 24 of 25 males establishes the need that speech and language therapy addresses; the source does not itself evaluate the therapy.
Genetic Counseling
Action: Genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Other
Genetic counseling and cascade testing of female relatives, because most variants are inherited from unaffected carrier mothers, a carrier mother has a 50% risk of an affected son, and de novo variants also occur.
Show evidence (1 reference)
PMID:38813790 SUPPORT Human Clinical
"It is important to recognize the phenotype for the diagnosis and follow up of the patients, and also to carry out the family genetic analysis in order to identify and give genetic counselling to the women who also have the genetic defect, because the majority of them are asymptomatic, as the..."
Recommends family testing and genetic counseling for asymptomatic carrier women.
🔬

Diagnosis

3
Exome or genome sequencing
Because the phenotype is largely non-specific, the diagnosis is usually reached genotype-first, by exome or genome sequencing of a patient with intellectual disability, speech delay or macrocephaly, identifying a hemizygous (males) or heterozygous (females) pathogenic BRWD3 variant.
exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Results: A pathogenic BRWD3 truncating, splice, missense or intragenic deletion variant consistent with the phenotype and its segregation.
Show evidence (1 reference)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"This study demonstrates that the BRWD3-related phenotypes are largely non-specific, leading to difficulty in clinical recognition of this disorder. A genotype-first approach, however, allows for the more efficient diagnosis of the BRWD3-related nonsyndromic ID."
The pooled series of 45 patients, ascertained by exome sequencing, concludes that a genotype-first approach is the efficient route to diagnosis.
Chromosomal microarray for BRWD3 deletions
Intragenic and whole-gene BRWD3 deletions, and larger contiguous Xq21.1 deletions, have been detected by array-CGH or SNP array, which is suited to copy-number changes that sequencing may miss.
array comparative genomic hybridization NCIT:C198497 NCI Thesaurus (NCIT)
Results: A deletion at Xq21.1 involving BRWD3, intragenic or including only BRWD3.
Show evidence (2 references)
PMID:24462886 SUPPORT PRIMARY RESULT Human Clinical
"By using array-CGH, we detected a 74 Kb de novo deletion encompassing exons 11 through 41 of BRWD3 at Xq21.1 in a 20 year old boy presenting with syndromic intellectual disability."
An intragenic BRWD3 deletion found by array-CGH.
PMID:38813790 SUPPORT PRIMARY RESULT Human Clinical
"The array-CGH analysis showed a 586 kb deletion at Xq21.1 including only one gene with associated disorder, BRWD3."
A whole-gene BRWD3 deletion found by array-CGH.
X-chromosome inactivation testing in females
In an affected female carrying a BRWD3 variant, X-inactivation analysis (methylation-sensitive restriction digestion and capillary electrophoresis) shows whether the mutant or the normal X is preferentially inactivated, which tracked phenotype severity in the few females tested.
X-chromosome inactivation analysis NCIT:C15709 NCI Thesaurus (NCIT)
Results: Skewed X inactivation; preferential inactivation of the normal X was associated with the more severe phenotypes.
NCIT has X-Chromosome Inactivation (NCIT:C20674) only as a biological process, which is not a procedure term, so the assay is bound to the generic Genetic Testing term and named in preferred_term.
Show evidence (1 reference)
PMID:42298746 SUPPORT PRIMARY RESULT Human Clinical
"Clinicians should recommend early genetic testing for children with intellectual disability, language development delay, macrocephaly, or epilepsy. For female patients, X-chromosome inactivation testing should also be completed."
The female case series recommends X-inactivation testing alongside genetic testing in affected females.
📊

Prevalence

1
Worldwide, published cases
Cases In Literature Not yet documented
The 2023 pooled analysis described 43 males and 2 females with 33 different BRWD3 variants; a 2026 review counted five reported affected females. No population prevalence estimate exists and none is asserted.
Show evidence (1 reference)
PMID:36414205 SUPPORT PRIMARY RESULT Human Clinical
"We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants."
The published case count as of the 2023 pooled analysis.
🐁

Animal Models

1
Drosophila dBRWD3 mutant Loss-of-function
The only in vivo model bearing on the disease mechanism. dBRWD3 mutants show increased H3.3 levels, global transcriptome changes, and defects of dendritic morphogenesis and sensory organ differentiation, all suppressed by inactivating yem or H3.3. There is no fly readout corresponding to macrocephaly or obesity, and no mammalian Brwd3 knockout has been reported.
Species
Drosophila melanogaster
Genotype
dBRWD3 (ramshackle, CG31132) loss-of-function mutants
Pathograph links
Excess Histone H3.3 Deposition recapitulates fidelity: unknown observes: molecular
Limitations: Invertebrate model; the H3.3 mechanism has not been tested in mammalian neurons or patient cells.
Show evidence (1 reference)
PMID:25666827 SUPPORT PRIMARY RESULT Model Organism
"In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
The model shows the H3.3 excess this node describes.
Impaired Dendrite Morphogenesis partially recapitulates fidelity: low observes: cellular
Limitations: Dendrite and sensory-organ defects in fly neurons stand in for human cognitive impairment; no behavioural or learning readout was reported.
Show evidence (1 reference)
PMID:25666827 SUPPORT PRIMARY RESULT Model Organism
"In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
The dendritic morphogenesis defect in the model.
Show evidence (1 reference)
PMID:25666827 SUPPORT PRIMARY RESULT Model Organism
"Here, we report that dBRWD3, the Drosophila ortholog of the intellectual disability gene BRWD3, regulates gene expression through H3.3, HIRA, and its associated chaperone Yemanuclein (YEM), the fly ortholog of mammalian Ubinuclein1."
Establishes dBRWD3 as the fly orthologue and the pathway studied.
{ }

Source YAML

click to show 
name: Intellectual Disability X-linked 93
creation_date: "2026-10-01T14:46:12Z"
description: >-
  Intellectual disability, X-linked 93 (MRX93, XLID93) is the X-linked
  neurodevelopmental disorder caused by loss-of-function variants in BRWD3, a
  bromodomain and WD40-repeat protein encoded at Xq21.1. Affected individuals
  are overwhelmingly hemizygous males carrying stop-gain, frameshift or
  canonical splice variants or partial or whole-gene deletions, most often
  inherited from an unaffected carrier mother and less often de novo.

  Although MONDO files it under non-syndromic X-linked intellectual disability,
  the published series describe a recognisable syndrome: mild-to-moderate
  intellectual disability with speech delay, postnatal macrocephaly (mean head
  circumference about +2.8 SD), a tendency to obesity, behavioural difficulties
  (aggression, attention deficit, autism spectrum features, shyness), and a
  shared face with a prominent or broad forehead, large or cupped ears, a tall
  or pointed chin, prognathism and prominent supraorbital ridges. Because of the
  macrocephaly and mild tall stature it is now discussed within the
  overgrowth-intellectual disability (OGID) group.

  The molecular mechanism in human neurons is not established. BRWD3 is a
  substrate receptor of the CUL4-DDB1 (CRL4) E3 ubiquitin ligase and a chromatin
  reader; in Drosophila cells it targets the H3K4 demethylase KDM5 for
  degradation, and fly dBRWD3 mutants accumulate histone H3.3 through
  HIRA/Yemanuclein, with transcriptome and dendrite defects that are suppressed
  by reducing H3.3 deposition. dBRWD3 was also identified as a positive
  regulator of JAK/STAT signalling in a Drosophila RNAi screen. None of these
  links has been tested in a mammalian model of the disease, and the route from
  BRWD3 loss to macrocephaly and obesity is unexplained.
category: Mendelian
parents:
- hereditary disease
- X-linked intellectual disability
synonyms:
- MRX93
- XLID93
- BRWD3-related intellectual disability
- mental retardation, X-linked 93
- intellectual developmental disorder, X-linked 93
- intellectual disability, X-linked, with macrocephaly
- mental retardation, X-linked, with macrocephaly
- XMR93 syndrome
disease_term:
  preferred_term: intellectual disability, X-linked 93
  term:
    id: MONDO:0010393
    label: intellectual disability, X-linked 93
inheritance:
- name: X-linked recessive
  description: >-
    Hemizygous BRWD3 null variants or deletions in males. In the largest single
    series every sequence variant with inheritance data (12 patients) was
    maternally inherited, while both partial gene deletions arose de novo;
    across the pooled literature 19 of 28 variants with segregation data came
    from unaffected mothers and 9 were de novo, so a negative family history
    does not exclude the diagnosis. Carrier females are usually unaffected, and
    in the founding family the three tested carriers preferentially inactivated
    the mutant X. A small number of affected heterozygous females have been
    reported, all milder than males and with skewed X inactivation in each one
    tested.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Inheritance data were available for 12 patients with sequence variants; all were maternally inherited."
    explanation: Maternal transmission of every sequence variant with segregation data in the 17-male series.
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Among the 28 variants with available segregation reported, 19 were inherited from unaffected mothers and 9 were de novo."
    explanation: Pooled segregation across the literature, showing both carrier-mother transmission and de novo occurrence.
  - reference: PMID:17668385
    reference_title: "Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In all three carriers, it is the chromosome carrying the BRWD3 c.3325+1G→T mutation that is preferentially inactivated (data not shown)."
    explanation: Skewed inactivation of the mutant X in unaffected carrier females of the founding family.
  - reference: PMID:42298746
    reference_title: "X-Linked Intellectual Developmental Disorder-93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "with the overall clinical manifestations being milder than those in the male population"
    explanation: Affected heterozygous females exist and are milder than hemizygous males.
pathophysiology:
- name: BRWD3 Loss of Function
  description: >-
    The initiating lesion. Reported pathogenic alleles are stop-gain,
    frameshift and canonical splice variants and partial or whole-gene
    deletions, predicted to abolish BRWD3 function. A 586 kb Xq21.1 deletion
    whose only disease-associated gene is BRWD3 reproduces the phenotype, which
    supports loss of function as sufficient to cause the disorder. BRWD3 contains eight N-terminal WD40 repeats and two C-terminal
    bromodomains. Its best-characterised molecular activity is as a
    substrate-recognition subunit of the CUL4-DDB1-ROC1 (CRL4) E3 ubiquitin
    ligase, shown biochemically for Drosophila BRWD3 with human CRL4 components;
    the molecular function binding records that activity as lost.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: BRWD3
    term:
      id: hgnc:17342
      label: BRWD3
  molecular_functions:
  - preferred_term: CRL4 ubiquitin ligase substrate receptor activity
    term:
      id: GO:1990756
      label: ubiquitin-like ligase-substrate adaptor activity
    modifier: DECREASED
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    allele_type: null (stop-gain, frameshift, canonical splice, partial or whole-gene deletion)
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
  downstream:
  - target: KDM5 Stabilization and H3K4 Methylation Imbalance
    causal_link_type: DIRECT
    description: >-
      Shown in Drosophila cultured cells: BRWD3 depletion stabilises KDM5 and
      shifts H3K4 methylation. Not tested in human or mammalian neurons.
  - target: Excess Histone H3.3 Deposition
    causal_link_type: DIRECT
    description: >-
      Shown in Drosophila dBRWD3 mutants, where H3.3 levels rise. Not tested in
      a mammalian system.
  - target: Reduced JAK-STAT Pathway Signaling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Based on a Drosophila genome-wide RNAi screen hit and fly in vivo
      epistasis, where dBRWD3 is required for JAK/STAT pathway activity; how
      dBRWD3 acts on the pathway was not determined. Whether BRWD3 loss alters JAK-STAT signalling in human cells
      relevant to this disorder is unknown.
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The 12 BRWD3 sequence variants included six stop-gain, four frameshift and two canonical splice site variants (predicted to disrupt normal splicing), which were predicted to result in haploinsufficiency of a gene which exhibits a high degree of loss-of-function constraint (pLI 1.00, haploinsufficiency index 28.62%, PVS1)."
    explanation: The allele spectrum of the largest series is entirely null, in a constrained gene.
  - reference: PMID:38813790
    reference_title: "[X-linked intellectual disability syndrome with macrocephaly due to BRWD3 gene deletion]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Our patient confirms that the haploinsufficiency due to BRWD3 deletion is a causal genetic mechanism of the BRWD3-related syndromic X-linked intellectual disability."
    explanation: A whole-gene deletion produces the same syndrome, supporting loss of function as the mechanism.
  - reference: PMID:17668385
    reference_title: "Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "Analysis of cDNA isolated from a lymphoblastoid cell line derived from III-6 demonstrates that this mutation leads to complete skipping of exon 29 and the introduction of a premature stop codon"
    explanation: Transcript analysis in patient cells confirming that a splice allele truncates the protein.
  - reference: PMID:23479607
    reference_title: "Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "Indeed, when BRWD3 was expressed in human HEK293T cells and immunopurified, DDB1, CUL4A, CUL4B, and ROC1 copurified with it, indicating that BRWD3 is a substrate receptor for a CRL4 E3 ligase"
    explanation: >-
      Biochemical basis for the ubiquitin ligase substrate adaptor activity
      bound here. INDIRECT because the BRWD3 used was the Drosophila protein and
      the substrate studied (Cryptochrome) is not implicated in the human
      disorder. The paper also calls fly BRWD3 the homolog of human WDR9
      (BRWD1), a BRWD3 paralog, so assigning the activity to human BRWD3 relies
      on family-level orthology.
  - reference: PMID:23479607
    reference_title: "Ramshackle (Brwd3) promotes light-induced ubiquitylation of Drosophila Cryptochrome by DDB1-CUL4-ROC1 E3 ligase complex."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "Thus, we conclude that dCRY is ubiquitylated by a CRL4 E3 ligase with BRWD3 as a substrate receptor and in a light-dependent manner"
    explanation: >-
      The authors' conclusion that BRWD3 is a CRL4 substrate receptor. Same
      orthology caveat as above: the paper names fly BRWD3 the homolog of human
      WDR9/BRWD1.
  - reference: PMID:37722046
    reference_title: "BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "BRWD3 functions as a substrate receptor of the Cul4 E3 ubiquitin ligase complex"
    explanation: Restates the CRL4 substrate-receptor role as established background.
- name: KDM5 Stabilization and H3K4 Methylation Imbalance
  description: >-
    In Drosophila cultured cells BRWD3 binds the H3K4 demethylase KDM5 (Lid),
    co-localises with it genome-wide, and promotes its K48-linked
    polyubiquitination and Cul4-dependent degradation. BRWD3 depletion raises
    H3K4me1 and lowers H3K4me3, and depleting KDM5 restores H3K4me3, placing
    KDM5 accumulation between BRWD3 loss and the methylation change. This is the
    best-characterised BRWD3 substrate relevant to chromatin, but it has not been
    examined in human cells or neurons.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: CRL4-BRWD3-dependent KDM5 degradation
    term:
      id: GO:0006511
      label: ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: KDM5 histone H3K4 demethylase activity
    term:
      id: GO:0034647
      label: histone H3K4me/H3K4me2/H3K4me3 demethylase activity
    modifier: INCREASED
  evidence:
  - reference: PMID:37722046
    reference_title: "BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4."
    explanation: >-
      KDM5 as a CRL4-BRWD3 substrate. INDIRECT because the work is in
      Drosophila cultured cells, not human tissue.
  - reference: PMID:37722046
    reference_title: "BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion."
    explanation: Epistasis placing KDM5 accumulation upstream of the H3K4 methylation change.
- name: Excess Histone H3.3 Deposition
  description: >-
    Drosophila dBRWD3 negatively regulates replication-independent deposition of
    the histone variant H3.3 by HIRA and its chaperone Yemanuclein (the fly
    orthologue of Ubinuclein1). In dBRWD3 mutants H3.3 levels rise, and
    inactivating yem or H3.3 suppresses the global transcriptome changes and the
    developmental defects, which places excess H3.3 deposition causally between
    dBRWD3 loss and the downstream phenotypes in the fly.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: HIRA/YEM-mediated H3.3 nucleosome assembly
    term:
      id: GO:0006334
      label: nucleosome assembly
    modifier: INCREASED
  downstream:
  - target: Neuronal Transcriptional Dysregulation
    causal_link_type: DIRECT
    description: >-
      Shown in Drosophila: reducing yem or H3.3 suppresses the global
      transcriptome changes of dBRWD3 mutants.
  - target: Impaired Dendrite Morphogenesis
    causal_link_type: DIRECT
    description: >-
      Shown in Drosophila: increased H3.3 in dBRWD3 mutants disrupts dendritic
      morphogenesis, and reducing yem or H3.3 suppresses the developmental
      defects.
  evidence:
  - reference: PMID:25666827
    reference_title: "Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
    explanation: >-
      Excess H3.3 after dBRWD3 loss. INDIRECT because the evidence is from
      Drosophila.
  - reference: PMID:25666827
    reference_title: "Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations."
    explanation: Genetic suppression placing H3.3 deposition upstream of the transcriptional and developmental defects.
- name: Neuronal Transcriptional Dysregulation
  description: >-
    The proposed molecular consequence of BRWD3 loss. In Drosophila dBRWD3
    mutants, excess H3.3 disrupts gene expression genome-wide. The authors of
    the largest human series propose this chromatin-level effect on
    transcription as a possible mechanism for the overgrowth-intellectual
    disability phenotype, while noting that no mammalian knockout or functional
    study exists.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: regulation of transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: ABNORMAL
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed. The link from chromatin-driven transcriptional change in flies
      to human cognitive impairment is an inference by analogy; no human or
      mammalian neuronal data exist.
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Speculative. The human series' authors suggest the H3.3/chromatin
      mechanism as a possible basis for the overgrowth component, without data
      on brain growth.
  evidence:
  - reference: PMID:25666827
    reference_title: "Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "Inactivation of yem or H3.3 remarkably suppresses the global transcriptome changes and various developmental defects caused by dBRWD3 mutations."
    explanation: Global transcriptome changes in the fly model, dependent on H3.3 deposition.
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "However, a possible mechanism of pathogenesis of the OGID phenotype is suggested by experiments in Drosophila, which found that loss of the BRWD3 homologue leads to increased histone H3.3 levels and wide-ranging effects on gene transcription mediated through histone-dependent chromatin regulation"
    explanation: The human series' authors propose the fly chromatin mechanism for the human phenotype, explicitly as a possibility.
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: NO_EVIDENCE
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: "Relatively little is known about the biology of the BRWD3 phenotype, and to our knowledge, there have been no reports of knockout models or functional studies in mammalian models."
    explanation: Records that no mammalian evidence bears on this node; the chain rests on Drosophila work.
- name: Impaired Dendrite Morphogenesis
  description: >-
    In Drosophila dBRWD3 mutants, increased H3.3 disrupts dendritic
    morphogenesis and sensory organ differentiation. This is the only neuronal
    morphology readout for BRWD3 loss; it has not been examined in mammalian
    neurons.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: dendrite morphogenesis
    term:
      id: GO:0048813
      label: dendrite morphogenesis
    modifier: DECREASED
  downstream:
  - target: Intellectual Disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed by analogy. Dendrite defects in fly sensory neurons are taken as
      a cellular correlate of cognitive impairment; no human or mammalian
      neuronal data exist.
  evidence:
  - reference: PMID:25666827
    reference_title: "Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
    explanation: Dendritic morphogenesis defects in the fly model.
- name: Reduced JAK-STAT Pathway Signaling
  description: >-
    A genome-wide RNAi screen in Drosophila haemocyte-like cells identified
    dBRWD3 as required for JAK/STAT pathway activity, and in vivo disruption of
    dBRWD3 suppressed leukaemia-like blood cell tumours driven by the pathway.
    The relevance of this to the neurodevelopmental disorder is not established;
    the node is recorded because BRWD3 was first characterised through it and it
    is the signalling pathway most often cited for the gene, but no edge to a
    clinical feature is asserted.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: DECREASED
  evidence:
  - reference: PMID:16094372
    reference_title: "Identification of JAK/STAT signalling components by genome-wide RNA interference."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "In addition to multiple human disease gene homologues, we have found the tyrosine phosphatase Ptp61F and the Drosophila homologue of BRWD3, a bromo-domain-containing protein disrupted in leukaemia."
    explanation: dBRWD3 identified as a JAK/STAT pathway component in a cell-based RNAi screen.
  - reference: PMID:16094372
    reference_title: "Identification of JAK/STAT signalling components by genome-wide RNA interference."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "Moreover, in vivo analysis demonstrates that disrupted dBRWD3 and overexpressed Ptp61F function as suppressors of leukaemia-like blood cell tumours."
    explanation: In vivo fly evidence that dBRWD3 loss dampens a JAK/STAT-driven phenotype.
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "BRWD3 was initially described as a putative transcription factor, and the Drosophila homologue was found to be a positive regulator of the JAK/STAT pathway"
    explanation: The human series summarises dBRWD3 as a positive JAK/STAT regulator.
phenotypes:
- name: Intellectual Disability
  category: Neurological
  description: >-
    Present in every reported affected male and the defining feature. Severity
    is mild or moderate: 11 of 17 males in the largest series were moderate and
    the rest mild, and severe intellectual disability has not been a feature of
    the null-allele series.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Mild to moderate intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The most common features in males (excluding one patient with a mosaic variant) 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)."
    explanation: Intellectual disability in 39 of 39 males across the pooled literature.
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%)."
    explanation: Universal intellectual disability, mild or moderate, in the largest single series.
  - reference: PMID:30628072
    reference_title: "MRX93 syndrome (BRWD3 gene): five new patients with novel mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The main features of these patients include ID, macrocephaly and dysmorphic facial features."
    explanation: An independent five-patient series with the same core features.
- name: Delayed Speech and Language Development
  category: Neurological
  description: >-
    Speech delay is nearly universal, and the founding report documented
    language delay disproportionate to delay in other domains.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The most common features in males (excluding one patient with a mosaic variant) 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)."
    explanation: Speech delay in 24 of 25 males (96%).
  - reference: PMID:17668385
    reference_title: "Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "A disproportionate delay in language skills has been documented in both families."
    explanation: Language delay out of proportion to other domains in the founding families.
- name: Macrocephaly
  category: Growth
  description: >-
    Postnatal macrocephaly in most males; mean head circumference +2.8 SD in
    the largest series, with 3 of 17 above +4 SD and every patient above the
    age-adjusted mean. CT in the founding proband showed megalencephaly without
    hydrocephalus.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Postnatal macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The most common features in males (excluding one patient with a mosaic variant) 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)."
    explanation: Postnatal macrocephaly in 28 of 35 males (80%).
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Macrocephaly (head circumference ≥ +2 SD) was reported in 12/17 (71%), of whom 3/17 (18%) had extreme macrocephaly (> +4 SD)."
    explanation: Macrocephaly frequency and range in the 17-male series.
- name: Obesity
  category: Growth
  description: >-
    A tendency to obesity in roughly half of males; mean BMI +2.0 SD in the
    largest series (range -1.1 to +6.6 SD). Not universal, and its mechanism is
    unexplained.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The most common features in males (excluding one patient with a mosaic variant) 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)."
    explanation: Obesity in 12 of 27 males (44%).
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The mean BMI was +2.0 SD. Nine of 17 (53%) patients had a BMI ≥ +2 SD."
    explanation: BMI at or above +2 SD in 9 of 17 males.
- name: Tall Stature
  category: Growth
  description: >-
    Height is shifted upward (mean +1.3 SD), but tall stature (+2 SD or more)
    is a minority finding (4 of 17 in the largest series). Because several
    other OGID syndromes can also present with macrocephaly without tall
    stature, its absence does not distinguish this disorder from them.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The mean height was +1.3 SD. Only four (24%) patients had a height ≥ +2 SD."
    explanation: Tall stature in 4 of 17 males (24%).
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In addition, although tall stature (above +2 SD) is an infrequent finding in the BRWD3 phenotype, other OGID syndromes including Sotos syndrome (OMIM 117550), Tatton-Brown-Rahman syndrome (OMIM 615879), Weaver syndrome (OMIM 277590), and the CHD8 overgrowth syndrome (OMIM 615032) can present with isolated macrocephaly without tall stature."
    explanation: Tall stature is infrequent, and its absence does not separate this disorder from other OGID syndromes.
- name: Prominent Forehead
  category: Craniofacial
  description: >-
    A prominent or broad forehead, often with frontal bossing, is the most
    consistent facial feature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Prominent forehead
    term:
      id: HP:0011220
      label: Prominent forehead
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The most common features in males (excluding one patient with a mosaic variant) 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)."
    explanation: Prominent forehead in 18 of 25 males (72%).
- name: Macrotia
  category: Craniofacial
  description: >-
    Large, prominent ears, described as cupped in the founding families.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Large ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The most common features in males (excluding one patient with a mosaic variant) 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)."
    explanation: Large ears in 14 of 26 males (54%).
- name: Cupped Ear
  category: Craniofacial
  description: Cupped helices noted in the founding families.
  phenotype_term:
    preferred_term: Cupped ear
    term:
      id: HP:0000378
      label: Cupped ear
  evidence:
  - reference: PMID:17668385
    reference_title: "Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability."
    explanation: Large cupped ears in the founding families.
- name: Tall Chin
  category: Craniofacial
  description: >-
    A tall chin with a horizontal skin crease, described as pointed in earlier
    reports; one of the shared facial features of the largest series. No
    frequency is reported.
  phenotype_term:
    preferred_term: Tall chin
    term:
      id: HP:0400000
      label: Tall chin
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Shared facial features included a tall chin with associated horizontal skin crease, prognathism, broad forehead, and prominent supraorbital ridge (Figure 1C)."
    explanation: Tall chin as a shared facial feature.
- name: Pointed Chin
  category: Craniofacial
  description: Pointed chin, reported in the founding families and in later series.
  phenotype_term:
    preferred_term: Pointed chin
    term:
      id: HP:0000307
      label: Pointed chin
  evidence:
  - reference: PMID:24462886
    reference_title: "Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6)"
    explanation: Pointed chin among the dysmorphic features in a nine-patient comparison.
- name: Mandibular Prognathia
  category: Craniofacial
  description: Prognathism is one of the shared facial features of the largest series.
  phenotype_term:
    preferred_term: Prognathism
    term:
      id: HP:0000303
      label: Mandibular prognathia
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Shared facial features included a tall chin with associated horizontal skin crease, prognathism, broad forehead, and prominent supraorbital ridge (Figure 1C)."
    explanation: Prognathism as a shared facial feature.
- name: Prominent Supraorbital Ridges
  category: Craniofacial
  description: Prominent supraorbital ridges are one of the shared facial features of the largest series.
  phenotype_term:
    preferred_term: Prominent supraorbital ridge
    term:
      id: HP:0000336
      label: Prominent supraorbital ridges
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Shared facial features included a tall chin with associated horizontal skin crease, prognathism, broad forehead, and prominent supraorbital ridge (Figure 1C)."
    explanation: Prominent supraorbital ridge as a shared facial feature.
- name: Aggressive Behavior
  category: Behavioral
  description: >-
    Behavioural problems affect about three quarters of males; aggression is
    the most frequent single behaviour.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Aggressive behavior
    term:
      id: HP:0000718
      label: Aggressive behavior
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patients presented with combinations of aggressive behavior (6/16, 38%), attention deficit/hyperactivity disorder (4/16, 25%), and autistic spectrum disorder (3/16, 19%)."
    explanation: Aggressive behaviour in 6 of 16 males (38%).
- name: Attention Deficit Hyperactivity Disorder
  category: Behavioral
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patients presented with combinations of aggressive behavior (6/16, 38%), attention deficit/hyperactivity disorder (4/16, 25%), and autistic spectrum disorder (3/16, 19%)."
    explanation: ADHD in 4 of 16 males (25%).
- name: Autistic Behavior
  category: Behavioral
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Autism spectrum disorder
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Patients presented with combinations of aggressive behavior (6/16, 38%), attention deficit/hyperactivity disorder (4/16, 25%), and autistic spectrum disorder (3/16, 19%)."
    explanation: Autism spectrum disorder in 3 of 16 males (19%).
- name: Excessive Shyness
  category: Behavioral
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Shyness in social situations
    term:
      id: HP:0100962
      label: Excessive shyness
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Shyness in social situations was commonly reported (3/16, 19%)."
    explanation: Shyness in 3 of 16 males (19%).
- name: Cryptorchidism
  category: Genitourinary
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Cryptorchidism
    term:
      id: HP:0000028
      label: Cryptorchidism
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Clinical features reported in multiple patients included cryptorchidism (5/17, 29%), neonatal hypotonia (4/17, 24%), and small joint hypermobility (4/17, 24%)."
    explanation: Cryptorchidism in 5 of 17 males (29%).
- name: Neonatal Hypotonia
  category: Neurological
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Clinical features reported in multiple patients included cryptorchidism (5/17, 29%), neonatal hypotonia (4/17, 24%), and small joint hypermobility (4/17, 24%)."
    explanation: Neonatal hypotonia in 4 of 17 males (24%).
- name: Small Joint Hypermobility
  category: Musculoskeletal
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Small joint hypermobility
    term:
      id: HP:0430046
      label: Small joint hypermobility
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Clinical features reported in multiple patients included cryptorchidism (5/17, 29%), neonatal hypotonia (4/17, 24%), and small joint hypermobility (4/17, 24%)."
    explanation: Small joint hypermobility in 4 of 17 males (24%).
- name: Pes Planus
  category: Musculoskeletal
  description: >-
    Skeletal findings (pes planus, scoliosis, kyphosis, cubitus valgus) were
    present in all seven patients assessed in one nine-patient comparison; pes
    planus is the most often named. No pooled frequency for pes planus alone is
    available.
  phenotype_term:
    preferred_term: Pes planus
    term:
      id: HP:0001763
      label: Pes planus
  evidence:
  - reference: PMID:24462886
    reference_title: "Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus"
    explanation: Skeletal findings including pes planus across the patients assessed.
- name: Deeply Set Eye
  category: Craniofacial
  description: Deep-set eyes, reported among the facial features in a nine-patient comparison and in a patient with a BRWD3 deletion.
  phenotype_term:
    preferred_term: Deep-set eyes
    term:
      id: HP:0000490
      label: Deeply set eye
  evidence:
  - reference: PMID:24462886
    reference_title: "Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6)"
    explanation: Deep-set eyes among the dysmorphic features.
  - reference: PMID:38813790
    reference_title: "[X-linked intellectual disability syndrome with macrocephaly due to BRWD3 gene deletion]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Phenotype with facial dysmorphic features: wide forehead, deep set eyes, bulbous nose, prominent ears and pointed chin."
    explanation: Deep-set eyes in a male with a BRWD3 deletion.
- name: Broad Foot
  category: Musculoskeletal
  description: >-
    Broad hands and feet were present in all six patients assessed in one
    nine-patient comparison; the denominator is too small for a frequency band.
  phenotype_term:
    preferred_term: Broad feet
    term:
      id: HP:0001769
      label: Broad foot
  evidence:
  - reference: PMID:24462886
    reference_title: "Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6)"
    explanation: Broad hands and feet in 6 of 6 patients assessed.
- name: Scoliosis
  category: Musculoskeletal
  description: >-
    Scoliosis is among the skeletal findings (with pes planus, kyphosis and
    cubitus valgus) reported in one nine-patient comparison; no frequency for
    scoliosis alone is given.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:24462886
    reference_title: "Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus"
    explanation: Scoliosis among the skeletal findings.
- name: Seizure
  category: Neurological
  description: >-
    Uncommon in males (about one in ten) but present in both affected females
    in the 2023 pooled analysis. A separate cohort associates BRWD3 missense
    variants with partial epilepsy without intellectual disability, which is
    treated here as a possible allelic condition rather than part of this
    entry's phenotype (see genetic notes).
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Both females presented with macrocephaly, speech delay, and epilepsy, while epilepsy was only observed in 4/41 males."
    explanation: Epilepsy in 4 of 41 males (about 10%) and in both affected females.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    The 2023 pooled analysis described 43 males and 2 females with 33 different
    BRWD3 variants; a 2026 review counted five reported affected females. No
    population prevalence estimate exists and none is asserted.
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We reviewed the 31 previously published cases in the literature with clinical data available, and describe the collective phenotypes of 43 males and 2 females, with 33 different BRWD3 variants."
    explanation: The published case count as of the 2023 pooled analysis.
genetic:
- name: BRWD3
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: BRWD3
    term:
      id: hgnc:17342
      label: BRWD3
  notes: >-
    BRWD3 (bromodomain and WD repeat domain containing 3) maps to Xq21.1 and
    encodes an 1802-residue protein with eight WD40 repeats and two
    bromodomains. All disease alleles in the largest series are null (stop-gain,
    frameshift, canonical splice) or partial gene deletions, and none is in
    gnomAD. The founding screen found truncating BRWD3 variants in 2 of 250
    XLID families (about 1%); a missense variant (p.K1596E) segregating in a
    third family without macrocephaly was of uncertain significance and is not
    counted here.

    ClinGen's Intellectual Disability and Autism expert panel classifies BRWD3
    as Definitive for X-linked syndromic intellectual disability
    (MONDO:0020119), a broader MONDO term than this entry's disease_term, so the
    classification is cited as evidence but not recorded as a
    gene_disease_validity assertion for MONDO:0010393.

    A Chinese epilepsy cohort reported maternally inherited BRWD3 missense and
    near-splice variants in five individuals with idiopathic partial epilepsy
    and normal intellect, and proposed that truncating alleles cause
    intellectual disability while WD40/bromodomain missense alleles cause
    epilepsy. That association rests on a single cohort and on case-control
    allele counting without functional data; it is not modelled as a subtype of
    this entry.
  evidence:
  - reference: PMID:17668385
    reference_title: "Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "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."
    explanation: The founding gene discovery in two XLID families.
  - reference: PMID:17668385
    reference_title: "Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "No truncating variants were found in 520 control X chromosomes."
    explanation: Absence of truncating variants in controls.
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We report the largest BRWD3 patient series to date, comprising 17 males with 12 distinct null variants and 2 partial gene deletions."
    explanation: The largest single series, all null alleles or deletions.
  - reference: CGGV:assertion_b8a924e2-e76b-4363-bf38-d95fd53d6141-2018-07-18T100000.000Z
    reference_title: "BRWD3 / X-linked syndromic intellectual disability (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BRWD3 | HGNC:17342 | X-linked syndromic intellectual disability | MONDO:0020119 | XL | Definitive"
    explanation: >-
      The expert-panel classification, keyed to the broader X-linked syndromic
      intellectual disability term rather than to MONDO:0010393.
  - reference: PMID:36514184
    reference_title: "Variants in BRWD3 associated with X-linked partial epilepsy without intellectual disability."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Further analysis demonstrated that all previously reported destructive variants of BRWD3 caused intellectual disability, while missense variants located in WD40 repeat domains and bromodomains of BRWD3 were associated with epilepsy."
    explanation: >-
      Literature synthesis that truncating BRWD3 alleles are the ones associated
      with intellectual disability; the epilepsy half of the sentence is the
      separate, unconfirmed allelic proposal discussed in notes.
diagnosis:
- name: Exome or genome sequencing
  description: >-
    Because the phenotype is largely non-specific, the diagnosis is usually
    reached genotype-first, by exome or genome sequencing of a patient with
    intellectual disability, speech delay or macrocephaly, identifying a
    hemizygous (males) or heterozygous (females) pathogenic BRWD3 variant.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  results: >-
    A pathogenic BRWD3 truncating, splice, missense or intragenic deletion
    variant consistent with the phenotype and its segregation.
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      This study demonstrates that the BRWD3-related phenotypes are largely
      non-specific, leading to difficulty in clinical recognition of this
      disorder. A genotype-first approach, however, allows for the more
      efficient diagnosis of the BRWD3-related nonsyndromic ID.
    explanation: >-
      The pooled series of 45 patients, ascertained by exome sequencing,
      concludes that a genotype-first approach is the efficient route to
      diagnosis.
- name: Chromosomal microarray for BRWD3 deletions
  description: >-
    Intragenic and whole-gene BRWD3 deletions, and larger contiguous Xq21.1
    deletions, have been detected by array-CGH or SNP array, which is suited
    to copy-number changes that sequencing may miss.
  diagnosis_term:
    preferred_term: array comparative genomic hybridization
    term:
      id: NCIT:C198497
      label: Array-based Comparative Genomic Hybridization
  results: >-
    A deletion at Xq21.1 involving BRWD3, intragenic or including only BRWD3.
  evidence:
  - reference: PMID:24462886
    reference_title: Clinical assessment of five patients with BRWD3 mutation at Xq21.1 gives further evidence for mild to moderate intellectual disability and macrocephaly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      By using array-CGH, we detected a 74 Kb de novo deletion encompassing
      exons 11 through 41 of BRWD3 at Xq21.1 in a 20 year old boy presenting
      with syndromic intellectual disability.
    explanation: An intragenic BRWD3 deletion found by array-CGH.
  - reference: PMID:38813790
    reference_title: "[X-linked intellectual disability syndrome with macrocephaly due to BRWD3 gene deletion]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The array-CGH analysis showed a 586 kb deletion at Xq21.1 including only
      one gene with associated disorder, BRWD3.
    explanation: A whole-gene BRWD3 deletion found by array-CGH.
- name: X-chromosome inactivation testing in females
  description: >-
    In an affected female carrying a BRWD3 variant, X-inactivation analysis
    (methylation-sensitive restriction digestion and capillary
    electrophoresis) shows whether the mutant or the normal X is
    preferentially inactivated, which tracked phenotype severity in the few
    females tested.
  diagnosis_term:
    preferred_term: X-chromosome inactivation analysis
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Skewed X inactivation; preferential inactivation of the normal X was
    associated with the more severe phenotypes.
  notes: >-
    NCIT has X-Chromosome Inactivation (NCIT:C20674) only as a biological
    process, which is not a procedure term, so the assay is bound to the
    generic Genetic Testing term and named in preferred_term.
  evidence:
  - reference: PMID:42298746
    reference_title: "X-Linked Intellectual Developmental Disorder-93 Caused by BRWD3 Mutation in Females: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Clinicians should recommend early genetic testing for children with
      intellectual disability, language development delay, macrocephaly, or
      epilepsy. For female patients, X-chromosome inactivation testing should
      also be completed.
    explanation: >-
      The female case series recommends X-inactivation testing alongside
      genetic testing in affected females.
treatments:
- name: Developmental and Therapy Support
  description: >-
    No disease-specific therapy exists. The largest series found no medical
    association requiring ongoing surveillance and recommends support for
    cognitive and motor development, with physiotherapy or occupational therapy
    for small joint hypermobility.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physiotherapy within developmental support
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "However, we propose that patients receive support to optimize their cognitive and motor development, and may require physiotherapy and/or occupational therapy input for small joint hypermobility."
    explanation: The management recommendation of the largest series.
- name: Occupational Therapy
  description: >-
    Occupational therapy for small joint hypermobility and fine-motor
    difficulties, as recommended by the largest series.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Occupational therapy
    term:
      id: NCIT:C121351
      label: Occupational Therapy
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "However, we propose that patients receive support to optimize their cognitive and motor development, and may require physiotherapy and/or occupational therapy input for small joint hypermobility."
    explanation: Occupational therapy is part of the proposed management.
- name: Speech and Language Therapy
  description: >-
    Speech delay is present in nearly all affected males, and speech and
    language therapy is part of the developmental support the series
    recommend. No source evaluates it in this disease specifically.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Speech language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:36414205
    reference_title: "Further clinical and molecular characterization of an XLID syndrome associated with BRWD3 variants, a gene implicated in the leukemia-related JAK-STAT pathway."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The most common features in males (excluding one patient with a mosaic
      variant) included ID (39/39 males), speech delay (24/25 males)
    explanation: >-
      Speech delay in 24 of 25 males establishes the need that speech and
      language therapy addresses; the source does not itself evaluate the
      therapy.
- name: Genetic Counseling
  description: >-
    Genetic counseling and cascade testing of female relatives, because most
    variants are inherited from unaffected carrier mothers, a carrier mother
    has a 50% risk of an affected son, and de novo variants also occur.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38813790
    reference_title: "[X-linked intellectual disability syndrome with macrocephaly due to BRWD3 gene deletion]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is important to recognize the phenotype for the diagnosis and follow
      up of the patients, and also to carry out the family genetic analysis in
      order to identify and give genetic counselling to the women who also have
      the genetic defect, because the majority of them are asymptomatic, as the
      mother and sister of our patient.
    explanation: >-
      Recommends family testing and genetic counseling for asymptomatic carrier
      women.
animal_models:
- name: Drosophila dBRWD3 mutant
  species: Drosophila melanogaster
  genotype: dBRWD3 (ramshackle, CG31132) loss-of-function mutants
  category: Loss-of-function
  description: >-
    The only in vivo model bearing on the disease mechanism. dBRWD3 mutants
    show increased H3.3 levels, global transcriptome changes, and defects of
    dendritic morphogenesis and sensory organ differentiation, all suppressed by
    inactivating yem or H3.3. There is no fly readout corresponding to
    macrocephaly or obesity, and no mammalian Brwd3 knockout has been reported.
  modeled_mechanisms:
  - target: Excess Histone H3.3 Deposition
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: MOLECULAR
    limitations: >-
      Invertebrate model; the H3.3 mechanism has not been tested in mammalian
      neurons or patient cells.
    evidence:
    - reference: PMID:25666827
      reference_title: "Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
      explanation: The model shows the H3.3 excess this node describes.
  - target: Impaired Dendrite Morphogenesis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    limitations: >-
      Dendrite and sensory-organ defects in fly neurons stand in for human
      cognitive impairment; no behavioural or learning readout was reported.
    evidence:
    - reference: PMID:25666827
      reference_title: "Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "In dBRWD3 mutants, increased H3.3 levels disrupt gene expression, dendritic morphogenesis, and sensory organ differentiation."
      explanation: The dendritic morphogenesis defect in the model.
  evidence:
  - reference: PMID:25666827
    reference_title: "Intellectual disability-associated dBRWD3 regulates gene expression through inhibition of HIRA/YEM-mediated chromatin deposition of histone H3.3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Here, we report that dBRWD3, the Drosophila ortholog of the intellectual disability gene BRWD3, regulates gene expression through H3.3, HIRA, and its associated chaperone Yemanuclein (YEM), the fly ortholog of mammalian Ubinuclein1."
    explanation: Establishes dBRWD3 as the fly orthologue and the pathway studied.
discussions:
- discussion_id: brwd3_macrocephaly_obesity_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    How does loss of BRWD3 produce macrocephaly and a tendency to obesity?
  attaches_to:
  - phenotypes#Macrocephaly
  - phenotypes#Obesity
  - pathophysiology#Neuronal Transcriptional Dysregulation
  - pathophysiology#Impaired Dendrite Morphogenesis
  rationale: >-
    The growth phenotype is what makes this disorder recognisable, and nothing
    explains it. The only proposed route is the fly H3.3/chromatin mechanism,
    which its proponents state as a possibility. The obesity is harder still:
    in mouse adipogenesis work, DDB1 binds BRWD3 to recruit it to acetylated
    histones and promote the adipogenic transcriptional cascade, and Ddb1
    heterozygous mice resist diet-induced obesity, which would predict that
    losing BRWD3 reduces rather than increases adiposity. Whether the human
    obesity is central (hypothalamic), a consequence of reduced activity, or an
    adipocyte-autonomous effect of a different BRWD3 function is untested.
  evidence:
  - reference: PMID:34161765
    reference_title: "DDB1 binds histone reader BRWD3 to activate the transcriptional cascade in adipogenesis and promote onset of obesity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: "Here, we show that DDB1 binds the histone reader BRWD3 to promote adipogenesis and diet-induced obesity."
    explanation: >-
      The mammalian BRWD3 adipogenesis finding whose direction does not obviously
      fit the human obesity phenotype.
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "However, further work is required to investigate this and establish the specific mechanism by which BRWD3 haploinsufficiency leads to overgrowth and intellectual disability."
    explanation: The human series' authors state that the mechanism is not established.
- discussion_id: brwd3_no_mammalian_model
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do the Drosophila BRWD3 mechanisms (KDM5 degradation, restraint of H3.3
    deposition, JAK/STAT regulation) operate in human or mouse neurons, and does
    any of them account for the human phenotype?
  attaches_to:
  - pathophysiology#KDM5 Stabilization and H3K4 Methylation Imbalance
  - pathophysiology#Excess Histone H3.3 Deposition
  - pathophysiology#Reduced JAK-STAT Pathway Signaling
  - animal_models#Drosophila melanogaster
  rationale: >-
    Every mechanistic node below BRWD3 loss comes from Drosophila mutants or
    Drosophila cultured cells. The fly null is a developmental lethal with eye
    and dendrite phenotypes, whereas hemizygous human loss is viable and causes
    mild-to-moderate intellectual disability with overgrowth, so the two may
    not share the limiting pathway. A mammalian Brwd3 knockout, or patient iPSC
    neurons measuring KDM5 levels, H3K4me3, H3.3 occupancy and dendrite
    morphology, would test whether any of the fly mechanisms carries over.
  proposed_experiments:
  - experiment_id: brwd3_mammalian_knockout
    name: Mammalian Brwd3 knockout phenotyping
    description: >-
      Generate a hemizygous Brwd3 null mouse and measure brain and body growth,
      adiposity, learning and behaviour, together with neuronal KDM5 protein
      levels, H3K4me3 and H3.3 occupancy, and dendrite morphology.
    decision_criterion: >-
      Macrocephaly or adiposity with altered KDM5, H3K4me3 or H3.3 in neurons
      would support the fly-derived nodes; normal chromatin readouts despite a
      phenotype would refute them as the limiting mechanism.
    would_support:
    - pathophysiology#KDM5 Stabilization and H3K4 Methylation Imbalance
    - pathophysiology#Excess Histone H3.3 Deposition
  - experiment_id: brwd3_patient_ipsc_neurons
    name: Patient iPSC-derived neuron chromatin and morphology study
    description: >-
      Derive cortical neurons from iPSCs of hemizygous BRWD3-null patients and
      isogenic corrected controls; measure KDM5 protein stability, H3K4me3 and
      H3K4me1 profiles, H3.3 deposition, transcriptome, and dendrite
      arborization.
    decision_criterion: >-
      KDM5 stabilisation or H3.3 excess in patient neurons that is reversed by
      correction would support carry-over of the fly mechanisms to human
      neurons.
    would_support:
    - pathophysiology#KDM5 Stabilization and H3K4 Methylation Imbalance
    - pathophysiology#Excess Histone H3.3 Deposition
    - pathophysiology#Impaired Dendrite Morphogenesis
  evidence:
  - reference: PMID:31714006
    reference_title: "Null variants and deletions in BRWD3 cause an X-linked syndrome of mild-moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: PRIMARY_RESULT
    snippet: "Relatively little is known about the biology of the BRWD3 phenotype, and to our knowledge, there have been no reports of knockout models or functional studies in mammalian models."
    explanation: Absence of mammalian functional work as of the largest series.
notes: >-
  Evidence for this entry is thin by construction: about 45 affected
  individuals, three case series and a handful of case reports, and no
  mammalian functional study. Phenotype frequencies come from the 2023 pooled
  analysis (up to 41 males per feature) and the 17-male 2019 series, and
  denominators vary by feature because not every report records every feature.
  The mechanistic chain below the loss-of-function node rests on Drosophila
  work and is graded INDIRECT throughout.

  MONDO places MONDO:0010393 under non-syndromic X-linked intellectual
  disability, while the published phenotype is reproducibly syndromic
  (macrocephaly, obesity tendency, shared face), and ClinGen curates the gene
  against X-linked syndromic intellectual disability. The entry curates the
  syndromic phenotype the literature reports.

  No GeneReviews chapter covers this disorder. The BRWD3 cytoband is Xq21.1
  (HGNC); the 2019 series text gives Xp21.1, which is a typographical error in
  that paper.
📚

References & Deep Research

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Evaluations and curation notes (2)

Review fixes: Intellectual_Disability_X-linked_93 · 2026-10-01T15:35:06Z · View source

Applied independent review of the initial curation. JAK-STAT edge downgraded to INDIRECT_UNKNOWN_INTERMEDIATES (RNAi screen hit, PMID:16094372). Unsourced KDM5 -> transcription edge removed; KDM5 node is terminal. 586 kb deletion reworded to match PMID:38813790 (only disease-associated gene is BRWD3). Tall-stature description corrected to a 4/17 minority finding that does not distinguish from other OGID syndromes, with the PMID:31714006 differential sentence added as evidence. Added the PMID:23479607 CRL4 substrate-receptor conclusion snippet and an orthology caveat (the paper names fly BRWD3 the homolog of human WDR9/BRWD1). Added directness INDIRECT to the PMID:31714006 JAK/STAT background item. Split the transcription/dendrite node into Neuronal Transcriptional Dysregulation and Impaired Dendrite Morphogenesis, both downstream of Excess Histone H3.3 Deposition, with targets, animal-model links and attaches_to updated. Added phenotypes Deeply set eye (HP:0000490), Broad foot (HP:0001769) and Scoliosis (HP:0002650) from PMID:24462886 and PMID:38813790; no separate Atypical behavior phenotype because aggression, ADHD, autistic behavior and shyness are already curated. Cited PMID:30628072 on Intellectual Disability. Added two proposed_experiments (mammalian Brwd3 knockout; patient iPSC neurons measuring KDM5, H3K4me3, H3.3, dendrites) to the HUMAN_MODEL_MISMATCH discussion. Cache files PMID_15543602, 16904300, 26323392, 27588417, 30086552 and 36926587 were kept because the committed DR report cites each of them. Validation: just validate 0 issues; validate-disorders passed; entity-refs, causal-targets, duplicate-keys, qualifier-terms, snippet-length, title-snippets, snippet-grading, folded-hyphens, coarse-phenotypes, term-cache-integrity, cache-order OK; grounding gate (baseline origin/main) no newly ungrounded genes.

Create: Intellectual_Disability_X-linked_93 · 2026-10-01T15:13:03Z · View source

New entry for intellectual disability, X-linked 93 (MONDO:0010393, BRWD3), replacing stubs/Intellectual_Disability_X-linked_93.yaml, as the Non-Syndromic_X-Linked_Intellectual_Disability entry recommended. Slug follows the stub's proposed_name and the existing Intellectual_Disability_X-linked_NNN convention. Deep research: requested falcon with fallback; falcon was not configured (no Edison key) and the run fell back to claude_code (research/Intellectual_Disability_X-linked_93-deep-research-claude_code.md, fell_back recorded in frontmatter). Its reference validation resolved 22/22 identifiers; 2 quotes flagged as unsupported were ellipsis-joined abstract excerpts (PMID:17668385, PMID:36414205), and all snippets in the entry were instead copied from references_cache. just preflight-dr returned PASS (BRWD3 mentioned 40 times). Curated: X-linked recessive inheritance with de novo and affected-female caveats; a BRWD3 loss-of-function root node bound to GO:1990756 ubiquitin-like ligase-substrate adaptor activity (CRL4 substrate receptor; Drosophila BRWD3 with human CRL4 components, PMID:23479607), three Drosophila-derived downstream nodes (KDM5 stabilisation/H3K4 methylation, PMID:37722046; excess H3.3 deposition, PMID:25666827; reduced JAK-STAT signalling, PMID:16094372) graded INDIRECT, a transcription/dendrite node linked to intellectual disability and macrocephaly only as INDIRECT_UNKNOWN_INTERMEDIATES; 21 phenotypes with frequencies from PMID:36414205 and PMID:31714006; CASES_IN_LITERATURE prevalence; supportive therapy per PMID:31714006; Drosophila model; a knowledge gap on macrocephaly/obesity (the DDB1-BRWD3 adipogenesis data, PMID:34161765, predict the opposite direction) and a human-model mismatch discussion. Key decisions: ClinGen Definitive is against MONDO:0020119 (X-linked syndromic ID), so it is cited as evidence but not recorded as gene_disease_validity; the BRWD3 missense partial-epilepsy cohort (PMID:36514184) is noted, not modelled as a subtype; no PP2A/autophagy-lysosome claim was included because no source for it was found. No GeneReviews chapter (check-genereviews --online: NO_CHAPTER). Validation: just validate 0 issues; validate-disorders passed (58 snippets, 58 titles); check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens, check-coarse-phenotypes, check-term-cache-integrity, check-cache-order all OK; gene activity grounding gate reports no newly ungrounded genes.

Claude Code ▸
Intellectual Disability, X-linked 93 (MRX93 / XLID93; BRWD3-related XLID): Research Report
claude-haiku-4-5-20251001, claude-opus-5-5 28 citations 2026-10-01T10:51:31.901740

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

System ID
MONDO MONDO:0010393 "intellectual disability, X-linked 93" (parent MONDO:0019181 non-syndromic X-linked ID)
OMIM phenotype #300659 (XLID93), cited in PMID:42298746
OMIM gene *300553 BRWD3
DOID DOID:0112045 "non-syndromic X-linked intellectual disability 93"
Gene hgnc:17342 BRWD3 · Entrez 254065 · Ensembl ENSG00000165288 · UniProt Q6RI45
ClinGen BRWD3 is Definitive for X-linked syndromic intellectual disability (MONDO:0020119), from the Syndromic Disorders GCEP. This is not MONDO:0010393 (see §4).
Orphanet / ICD No disease-specific ORPHA code was confirmed; the orpha.net page was blocked. Specific ICD-10/11 codes are not applicable: it falls under the general X-linked ID codes. [lookup needed]
GeneReviews No chapter. Confirmed against the repo's cache/bookshelf/genereviews.csv, where the only XLID match is ATR-X.

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).

Phenotype HPO Frequency (males) Source
Intellectual disability (mild 35%, moderate 65%) HP:0001249; mild/moderate child terms [lookup needed] 39/39 (c), (b)
Delayed speech and language development HP:0000750 24/25 (c)
Macrocephaly (postnatal; mean OFC +2.8 SD) HP:0000256 28/35 (c), (b)
Prominent forehead HP:0011220 18/25 (c)
Broad forehead HP:0000337 shared feature (b)
Large ears / cupped ears HP:0000400 Macrotia; HP:0000378 Cupped ear 14/26 (c), PMID:17668385
Obesity (mean BMI +2.0 SD) HP:0001513 12/27 (c), (b)
Tall stature (mean height +1.3 SD; overgrowth) HP:0000098; HP:0001548 mild trend (b), PMID:30628072
Tall chin / pointed chin HP:0400000; HP:0000307 shared (b), (a)
Prognathism HP:0000303 Mandibular prognathia shared (b)
Prominent supraorbital ridges HP:0000336 shared (b)
Deeply set eye HP:0000490 reported (a)
Behavioral abnormality (aggression, ADHD, ASD) HP:0000718; HP:0007018; HP:0000729 75% (b); 7/8 (a) (a), (b)
Broad hands and feet HP:0001769 Broad foot; broad hand [lookup needed] 6/6 (a)
Skeletal: pes planus, scoliosis, kyphosis, cubitus valgus HP:0001763; HP:0002650; HP:0002808; HP:0002967 7/7 (any) (a)
Cryptorchidism HP:0000028 <30% (b)
Neonatal hypotonia HP:0001319 <30% (b)
Joint hypermobility (small joints) HP:0001382 <30% (b)
Seizure HP:0001250 4/41 males; 2/2 females (c)

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:

Intervention NCIT (cache-verified)
Early developmental intervention / special education free text; NCIT term [lookup needed]
Speech and language therapy NCIT:C159273 per CLAUDE.md table [not in cache, verify]
Physical therapy (hypotonia) NCIT:C15302
Occupational therapy NCIT:C121351
Behavioral management (ADHD/ASD/aggression); pharmacotherapy as indicated NCIT:C15986 Pharmacotherapy
Antiseizure medication where seizures occur (valproate and lamotrigine effective in the allelic IPE cohort, PMID:36514184) NCIT:C15986 + CHEBI agent [lookup needed]
Weight and dietary management NCIT:C15447 Dietary Intervention (from CLAUDE.md; not in cache)
Orthopedic follow-up (scoliosis, pes planus) —
Genetic counseling NCIT:C15240
Supportive care NCIT:C15747

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

Model Findings Fidelity / limits
Drosophila ram/dBRWD3 null mutants Larval lethal; eye cells show disrupted apical junctions and cytoskeleton (PMID:16904300). Excess H3.3, altered transcriptome, defective dendrite morphogenesis, rescued by yem/H3.3 loss (PMID:25666827). Required for PcG-mutant overgrowth (PMID:27588417). Invertebrate. The null is lethal, unlike the human hemizygous viable phenotype. No macrocephaly or obesity readout.
Drosophila S2 cells (in vitro) BRWD3 as a CRL4 DCAF for Cryptochrome (PMID:23479607) and KDM5 (PMID:37722046). JAK/STAT RNAi hit (PMID:16094372). Non-neuronal cell line.
Mouse (Ddb1+/-, 3T3-L1 adipogenesis) DDB1–BRWD3 promotes adipogenesis (PMID:34161765). Not a Brwd3 knockout. The direction conflicts with human obesity.
Brwd3 knockout mouse / iPSC neurons None identified (check MGI/IMPC [lookup needed]) The main translational gap; a HUMAN_MODEL_MISMATCH / KNOWLEDGE_GAP candidate

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

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome Count
References checked 22
Resolved 22
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 7
Quoted claims found in source 5
Quoted claims not found in source 2
References weighed for topical relevance 22
On topic 15
Off topic 0

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.

Outcome Count
Terms checked 56
Resolved 56
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 19
Terms named correctly 13
Terms named as a different term 3
Terms whose name is worth a second look 3

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