Weaver Syndrome

Mendelian MONDO:0010193 Pathograph 22 Show in embeddings browser Overgrowth Syndrome

Weaver syndrome (MONDO:0010193; OMIM 277590), also termed EZH2-related overgrowth, is a rare autosomal dominant overgrowth-intellectual disability syndrome caused by heterozygous germline pathogenic variants in EZH2, which encodes the catalytic histone methyltransferase subunit of Polycomb repressive complex 2 (PRC2). It is characterized by pre- and postnatal tall stature, markedly advanced (accelerated) bone age, macrocephaly, a distinctive craniofacial appearance (hypertelorism, broad forehead, almond-shaped palpebral fissures, retrognathia, and a pointed "stuck-on" chin with a horizontal crease), and variable, frequently mild intellectual disability. Additional features include camptodactyly, soft doughy skin, umbilical hernia, a low hoarse cry, and abnormal tone. There is an increased frequency of neuroblastoma. WS shows considerable clinical overlap with Sotos syndrome (NSD1); molecular confirmation of an EZH2 pathogenic variant provides an objective distinction, while a PRC2 DNA-methylation episignature can assist functional classification of uncertain PRC2 variants. EZH2 variants are predominantly missense, and isogenic studies of ten representative variants support dominant-negative interference with PRC2 H3K27 methylation.

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1
Inheritance
4
Pathophys.
16
Phenotypes
2
Hypotheses
2
Gaps
22
Pathograph
1
Genes
7
Medical Actions
1
Differentials
1
Models
1
References
1
Deep Research
🏷

Classifications

ISDS Skeletal Nosology
overgrowth syndromes with skeletal involvement
👪

Inheritance

1
Autosomal Dominant HP:0000006
EZH2-related overgrowth (Weaver syndrome) is inherited in an autosomal dominant manner. Both inherited and de novo pathogenic variants occur, but the proportion of de novo cases is unknown. Each child of an affected individual has a 50% chance of inheriting the variant, and phenotype in an individual who inherits a familial variant cannot be predicted.
Autosomal dominant inheritance Expressivity: VARIABLE
Show evidence (3 references)
PMID:23865096 SUPPORT Human Clinical
"EZH2-related overgrowth is inherited in an autosomal dominant manner."
GeneReviews establishes autosomal dominant inheritance for EZH2-related overgrowth (Weaver syndrome).
PMID:23865096 SUPPORT Human Clinical
"Some individuals diagnosed with EZH2-related overgrowth have an affected parent; some individuals diagnosed with EZH2-related overgrowth have the disorder as the result of a de novo EZH2 pathogenic variant. The proportion of individuals with EZH2-related overgrowth caused by a de novo pathogenic..."
GeneReviews documents both inherited and de novo cases and explicitly states that the de novo proportion is unknown.
PMID:23865096 SUPPORT Human Clinical
"Each child of an individual with EZH2-related overgrowth has a 50% chance of inheriting the pathogenic variant; the phenotype in individuals who inherit a familial EZH2 pathogenic variant cannot be predicted."
Supports the 50% transmission risk and variable expressivity relevant to family counseling.
◈

Mechanistic Hypotheses

2
Dominant-negative interference with PRC2
dominant_negative_prc2
Evidence balance 2 support
The scarcity of early truncating EZH2 variants and structural analysis support a dominant-negative mechanism, in which mutant EZH2 interferes with PRC2 activity (lowering H3K27me2/3 and increasing H3K27ac) rather than acting purely by haploinsufficiency. This contrasts with gain-of-function EZH2 variants that cause growth restriction, producing reciprocal chromatin/transcriptional changes.
Pathograph links
Reduced EZH2/PRC2 Histone Methyltransferase Activity -> H3K27me2/3 Depletion and Chromatin Decompaction DIRECT
Show evidence (2 references)
PMID:40846643 SUPPORT In Vitro
"the lack of early truncating mutations in EZH2 led us to hypothesize a dominant-negative mechanism for WS, which was supported by our structural analysis of all known WS-associated EZH2 variants."
Directly states the dominant-negative hypothesis and its structural support.
PMID:40846643 SUPPORT In Vitro
"Comparative analysis of a gain-of-function EZH2 variant causing growth restriction revealed reciprocal chromatin and transcriptional changes compared with WS-associated variants."
Supports the stated reciprocal relationship between Weaver-associated variants and a growth-restriction gain-of-function variant.
Loss-of-function / reduced PRC2 catalytic activity
loss_of_function_prc2
Evidence balance 2 support
Reduced PRC2 catalytic activity is a directly observed biochemical effect and is compatible with, rather than necessarily competing with, dominant-negative interference. In vitro reconstitution of tested Weaver-associated EZH2 alterations shows reduced H3K27 methyltransferase function, though activity differences among variants do not directly correlate with phenotypic severity.
Pathograph links
Reduced EZH2/PRC2 Histone Methyltransferase Activity -> H3K27me2/3 Depletion and Chromatin Decompaction DIRECT
Show evidence (2 references)
PMID:26694085 SUPPORT In Vitro
"Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2."
Supports impaired PRC2 catalytic function as a contributing mechanism.
PMID:26694085 SUPPORT In Vitro
"However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2."
Directly supports the caution that measured in vitro activity does not map simply to phenotypic variability.
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Discussions and Knowledge Gaps

2
Does the skeletal mechanism observed in the Ezh2 p.R684C knock-in mouse generalize to the diverse heterozygous EZH2 variants and developing human bone represented in Weaver syndrome?
HUMAN MODEL MISMATCH OPEN weaver_r684c_skeletal_model_generalizability
Attached to
pathophysiology#Dysregulated Osteoblast Differentiation and Excess Osteogenesis
The p.R684C mouse provides coherent molecular, cellular, and bone-level evidence for excess osteogenesis, but it models one recurrent allele. Its H3K27me3 readout was measured in homozygous mouse embryonic fibroblasts, whereas its skeletal phenotype was measured in heterozygous mice and osteoblasts. Human disease is heterozygous and genetically heterogeneous, and no cited study directly measures osteoblast differentiation or advanced bone age in human variant-bearing skeletal cells. The model therefore supports a candidate skeletal mechanism without establishing pan-allelic human generality.
Proposed experiments
Isogenic human osteoblast allelic-series study
weaver-human-osteoblast-allelic-series
Generate heterozygous p.R684C and several structurally diverse Weaver-associated EZH2 variants in the same human iPSC background, differentiate them through mesenchymal progenitors into osteoblasts, and compare them with corrected isogenic controls across matched time points.
Readouts
H3K27me2/3 abundance, BMP-pathway transcription, and osteogenic differentiation kinetics by allele
pathophysiology#Dysregulated Osteoblast Differentiation and Excess Osteogenesis
Decision criterion
Concordant H3K27 loss and excess osteogenesis across variant classes, with correction after restoration of wild-type EZH2 dosage, would support a general human skeletal mechanism. Absent, opposite, or allele-restricted effects would confine the mouse result to p.R684C or identify mechanistic subgroups.
Show evidence (1 reference)
PMID:38015625 SUPPORT Model Organism
"We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts..."
Establishes both the strength and the allele-, organism-, and zygosity-specific boundaries of the current skeletal model.
By what developmental and cell-type-specific mechanism does a germline heterozygous EZH2 pathogenic variant increase neuroblastoma frequency in Weaver syndrome?
KNOWLEDGE GAP OPEN weaver_neuroblastoma_mechanistic_bridge
Attached to
phenotypes#Neuroblastoma Predisposition pathophysiology#Impaired Polycomb Repression and Gene Derepression
The human association with neuroblastoma is recognized, but the curated molecular studies establish PRC2/H3K27 disruption and growth-gene derepression in stem-cell systems rather than a transformation mechanism in the sympathoadrenal lineage from which neuroblastoma arises. Connecting these observations without lineage-specific evidence would overstate the pathograph. Resolving the bridge matters both for biological interpretation and for determining whether surveillance should eventually be stratified by variant or molecular phenotype.
Proposed experiments
Isogenic human sympathoadrenal-lineage tumor-predisposition model
weaver-neural-crest-neuroblastoma-model
Differentiate isogenic human iPSCs carrying representative heterozygous Weaver EZH2 variants and corrected controls through neural crest into sympathoadrenal progenitors, then follow chromatin state, differentiation, proliferation, and transformation-associated phenotypes longitudinally.
Readouts
Variant-dependent H3K27/cPRC1 state and sympathoadrenal differentiation trajectory
pathophysiology#Impaired Polycomb Repression and Gene Derepression
Persistent proliferative or transformation-associated phenotype in sympathoadrenal progenitors
phenotypes#Neuroblastoma Predisposition
Decision criterion
A reproducible variant-dependent chromatin defect that precedes impaired sympathoadrenal differentiation and persistent proliferative behavior, and is reversed by isogenic correction, would support a mechanistic bridge. Normal lineage behavior despite the expected H3K27 defect would argue that additional developmental, somatic, or environmental events are required.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"Neuroblastoma occurs at an increased frequency in individuals with a heterozygous EZH2 pathogenic variant."
Establishes the human tumor association whose molecular bridge remains unresolved.
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Pathophysiology

4
Reduced EZH2/PRC2 Histone Methyltransferase Activity
EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), the predominant enzyme that mono-, di-, and trimethylates histone H3 lysine 27 (H3K27me1/2/3). Heterozygous germline pathogenic EZH2 variants in Weaver syndrome are predominantly missense. In vitro reconstitution demonstrates reduced methyltransferase activity for tested Weaver-associated amino-acid changes. Isogenic work on ten representative variants further supports dominant-negative interference with PRC2 activity, but does not establish identical behavior for every reported allele.
Dominant-negative interference with PRC2 Loss-of-function / reduced PRC2 catalytic activity
EZH2 hgnc:3527 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves EZH2 (hgnc:3527). hgnc:3527 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context EZH2 hgnc:3527 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns EZH2 (hgnc:3527). hgnc:3527 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE allelic_event: PATHOGENIC_VARIANT zygosity: HETEROZYGOUS
Heterozygous germline EZH2 pathogenic variants are the disease trigger; most reported alleles are missense, but the structured context does not restrict the mechanism to one sequence-variant class.
PRC2 (PcG protein complex) GO:0031519 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves PRC2 (PcG protein complex), annotated with PcG protein complex (GO:0031519). GO:0031519 is a protein complex from the Gene Ontology.
peptidyl-lysine (H3K27) methylation GO:0018022 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased peptidyl-lysine (H3K27) methylation, annotated with peptidyl-lysine methylation (GO:0018022). GO:0018022 is a biological process from the Gene Ontology. ↓ DECREASED
histone H3K27 methyltransferase activity GO:0046976 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased histone H3K27 methyltransferase activity (GO:0046976). GO:0046976 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
H3K27me2/3 Depletion and Chromatin Decompaction Dominant-negative interference with PRC2 Loss-of-function / reduced PRC2 catalytic activity
Show evidence (4 references)
PMID:40846643 SUPPORT In Vitro
"Heterozygous missense mutations in EZH2 cause Weaver syndrome (WS), a developmental disorder characterized by intellectual disability and overgrowth. EZH2 encodes the enzymatic subunit of Polycomb repressive complex 2 (PRC2), which mediates monomethylation, dimethylation, and trimethylation of..."
Supports the causal heterozygous EZH2 context and the PRC2 H3K27 catalytic function represented by this node.
PMID:24214728 SUPPORT Human Clinical
"The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain."
Bounds the variant-spectrum claim: missense variants predominate, but truncating variants also occur.
PMID:26694085 SUPPORT In Vitro
"We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay."
In vitro PRC2 assays directly demonstrate impaired EZH2 methyltransferase activity for the tested Weaver-associated variants.
+ 1 more reference
H3K27me2/3 Depletion and Chromatin Decompaction
In isogenic embryonic stem-cell models, ten representative Weaver-associated EZH2 variants reduce global H3K27me2/3, increase H3K27ac, and decompact chromatin. These are model-system molecular readouts rather than measurements from affected human developmental tissues.
embryonic stem cell CL:0002322 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves embryonic stem cell (CL:0002322). CL:0002322 is a cell type from the Cell Ontology.
chromatin organization GO:0006325 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal chromatin organization (GO:0006325). GO:0006325 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Polycomb Repression and Gene Derepression
Show evidence (1 reference)
PMID:40846643 SUPPORT In Vitro
"We isogenically modeled 10 representative variants in embryonic stem cells and showed that they reduce global H3K27me2/3 with concomitant increases in H3K27ac and chromatin decompaction."
Defines the H3K27 and chromatin-state phenotype in the isogenic variant panel.
Impaired Polycomb Repression and Gene Derepression
Weaver-associated EZH2 variants cause loss of canonical PRC1 occupancy and derepression at weakly Polycomb-bound genes in an isogenic stem-cell system. Several affected genes regulate growth, providing a plausible bridge from altered chromatin to overgrowth; the tissue-specific developmental intermediates remain incompletely defined.
facultative heterochromatin formation GO:0140718 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased facultative heterochromatin formation (GO:0140718). GO:0140718 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Dysregulated Osteoblast Differentiation and Excess Osteogenesis
Tall Stature / Overgrowth
Large for Gestational Age (Prenatal Overgrowth)
Accelerated Skeletal Maturation (Advanced Bone Age)
Macrocephaly
Intellectual Disability / Developmental Delay
Ocular Hypertelorism
Broad Forehead
Almond-Shaped Palpebral Fissures
Retrognathia
Camptodactyly
Soft, Doughy Skin
Umbilical Hernia
Low, Hoarse Cry
Abnormal Muscle Tone
Poor Coordination
Show evidence (2 references)
PMID:40846643 SUPPORT In Vitro
"RNA-seq identified weakly Polycomb-bound genes that lose canonical PRC1 (cPRC1) occupancy and become derepressed, including several phenotypically relevant growth control genes."
WS EZH2 variants derepress Polycomb-bound growth control genes via loss of cPRC1 occupancy.
PMID:22190405 SUPPORT Human Clinical
"Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth."
Connects EZH2/histone modification dysregulation to the control of human growth.
Dysregulated Osteoblast Differentiation and Excess Osteogenesis
In the heterozygous Ezh2 p.R684C knock-in mouse, bone parameters indicate skeletal overgrowth and osteoblasts show increased osteogenic activity. Transcriptomic data from mouse bone-marrow mesenchymal stem cell-derived osteoblasts implicate dysregulated BMP signaling and osteoblast differentiation. This supports a variant-specific skeletal mechanism in a model organism; its generalization to diverse human EZH2 variants and human advanced bone age remains untested.
osteoblast CL:0000062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves osteoblast (CL:0000062). CL:0000062 is a cell type from the Cell Ontology. bone marrow mesenchymal stem cell CL:0002540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves bone marrow mesenchymal stem cell, annotated with mesenchymal stem cell of the bone marrow (CL:0002540). CL:0002540 is a cell type from the Cell Ontology.
osteoblast differentiation GO:0001649 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal osteoblast differentiation (GO:0001649). GO:0001649 is a biological process from the Gene Ontology. ⚠ ABNORMAL BMP signaling pathway GO:0030509 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal BMP signaling pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Tall Stature / Overgrowth
Show evidence (2 references)
PMID:38015625 SUPPORT Model Organism
"Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity."
Mouse model recapitulates skeletal overgrowth and excess osteoblast activity.
PMID:38015625 SUPPORT Model Organism
"RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation."
Transcriptomics implicate BMP pathway and osteoblast differentiation dysregulation in skeletal overgrowth.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Weaver Syndrome 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

16
Eye 1
Ocular Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38585548 SUPPORT Human Clinical
"The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed "stuck-on" chin with horizontal skin creases, and retrognathia."
Directly identifies ocular hypertelorism as a characteristic Weaver facial feature.
Head and Neck 2
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"EZH2-related overgrowth is a variable overgrowth syndrome characterized by tall stature, macrocephaly, variable intellect"
GeneReviews lists macrocephaly as a core characteristic.
Almond-Shaped Palpebral Fissures HP:0007874 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Almond-shaped palpebral fissure (HP:0007874). HP:0007874 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38585548 SUPPORT Human Clinical
"ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures"
Almond-shaped palpebral fissures are characteristic of WS.
Musculoskeletal 2
Accelerated Skeletal Maturation (Advanced Bone Age) HP:0005616 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Accelerated skeletal maturation (HP:0005616). HP:0005616 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly"
GeneReviews lists advanced bone age among the associated clinical features.
Camptodactyly HP:0012385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly (HP:0012385). HP:0012385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24214728 SUPPORT Human Clinical
"Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry."
Camptodactyly listed among additional discriminating WS features.
Nervous System 1
Intellectual Disability / Developmental Delay VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24214728 SUPPORT Human Clinical
"Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild."
Supports the approximately 80% frequency and explicitly variable degree of intellectual impairment.
Voice 1
Low, Hoarse Cry Hoarse voice HP:0001609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hoarse, low-pitched cry, annotated with Hoarse voice (HP:0001609), qualified as infantile onset. HP:0001609 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"abnormal tone, and hoarse, low cry in infancy."
GeneReviews lists a hoarse, low cry in infancy among the clinical features.
Growth 2
Tall Stature / Overgrowth VERY_FREQUENT 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 (1 reference)
PMID:24214728 SUPPORT Human Clinical
"tall stature is very common, reported in >90% of affected individuals."
Tall stature reported in >90% of the EZH2-positive cohort, supporting VERY_FREQUENT.
Large for Gestational Age (Prenatal Overgrowth) HP:0001520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large for gestational age (HP:0001520), qualified as congenital onset. HP:0001520 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"Families and their health care providers should be made aware that an affected baby may be large so that appropriate delivery plans can be made."
GeneReviews notes prenatal overgrowth manifesting as large babies.
Other 7
Broad Forehead HP:0000337 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Broad forehead (HP:0000337). HP:0000337 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38585548 SUPPORT Human Clinical
"The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures"
Broad forehead is part of the WS craniofacial gestalt.
Retrognathia HP:0000278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38585548 SUPPORT Human Clinical
"a pointed "stuck-on" chin with horizontal skin creases, and retrognathia."
Retrognathia with characteristic chin is part of the WS facial gestalt.
Soft, Doughy Skin HP:0001027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Soft, doughy skin (HP:0001027). HP:0001027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24214728 SUPPORT Human Clinical
"Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry."
Soft, doughy skin listed among additional WS features.
Umbilical Hernia HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24214728 SUPPORT Human Clinical
"Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry."
Umbilical hernia listed among additional WS features.
Abnormal Muscle Tone HP:0003808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal muscle tone (HP:0003808). HP:0003808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
GeneReviews lists abnormal tone among the clinical features.
Poor Coordination Incoordination HP:0002311 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Incoordination (HP:0002311). HP:0002311 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin"
GeneReviews lists poor coordination among the clinical features.
Neuroblastoma Predisposition HP:0003006 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neuroblastoma (HP:0003006). HP:0003006 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23865096 SUPPORT Human Clinical
"Neuroblastoma occurs at an increased frequency in individuals with a heterozygous EZH2 pathogenic variant."
GeneReviews documents increased neuroblastoma frequency in EZH2-related overgrowth.
PMID:23865096 SUPPORT Human Clinical
"There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency, though a few have been reported."
Bounds the cancer-predisposition claim: an increased frequency is currently established for neuroblastoma, not for other reported malignancies.
🧬

Genetic Associations

1
EZH2 (Pathogenic Variants)
Gene: EZH2 hgnc:3527 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is EZH2 (hgnc:3527). hgnc:3527 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:22177091 SUPPORT Human Clinical
"These data show that mutations in EZH2 cause Weaver syndrome."
Establishes EZH2 as the causal gene for Weaver syndrome.
PMID:24214728 SUPPORT Human Clinical
"The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain."
Characterizes the EZH2 variant spectrum (mostly missense, rare truncating in final exon).
PMID:23865096 SUPPORT Human Clinical
"The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing."
GeneReviews confirms heterozygous germline EZH2 variants are diagnostic.
+ 2 more references
💊

Medical Actions

7
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. NCIT:C15240
Genetic counseling for recurrence risk and reproductive planning. Inheritance is autosomal dominant; each child of an affected individual has a 50% chance of inheriting the variant, but phenotype in a child who inherits a familial variant cannot be predicted. Once a familial variant is identified, prenatal and preimplantation genetic testing are possible.
Show evidence (2 references)
PMID:23865096 SUPPORT Human Clinical
"Each child of an individual with EZH2-related overgrowth has a 50% chance of inheriting the pathogenic variant; the phenotype in individuals who inherit a familial EZH2 pathogenic variant cannot be predicted."
Supports counseling on both transmission probability and unpredictable expressivity.
PMID:23865096 SUPPORT Human Clinical
"Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
Directly supports the stated reproductive testing options.
Developmental Assessment and Support
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Individuals with developmental delay or learning disability may benefit from referral for learning, behavioral, and speech assessment and individualized support.
Target Phenotypes: Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"For individuals with developmental delay and/or learning disability, referral for learning/behavior/speech assessment and support may be indicated."
GeneReviews directly recommends developmental, learning, behavioral, and speech assessment and support.
Physical Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Physiotherapy may help joint pain related to ligamentous laxity or joint contractures.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"Physiotherapy may be of benefit to those experiencing joint pain secondary to ligamentous laxity or joint contractures."
GeneReviews recommends physiotherapy for joint pain in EZH2-related overgrowth.
Surgical Release of Camptodactyly
Action: surgical procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Toe camptodactyly may occasionally require surgical release.
Target Phenotypes: Camptodactyly HP:0012385 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Camptodactyly (HP:0012385). HP:0012385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"Occasionally, toe camptodactyly may require surgical release."
GeneReviews notes occasional surgical release for toe camptodactyly.
Developmental, Tone, and Camptodactyly Follow-up
Category: Monitoring Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Young children should receive regular medical follow-up to monitor developmental progress, camptodactyly for resolution or improvement, and hypotonia. Follow-up may be less frequent for older children and teenagers without medical complications.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"Regular medical follow up of young children with EZH2-related overgrowth to monitor developmental progress, camptodactyly (for resolution/improvement), and/or hypotonia; medical follow up of older children/teenagers who do not have medical complications may be less frequent."
Directly supports the age-stratified clinical follow-up recommendation.
Manifestation-Specific Specialist Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Epilepsy, scoliosis, and other clinical issues should receive standard treatment with appropriate specialist referral when present. Scoliosis monitoring should follow the treating orthopedist's recommendations.
Show evidence (2 references)
PMID:23865096 SUPPORT Human Clinical
"Standard treatment with appropriate specialist referral(s) is indicated for epilepsy, scoliosis, and other clinical issues."
Directly supports manifestation-specific treatment and specialist referral.
PMID:23865096 SUPPORT Human Clinical
"If scoliosis is present, monitoring per the recommendations of an orthopedist."
Directly supports specialist-directed scoliosis monitoring when scoliosis is present.
Neuroblastoma Surveillance
Category: Monitoring Action: surveillance for malignanciesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surveillance for malignancies, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
There are no internationally ratified neuroblastoma surveillance guidelines for individuals carrying inactivating EZH2 pathogenic variants, but US guidelines recommend imaging and urine biochemistry surveillance until age 10 years; clinicians should maintain a low threshold for investigating possible tumor-related symptoms.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"Clinicians should have a low threshold for investigating any possible tumor-related symptoms. There are no internationally ratified surveillance guidelines for screening of neuroblastoma in individuals carrying inactivating EZH2 pathogenic variants, but US guidelines recommend imaging and urine..."
Supports both the symptom-triggered vigilance and the qualified, jurisdiction-specific surveillance recommendation.
🔬

Diagnosis

2
Molecular Genetic Confirmation
The diagnosis of EZH2-related overgrowth is established by detecting a heterozygous germline pathogenic variant in EZH2 on molecular genetic testing.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Detection of a heterozygous germline pathogenic EZH2 variant establishes the diagnosis.
Show evidence (1 reference)
PMID:23865096 SUPPORT Human Clinical
"The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing."
GeneReviews states the defining molecular diagnostic criterion.
PRC2 DNA Methylation Episignature Analysis
Genome-wide DNA methylation analysis can detect a highly specific and sensitive Weaver-associated signature in the studied cohort. The signature can functionally classify loss-of-function versus gain-of-function missense variants, detect somatic mosaicism, and classify variants in the other PRC2 core genes EED and SUZ12. It is an adjunct to variant interpretation; the defining Weaver diagnosis remains a heterozygous germline EZH2 pathogenic variant.
DNA methylation episignature analysis NCIT:C63328 NCI Thesaurus (NCIT)
Results: A matching signature supports functional classification of an EZH2 or other core-PRC2 sequence variant, including mosaic and opposing functional states.
Show evidence (3 references)
PMID:32243864 SUPPORT Human Clinical
"Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from..."
Defines the study population, Weaver-associated signature, and its demonstrated functional-classification uses.
PMID:32243864 SUPPORT Human Clinical
"We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID."
Supports extension of the PRC2 signature to EED and SUZ12 variant classification.
PMID:23865096 SUPPORT Human Clinical
"The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing."
Prevents the adjunctive episignature from being misrepresented as a replacement for the defining molecular diagnosis.
📈

Progression

1
Age: Older individuals
Facial features may be subtle, and clinical recognition becomes particularly challenging in older individuals. This is an age-dependent recognition issue; the cited cohort does not establish a progressive loss of facial features.
Show evidence (1 reference)
PMID:24214728 SUPPORT Human Clinical
"Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals."
Directly supports age-dependent difficulty recognizing the facial phenotype.
📊

Prevalence

1
Worldwide
Unknown Rare
Weaver syndrome is rare, but a reliable population prevalence or incidence estimate has not been established. The evidence supports qualitative rarity; the published case-series count below is not treated as a prevalence estimate.
Show evidence (1 reference)
PMID:38585548 SUPPORT Human Clinical
"Weaver syndrome (WS) is a rare autosomal dominant disorder characterized by distinctive facial features, pre- and post-natal overgrowth, macrocephaly, and variable developmental delay."
This clinical report directly characterizes Weaver syndrome as rare; it does not provide a numerical population estimate.
🌍

Epidemiology

1
2013 EZH2-Positive Cohort Size
A 2013 series identified 48 individuals with EZH2 mutations. This is a historical case-series count rather than a population prevalence estimate and should not be interpreted as the current worldwide number of affected people.
Show evidence (1 reference)
PMID:24214728 SUPPORT Human Clinical
"To date, we have identified 48 individuals with EZH2 mutations."
Records the cohort size as reported in 2013 without converting it into a prevalence estimate or a time-stable worldwide case count.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Weaver Syndrome:

Sotos Syndrome
Overlapping Features Sotos syndrome (NSD1) is an important differential diagnosis because of its considerable phenotypic overlap with Weaver syndrome. Weaver facial features may be subtle, particularly in older individuals, so identification of an EZH2 pathogenic variant provides an objective means of confirming Weaver syndrome and distinguishing it from Sotos syndrome.
Show evidence (2 references)
PMID:24214728 SUPPORT Human Clinical
"Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident."
Documents the clinical overlap between Sotos and Weaver syndromes motivating differential diagnosis.
PMID:24214728 SUPPORT Human Clinical
"The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes."
Directly supports molecular EZH2 confirmation as the objective discriminator from Sotos syndrome.
🐁

Animal Models

1
Ezh2 p.R684C knock-in (Ezh2R684C/+ heterozygous; Ezh2R684C/R684C homozygous) Mouse knock-in mouse model
Knock-in mouse model of the most common Weaver syndrome EZH2 missense variant (p.R684C). Homozygous MEFs show global H3K27me3 depletion; heterozygous mice show abnormal bone parameters indicative of skeletal overgrowth and increased osteoblast osteogenic activity, with BMP-pathway and osteoblast-differentiation transcriptional dysregulation. Excess osteogenesis is reversible by inhibiting the opposing H3K27 demethylases KDM6A/KDM6B, demonstrating reversibility and therapeutic potential of epigenetic modulating agents.
Skeletal overgrowth Excess osteogenesis Global H3K27me3 depletion
Species
Mouse
Genotype
Ezh2 p.R684C knock-in (Ezh2R684C/+ heterozygous; Ezh2R684C/R684C homozygous)
Genes
EZH2 hgnc:3527 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns EZH2 (hgnc:3527). hgnc:3527 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:38015625 SUPPORT Model Organism
"We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3."
Describes the EZH2 p.R684C knock-in mouse model and its molecular phenotype.
PMID:38015625 SUPPORT Model Organism
"Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels."
Demonstrates pharmacologic reversibility of the osteogenic phenotype via KDM6A/6B inhibition.
PMID:38015625 SUPPORT Model Organism
"This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs."
Supports the model-level therapeutic-potential statement without implying demonstrated benefit in people with Weaver syndrome.
{ }

Source YAML

click to show 
name: Weaver Syndrome
synonyms:
- Weaver syndrome, EZH2-related
- EZH2-related overgrowth
- WVS
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >-
  Weaver syndrome (MONDO:0010193; OMIM 277590), also termed EZH2-related
  overgrowth, is a rare autosomal dominant overgrowth-intellectual disability
  syndrome caused by heterozygous germline pathogenic variants in EZH2, which
  encodes the catalytic histone methyltransferase subunit of Polycomb repressive
  complex 2 (PRC2). It is characterized by pre- and postnatal tall stature,
  markedly advanced (accelerated) bone age, macrocephaly, a distinctive
  craniofacial appearance (hypertelorism, broad forehead, almond-shaped
  palpebral fissures, retrognathia, and a pointed "stuck-on" chin with a
  horizontal crease), and variable, frequently mild intellectual disability.
  Additional features include camptodactyly, soft doughy skin, umbilical hernia,
  a low hoarse cry, and abnormal tone. There is an increased frequency of
  neuroblastoma. WS shows considerable clinical overlap with Sotos syndrome
  (NSD1); molecular confirmation of an EZH2 pathogenic variant provides an
  objective distinction, while a PRC2 DNA-methylation episignature can assist
  functional classification of uncertain PRC2 variants. EZH2 variants are
  predominantly missense, and isogenic studies of ten representative variants
  support dominant-negative interference with PRC2 H3K27 methylation.
disease_term:
  preferred_term: Weaver syndrome
  description: >-
    EZH2-related autosomal dominant overgrowth syndrome with advanced bone age,
    distinctive facies, and variable intellectual disability.
  term:
    id: MONDO:0010193
    label: Weaver syndrome
parents:
- Overgrowth Syndrome
references:
- reference: PMID:23865096
  title: "EZH2-Related Overgrowth."
  tags:
  - GeneReviews
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    Weaver syndrome is rare, but a reliable population prevalence or incidence
    estimate has not been established. The evidence supports qualitative rarity;
    the published case-series count below is not treated as a prevalence estimate.
  evidence:
  - reference: PMID:38585548
    reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Weaver syndrome (WS) is a rare autosomal dominant disorder characterized by distinctive facial features, pre- and post-natal overgrowth, macrocephaly, and variable developmental delay."
    explanation: This clinical report directly characterizes Weaver syndrome as rare; it does not provide a numerical population estimate.
inheritance:
- name: Autosomal Dominant
  description: >-
    EZH2-related overgrowth (Weaver syndrome) is inherited in an autosomal
    dominant manner. Both inherited and de novo pathogenic variants occur, but
    the proportion of de novo cases is unknown. Each child of an affected
    individual has a 50% chance of inheriting the variant, and phenotype in an
    individual who inherits a familial variant cannot be predicted.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  expressivity: VARIABLE
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EZH2-related overgrowth is inherited in an autosomal dominant manner."
    explanation: GeneReviews establishes autosomal dominant inheritance for EZH2-related overgrowth (Weaver syndrome).
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some individuals diagnosed with EZH2-related overgrowth have an affected parent; some individuals diagnosed with EZH2-related overgrowth have the disorder as the result of a de novo EZH2 pathogenic variant. The proportion of individuals with EZH2-related overgrowth caused by a de novo pathogenic variant is unknown."
    explanation: GeneReviews documents both inherited and de novo cases and explicitly states that the de novo proportion is unknown.
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with EZH2-related overgrowth has a 50% chance of inheriting the pathogenic variant; the phenotype in individuals who inherit a familial EZH2 pathogenic variant cannot be predicted."
    explanation: Supports the 50% transmission risk and variable expressivity relevant to family counseling.

classifications:
  isds_skeletal_category:
  - classification_value: overgrowth_syndromes_with_skeletal_involvement
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019
      revision (Mortier et al., PMID:31633310), Table 1 group 30 "Overgrowth (tall
      stature) syndromes with skeletal involvement"; listed as "Weaver syndrome".
pathophysiology:
- name: Reduced EZH2/PRC2 Histone Methyltransferase Activity
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Epigenetic Machinery Component Haploinsufficiency"
  description: >-
    EZH2 is the catalytic subunit of Polycomb repressive complex 2 (PRC2), the
    predominant enzyme that mono-, di-, and trimethylates histone H3 lysine 27
    (H3K27me1/2/3). Heterozygous germline pathogenic EZH2 variants in Weaver
    syndrome are predominantly missense. In vitro reconstitution demonstrates
    reduced methyltransferase activity for tested Weaver-associated amino-acid
    changes. Isogenic work on ten representative variants further supports
    dominant-negative interference with PRC2 activity, but does not establish
    identical behavior for every reported allele.
  biological_scale: MOLECULAR
  gene:
    preferred_term: EZH2
    term:
      id: hgnc:3527
      label: EZH2
  genetic_context:
    gene:
      preferred_term: EZH2
      term:
        id: hgnc:3527
        label: EZH2
    variant_origin: GERMLINE
    allelic_events:
    - PATHOGENIC_VARIANT
    zygosity: HETEROZYGOUS
    description: >-
      Heterozygous germline EZH2 pathogenic variants are the disease trigger;
      most reported alleles are missense, but the structured context does not
      restrict the mechanism to one sequence-variant class.
  biological_processes:
  - preferred_term: peptidyl-lysine (H3K27) methylation
    term:
      id: GO:0018022
      label: peptidyl-lysine methylation
    modifier: DECREASED
  molecular_functions:
  - preferred_term: histone H3K27 methyltransferase activity
    term:
      id: GO:0046976
      label: histone H3K27 methyltransferase activity
    modifier: DECREASED
  protein_complexes:
  - preferred_term: PRC2 (PcG protein complex)
    term:
      id: GO:0031519
      label: PcG protein complex
  evidence:
  - reference: PMID:40846643
    reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Heterozygous missense mutations in EZH2 cause Weaver syndrome (WS), a developmental disorder characterized by intellectual disability and overgrowth. EZH2 encodes the enzymatic subunit of Polycomb repressive complex 2 (PRC2), which mediates monomethylation, dimethylation, and trimethylation of histone H3 lysine 27 (H3K27me1/2/3)."
    explanation: Supports the causal heterozygous EZH2 context and the PRC2 H3K27 catalytic function represented by this node.
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain."
    explanation: >-
      Bounds the variant-spectrum claim: missense variants predominate, but
      truncating variants also occur.
  - reference: PMID:26694085
    reference_title: "Weaver syndrome-associated EZH2 protein variants show impaired histone methyltransferase function in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We found that WS-associated amino acid alterations reduce the histone methyltransferase function of EZH2 in this in vitro assay."
    explanation: In vitro PRC2 assays directly demonstrate impaired EZH2 methyltransferase activity for the tested Weaver-associated variants.
  - reference: PMID:40846643
    reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Notably, the pattern of H3K27me2/3 reductions indicated dominant-negative interference on PRC2 activity even when WS variants were expressed at low levels."
    explanation: The isogenic study supports dominant-negative interference with PRC2 for its representative Weaver variant panel.
  downstream:
  - target: H3K27me2/3 Depletion and Chromatin Decompaction
    causal_link_type: DIRECT
    hypothesis_groups:
    - dominant_negative_prc2
    - loss_of_function_prc2
    evidence:
    - reference: PMID:40846643
      reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We isogenically modeled 10 representative variants in embryonic stem cells and showed that they reduce global H3K27me2/3 with concomitant increases in H3K27ac and chromatin decompaction."
      explanation: Directly supports the modeled transition from reduced PRC2 activity to depleted H3K27me2/3 and decompacted chromatin in the representative isogenic variants.

- name: H3K27me2/3 Depletion and Chromatin Decompaction
  conforms_to: "epigenetic_machinery_neurodevelopmental_dysregulation#Permissive-Repressive Chromatin State Imbalance"
  description: >-
    In isogenic embryonic stem-cell models, ten representative
    Weaver-associated EZH2 variants reduce global H3K27me2/3, increase H3K27ac,
    and decompact chromatin. These are model-system molecular readouts rather
    than measurements from affected human developmental tissues.
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: embryonic stem cell
    term:
      id: CL:0002322
      label: embryonic stem cell
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40846643
    reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We isogenically modeled 10 representative variants in embryonic stem cells and showed that they reduce global H3K27me2/3 with concomitant increases in H3K27ac and chromatin decompaction."
    explanation: Defines the H3K27 and chromatin-state phenotype in the isogenic variant panel.
  downstream:
  - target: Impaired Polycomb Repression and Gene Derepression
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of canonical PRC1 occupancy at weakly Polycomb-bound loci
    evidence:
    - reference: PMID:40846643
      reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "RNA-seq identified weakly Polycomb-bound genes that lose canonical PRC1 (cPRC1) occupancy and become derepressed, including several phenotypically relevant growth control genes."
      explanation: The same isogenic study observes cPRC1 loss and derepression, although it does not isolate every causal intermediate between the H3K27 change and transcriptional output.

- name: Impaired Polycomb Repression and Gene Derepression
  description: >-
    Weaver-associated EZH2 variants cause loss of canonical PRC1 occupancy and
    derepression at weakly Polycomb-bound genes in an isogenic stem-cell system.
    Several affected genes regulate growth, providing a plausible bridge from
    altered chromatin to overgrowth; the tissue-specific developmental
    intermediates remain incompletely defined.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: facultative heterochromatin formation
    term:
      id: GO:0140718
      label: facultative heterochromatin formation
    modifier: DECREASED
  evidence:
  - reference: PMID:40846643
    reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA-seq identified weakly Polycomb-bound genes that lose canonical PRC1 (cPRC1) occupancy and become derepressed, including several phenotypically relevant growth control genes."
    explanation: WS EZH2 variants derepress Polycomb-bound growth control genes via loss of cPRC1 occupancy.
  - reference: PMID:22190405
    reference_title: "Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth."
    explanation: Connects EZH2/histone modification dysregulation to the control of human growth.
  downstream:
  - target: Dysregulated Osteoblast Differentiation and Excess Osteogenesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38015625
      reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity."
      explanation: The p.R684C mouse links an EZH2 Weaver variant to excess osteogenesis but does not resolve the intermediates from Polycomb target-gene derepression.
  - target: Tall Stature / Overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:22190405
      reference_title: "Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth."
      explanation: Links EZH2-dependent histone modification to human growth, while leaving the intervening developmental mechanism unresolved.
  - target: Large for Gestational Age (Prenatal Overgrowth)
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Families and their health care providers should be made aware that an affected baby may be large so that appropriate delivery plans can be made."
      explanation: Establishes prenatal overgrowth in EZH2-related overgrowth but not the tissue-specific intermediates from Polycomb dysregulation.
  - target: Accelerated Skeletal Maturation (Advanced Bone Age)
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
      explanation: Establishes advanced bone age in EZH2-related overgrowth while leaving its developmental bridge from Polycomb dysregulation unresolved.
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "EZH2-related overgrowth is a variable overgrowth syndrome characterized by tall stature, macrocephaly, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance"
      explanation: Establishes macrocephaly in the causal EZH2 condition but not a specific molecular-to-anatomic intermediate.
  - target: Intellectual Disability / Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "EZH2-related overgrowth is a variable overgrowth syndrome characterized by tall stature, macrocephaly, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance"
      explanation: Establishes variable intellectual impairment in the causal EZH2 condition while the neurodevelopmental intermediates remain unknown.
  - target: Ocular Hypertelorism
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38585548
      reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia."
      explanation: Establishes hypertelorism in Weaver syndrome but not its tissue-specific mechanistic bridge from Polycomb dysregulation.
  - target: Broad Forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38585548
      reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia."
      explanation: Establishes broad forehead in Weaver syndrome but not its tissue-specific mechanistic bridge from Polycomb dysregulation.
  - target: Almond-Shaped Palpebral Fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38585548
      reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia."
      explanation: Establishes the palpebral-fissure phenotype in Weaver syndrome but not its tissue-specific mechanistic bridge from Polycomb dysregulation.
  - target: Retrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38585548
      reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia."
      explanation: Establishes retrognathia in Weaver syndrome but not its tissue-specific mechanistic bridge from Polycomb dysregulation.
  - target: Camptodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
      explanation: Establishes camptodactyly in EZH2-related overgrowth while its tissue-specific mechanistic bridge remains unknown.
  - target: Soft, Doughy Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
      explanation: Establishes soft, doughy skin in EZH2-related overgrowth while its tissue-specific mechanistic bridge remains unknown.
  - target: Umbilical Hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
      explanation: Establishes umbilical hernia in EZH2-related overgrowth while its tissue-specific mechanistic bridge remains unknown.
  - target: Low, Hoarse Cry
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
      explanation: Establishes the infantile hoarse, low cry in EZH2-related overgrowth while its tissue-specific mechanistic bridge remains unknown.
  - target: Abnormal Muscle Tone
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
      explanation: Establishes abnormal tone in EZH2-related overgrowth while its neurodevelopmental intermediates remain unknown.
  - target: Poor Coordination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23865096
      reference_title: "EZH2-Related Overgrowth."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
      explanation: Establishes poor coordination in EZH2-related overgrowth while its neurodevelopmental intermediates remain unknown.

- name: Dysregulated Osteoblast Differentiation and Excess Osteogenesis
  description: >-
    In the heterozygous Ezh2 p.R684C knock-in mouse, bone parameters indicate
    skeletal overgrowth and osteoblasts show increased osteogenic activity.
    Transcriptomic data from mouse bone-marrow mesenchymal stem cell-derived
    osteoblasts implicate dysregulated BMP signaling and osteoblast
    differentiation. This supports a variant-specific skeletal mechanism in a
    model organism; its generalization to diverse human EZH2 variants and human
    advanced bone age remains untested.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  - preferred_term: bone marrow mesenchymal stem cell
    term:
      id: CL:0002540
      label: mesenchymal stem cell of the bone marrow
  biological_processes:
  - preferred_term: osteoblast differentiation
    term:
      id: GO:0001649
      label: osteoblast differentiation
    modifier: ABNORMAL
  - preferred_term: BMP signaling pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity."
    explanation: Mouse model recapitulates skeletal overgrowth and excess osteoblast activity.
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RNA-Seq comparing osteoblasts differentiated from Ezh2R684C/+, and Ezh2+/+ BM-mesenchymal stem cells (BM-MSCs) indicated collective dysregulation of the BMP pathway and osteoblast differentiation."
    explanation: Transcriptomics implicate BMP pathway and osteoblast differentiation dysregulation in skeletal overgrowth.
  downstream:
  - target: Tall Stature / Overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38015625
      reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity."
      explanation: Supports skeletal overgrowth downstream of excess osteogenesis in the p.R684C mouse, but is indirect evidence for human tall stature.

mechanistic_hypotheses:
- hypothesis_group_id: dominant_negative_prc2
  hypothesis_label: Dominant-negative interference with PRC2
  description: >-
    The scarcity of early truncating EZH2 variants and structural analysis support
    a dominant-negative mechanism, in which mutant EZH2 interferes with PRC2
    activity (lowering H3K27me2/3 and increasing H3K27ac) rather than acting purely
    by haploinsufficiency. This contrasts with gain-of-function EZH2 variants that
    cause growth restriction, producing reciprocal chromatin/transcriptional
    changes.
  evidence:
  - reference: PMID:40846643
    reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the lack of early truncating mutations in EZH2 led us to hypothesize a dominant-negative mechanism for WS, which was supported by our structural analysis of all known WS-associated EZH2 variants."
    explanation: Directly states the dominant-negative hypothesis and its structural support.
  - reference: PMID:40846643
    reference_title: "Dominant-negative effects of Weaver syndrome-associated EZH2 variants."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Comparative analysis of a gain-of-function EZH2 variant causing growth restriction revealed reciprocal chromatin and transcriptional changes compared with WS-associated variants."
    explanation: Supports the stated reciprocal relationship between Weaver-associated variants and a growth-restriction gain-of-function variant.
- hypothesis_group_id: loss_of_function_prc2
  hypothesis_label: Loss-of-function / reduced PRC2 catalytic activity
  description: >-
    Reduced PRC2 catalytic activity is a directly observed biochemical effect and
    is compatible with, rather than necessarily competing with, dominant-negative
    interference. In vitro reconstitution of tested Weaver-associated EZH2
    alterations shows reduced H3K27 methyltransferase function, though activity
    differences among variants do not directly correlate with phenotypic severity.
  evidence:
  - reference: PMID:26694085
    reference_title: "Weaver syndrome-associated EZH2 protein variants show impaired histone methyltransferase function in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our results support the hypothesis that WS is caused by constitutional mutations in EZH2 that alter the histone methyltransferase function of PRC2."
    explanation: Supports impaired PRC2 catalytic function as a contributing mechanism.
  - reference: PMID:26694085
    reference_title: "Weaver syndrome-associated EZH2 protein variants show impaired histone methyltransferase function in vitro."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, histone methyltransferase activities of different EZH2 variants do not appear to correlate directly with the phenotypic variability between WS patients and individuals with a common c.553G>C (p.Asp185His) polymorphism in EZH2."
    explanation: Directly supports the caution that measured in vitro activity does not map simply to phenotypic variability.

phenotypes:
- name: Tall Stature / Overgrowth
  category: Physical
  phenotype_term:
    preferred_term: Tall stature
    term:
      id: HP:0000098
      label: Tall stature
  frequency: VERY_FREQUENT
  description: >-
    Pre- and postnatal generalized overgrowth with tall stature, the most
    consistent feature, reported in >90% of EZH2 mutation-positive individuals.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "tall stature is very common, reported in >90% of affected individuals."
    explanation: Tall stature reported in >90% of the EZH2-positive cohort, supporting VERY_FREQUENT.
- name: Large for Gestational Age (Prenatal Overgrowth)
  category: Physical
  phenotype_term:
    preferred_term: Large for gestational age
    term:
      id: HP:0001520
      label: Large for gestational age
    onset:
      onset_category: CONGENITAL
  description: >-
    Prenatal overgrowth; affected babies may be large at birth, prompting
    anticipatory delivery planning.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Families and their health care providers should be made aware that an affected baby may be large so that appropriate delivery plans can be made."
    explanation: GeneReviews notes prenatal overgrowth manifesting as large babies.
- name: Accelerated Skeletal Maturation (Advanced Bone Age)
  category: Physical
  phenotype_term:
    preferred_term: Accelerated skeletal maturation
    term:
      id: HP:0005616
      label: Accelerated skeletal maturation
  description: >-
    Markedly advanced bone age (accelerated osseous maturation) is a
    characteristic skeletal feature of Weaver syndrome.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin, camptodactyly"
    explanation: GeneReviews lists advanced bone age among the associated clinical features.
- name: Macrocephaly
  category: Physical
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  description: Enlarged head circumference is a recurrent feature.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EZH2-related overgrowth is a variable overgrowth syndrome characterized by tall stature, macrocephaly, variable intellect"
    explanation: GeneReviews lists macrocephaly as a core characteristic.
- name: Intellectual Disability / Developmental Delay
  category: Neurologic
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  description: >-
    Intellectual disability is present in approximately 80% of affected
    individuals but is highly variable and frequently mild; intellect can range
    from normal to severe.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild."
    explanation: Supports the approximately 80% frequency and explicitly variable degree of intellectual impairment.
- name: Ocular Hypertelorism
  category: Physical
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  description: >-
    Ocular hypertelorism is part of the characteristic Weaver facial gestalt.
    Other facial components are represented separately rather than bundled under
    this HPO binding.
  evidence:
  - reference: PMID:38585548
    reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures and, in early childhood, large, fleshy ears, a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia."
    explanation: Directly identifies ocular hypertelorism as a characteristic Weaver facial feature.
- name: Broad Forehead
  category: Physical
  phenotype_term:
    preferred_term: Broad forehead
    term:
      id: HP:0000337
      label: Broad forehead
  evidence:
  - reference: PMID:38585548
    reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The characteristic facial features are ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures"
    explanation: Broad forehead is part of the WS craniofacial gestalt.
- name: Almond-Shaped Palpebral Fissures
  category: Physical
  phenotype_term:
    preferred_term: Almond-shaped palpebral fissure
    term:
      id: HP:0007874
      label: Almond-shaped palpebral fissure
  evidence:
  - reference: PMID:38585548
    reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular hypertelorism, a broad forehead, almond-shaped palpebral fissures"
    explanation: Almond-shaped palpebral fissures are characteristic of WS.
- name: Retrognathia
  category: Physical
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  description: >-
    Retrognathia occurs with the characteristic pointed "stuck-on" chin and
    horizontal chin crease in the Weaver facial gestalt.
  evidence:
  - reference: PMID:38585548
    reference_title: "Expanding the Phenotypic and Genotypic Spectrum of Weaver Syndrome: A Missense Variant of the EZH2 Gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a pointed \"stuck-on\" chin with horizontal skin creases, and retrognathia."
    explanation: Retrognathia with characteristic chin is part of the WS facial gestalt.
- name: Camptodactyly
  category: Physical
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  description: >-
    Camptodactyly of the fingers and/or toes; a recurrent feature useful for
    stratifying individuals to EZH2 testing.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry."
    explanation: Camptodactyly listed among additional discriminating WS features.
- name: Soft, Doughy Skin
  category: Physical
  phenotype_term:
    preferred_term: Soft, doughy skin
    term:
      id: HP:0001027
      label: Soft, doughy skin
  description: Soft, doughy skin is a recurrent feature of Weaver syndrome.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry."
    explanation: Soft, doughy skin listed among additional WS features.
- name: Umbilical Hernia
  category: Physical
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  description: Umbilical hernia is a recurrent feature of Weaver syndrome.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry."
    explanation: Umbilical hernia listed among additional WS features.
- name: Low, Hoarse Cry
  category: Physical
  phenotype_term:
    preferred_term: Hoarse, low-pitched cry
    term:
      id: HP:0001609
      label: Hoarse voice
    onset:
      onset_category: INFANTILE
  description: A low, hoarse cry in infancy is a recognizable feature of Weaver syndrome.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal tone, and hoarse, low cry in infancy."
    explanation: GeneReviews lists a hoarse, low cry in infancy among the clinical features.
- name: Abnormal Muscle Tone
  category: Neurologic
  phenotype_term:
    preferred_term: Abnormal muscle tone
    term:
      id: HP:0003808
      label: Abnormal muscle tone
  description: >-
    Abnormal muscle tone is part of the clinical spectrum. The cited GeneReviews
    summary does not specify direction or frequency, so this entry does not
    narrow the finding to hypotonia or hypertonia.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse, low cry in infancy."
    explanation: GeneReviews lists abnormal tone among the clinical features.
- name: Poor Coordination
  category: Neurologic
  phenotype_term:
    preferred_term: Incoordination
    term:
      id: HP:0002311
      label: Incoordination
  description: Poor coordination/clumsiness is part of the reported clinical spectrum.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a range of associated clinical features including advanced bone age, poor coordination, soft, doughy skin"
    explanation: GeneReviews lists poor coordination among the clinical features.
- name: Neuroblastoma Predisposition
  category: Neoplasm
  phenotype_term:
    preferred_term: Neuroblastoma
    term:
      id: HP:0003006
      label: Neuroblastoma
  description: >-
    Neuroblastoma occurs at increased frequency in individuals with a heterozygous
    EZH2 pathogenic variant. There is currently no evidence that additional
    malignancies occur with increased frequency, though a few have been reported.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroblastoma occurs at an increased frequency in individuals with a heterozygous EZH2 pathogenic variant."
    explanation: GeneReviews documents increased neuroblastoma frequency in EZH2-related overgrowth.
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency, though a few have been reported."
    explanation: >-
      Bounds the cancer-predisposition claim: an increased frequency is currently
      established for neuroblastoma, not for other reported malignancies.

progression:
- age_range: Older individuals
  notes: >-
    Facial features may be subtle, and clinical recognition becomes particularly
    challenging in older individuals. This is an age-dependent recognition issue;
    the cited cohort does not establish a progressive loss of facial features.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals."
    explanation: Directly supports age-dependent difficulty recognizing the facial phenotype.

genetic:
- name: EZH2
  gene_term:
    preferred_term: EZH2
    term:
      id: hgnc:3527
      label: EZH2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    EZH2 encodes the catalytic histone methyltransferase subunit of PRC2.
    Pathogenic variants are predominantly missense and occur throughout the gene,
    with some clustering in the SET domain; truncating variants are uncommon and
    confined to the final exon after the SET domain. The recurrent p.Arg684Cys
    (R684C) was described as the most common Weaver missense variant in the 2023
    mouse-model report. Both de novo and inherited pathogenic variants occur, but
    their relative proportions are unknown.
  evidence:
  - reference: PMID:22177091
    reference_title: "Mutations in EZH2 cause Weaver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data show that mutations in EZH2 cause Weaver syndrome."
    explanation: Establishes EZH2 as the causal gene for Weaver syndrome.
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain."
    explanation: Characterizes the EZH2 variant spectrum (mostly missense, rare truncating in final exon).
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing."
    explanation: GeneReviews confirms heterozygous germline EZH2 variants are diagnostic.
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C."
    explanation: Supports the report-specific statement that p.R684C is the most common Weaver missense variant.
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Some individuals diagnosed with EZH2-related overgrowth have an affected parent; some individuals diagnosed with EZH2-related overgrowth have the disorder as the result of a de novo EZH2 pathogenic variant. The proportion of individuals with EZH2-related overgrowth caused by a de novo pathogenic variant is unknown."
    explanation: >-
      Correctly bounds the origin distribution: both inherited and de novo
      variants occur, but their relative proportions are unknown.

diagnosis:
- name: Molecular Genetic Confirmation
  description: >-
    The diagnosis of EZH2-related overgrowth is established by detecting a
    heterozygous germline pathogenic variant in EZH2 on molecular genetic testing.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Detection of a heterozygous germline pathogenic EZH2 variant establishes the diagnosis.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing."
    explanation: GeneReviews states the defining molecular diagnostic criterion.
- name: PRC2 DNA Methylation Episignature Analysis
  description: >-
    Genome-wide DNA methylation analysis can detect a highly specific and
    sensitive Weaver-associated signature in the studied cohort. The signature
    can functionally classify loss-of-function versus gain-of-function missense
    variants, detect somatic mosaicism, and classify variants in the other PRC2
    core genes EED and SUZ12. It is an adjunct to variant interpretation; the
    defining Weaver diagnosis remains a heterozygous germline EZH2 pathogenic
    variant.
  diagnosis_term:
    preferred_term: DNA methylation episignature analysis
    term:
      id: NCIT:C63328
      label: DNA Methylation Analysis
  results: >-
    A matching signature supports functional classification of an EZH2 or other
    core-PRC2 sequence variant, including mosaic and opposing functional states.
  evidence:
  - reference: PMID:32243864
    reference_title: "DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using genome-wide DNA methylation (DNAm) data for 187 individuals with OGID and 969 control subjects, we show that pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature reflecting the phenotype of WS. This signature can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism."
    explanation: Defines the study population, Weaver-associated signature, and its demonstrated functional-classification uses.
  - reference: PMID:32243864
    reference_title: "DNA Methylation Signature for EZH2 Functionally Classifies Sequence Variants in Three PRC2 Complex Genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also show that the signature can accurately classify sequence variants in EED and SUZ12, which encode two other core components of PRC2, and predict the presence of pathogenic variants in undiagnosed individuals with OGID."
    explanation: Supports extension of the PRC2 signature to EED and SUZ12 variant classification.
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing."
    explanation: Prevents the adjunctive episignature from being misrepresented as a replacement for the defining molecular diagnosis.

differential_diagnoses:
- name: Sotos Syndrome
  description: >-
    Sotos syndrome (NSD1) is an important differential diagnosis because of its
    considerable phenotypic overlap with Weaver syndrome. Weaver facial features
    may be subtle, particularly in older individuals, so identification of an EZH2
    pathogenic variant provides an objective means of confirming Weaver syndrome
    and distinguishing it from Sotos syndrome.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident."
    explanation: Documents the clinical overlap between Sotos and Weaver syndromes motivating differential diagnosis.
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes."
    explanation: Directly supports molecular EZH2 confirmation as the objective discriminator from Sotos syndrome.

treatments:
- name: Genetic Counseling
  description: >-
    Genetic counseling for recurrence risk and reproductive planning. Inheritance
    is autosomal dominant; each child of an affected individual has a 50% chance of
    inheriting the variant, but phenotype in a child who inherits a familial
    variant cannot be predicted. Once a familial variant is identified, prenatal
    and preimplantation genetic testing are possible.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each child of an individual with EZH2-related overgrowth has a 50% chance of inheriting the pathogenic variant; the phenotype in individuals who inherit a familial EZH2 pathogenic variant cannot be predicted."
    explanation: Supports counseling on both transmission probability and unpredictable expressivity.
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible."
    explanation: Directly supports the stated reproductive testing options.
- name: Developmental Assessment and Support
  description: >-
    Individuals with developmental delay or learning disability may benefit from
    referral for learning, behavioral, and speech assessment and individualized
    support.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For individuals with developmental delay and/or learning disability, referral for learning/behavior/speech assessment and support may be indicated."
    explanation: GeneReviews directly recommends developmental, learning, behavioral, and speech assessment and support.
- name: Physical Therapy
  description: >-
    Physiotherapy may help joint pain related to ligamentous laxity or joint
    contractures.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physiotherapy may be of benefit to those experiencing joint pain secondary to ligamentous laxity or joint contractures."
    explanation: GeneReviews recommends physiotherapy for joint pain in EZH2-related overgrowth.
- name: Surgical Release of Camptodactyly
  description: >-
    Toe camptodactyly may occasionally require surgical release.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Occasionally, toe camptodactyly may require surgical release."
    explanation: GeneReviews notes occasional surgical release for toe camptodactyly.
- name: Developmental, Tone, and Camptodactyly Follow-up
  description: >-
    Young children should receive regular medical follow-up to monitor
    developmental progress, camptodactyly for resolution or improvement, and
    hypotonia. Follow-up may be less frequent for older children and teenagers
    without medical complications.
  therapeutic_modality: BEHAVIORAL
  action_category: MONITORING
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular medical follow up of young children with EZH2-related overgrowth to monitor developmental progress, camptodactyly (for resolution/improvement), and/or hypotonia; medical follow up of older children/teenagers who do not have medical complications may be less frequent."
    explanation: Directly supports the age-stratified clinical follow-up recommendation.
- name: Manifestation-Specific Specialist Care
  description: >-
    Epilepsy, scoliosis, and other clinical issues should receive standard
    treatment with appropriate specialist referral when present. Scoliosis
    monitoring should follow the treating orthopedist's recommendations.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard treatment with appropriate specialist referral(s) is indicated for epilepsy, scoliosis, and other clinical issues."
    explanation: Directly supports manifestation-specific treatment and specialist referral.
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If scoliosis is present, monitoring per the recommendations of an orthopedist."
    explanation: Directly supports specialist-directed scoliosis monitoring when scoliosis is present.
- name: Neuroblastoma Surveillance
  description: >-
    There are no internationally ratified neuroblastoma surveillance guidelines for
    individuals carrying inactivating EZH2 pathogenic variants, but US guidelines
    recommend imaging and urine biochemistry surveillance until age 10 years;
    clinicians should maintain a low threshold for investigating possible
    tumor-related symptoms.
  action_category: MONITORING
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinicians should have a low threshold for investigating any possible tumor-related symptoms. There are no internationally ratified surveillance guidelines for screening of neuroblastoma in individuals carrying inactivating EZH2 pathogenic variants, but US guidelines recommend imaging and urine biochemistry surveillance until age 10 years."
    explanation: Supports both the symptom-triggered vigilance and the qualified, jurisdiction-specific surveillance recommendation.

animal_models:
- species: Mouse
  genotype: Ezh2 p.R684C knock-in (Ezh2R684C/+ heterozygous; Ezh2R684C/R684C homozygous)
  category: knock-in mouse model
  description: >-
    Knock-in mouse model of the most common Weaver syndrome EZH2 missense variant
    (p.R684C). Homozygous MEFs show global H3K27me3 depletion; heterozygous mice
    show abnormal bone parameters indicative of skeletal overgrowth and increased
    osteoblast osteogenic activity, with BMP-pathway and osteoblast-differentiation
    transcriptional dysregulation. Excess osteogenesis is reversible by inhibiting
    the opposing H3K27 demethylases KDM6A/KDM6B, demonstrating reversibility and
    therapeutic potential of epigenetic modulating agents.
  genes:
  - preferred_term: EZH2
    term:
      id: hgnc:3527
      label: EZH2
  associated_phenotypes:
  - Skeletal overgrowth
  - Excess osteogenesis
  - Global H3K27me3 depletion
  evidence:
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3."
    explanation: Describes the EZH2 p.R684C knock-in mouse model and its molecular phenotype.
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis in Ezh2R684C/+ cells both at the transcriptional and phenotypic levels."
    explanation: Demonstrates pharmacologic reversibility of the osteogenic phenotype via KDM6A/6B inhibition.
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This supports both the ideas that writers and erasers of histone marks exist in a fine balance to maintain epigenome state and that epigenetic modulating agents have therapeutic potential for the treatment of MDEMs."
    explanation: Supports the model-level therapeutic-potential statement without implying demonstrated benefit in people with Weaver syndrome.

discussions:
- discussion_id: weaver_r684c_skeletal_model_generalizability
  prompt: >-
    Does the skeletal mechanism observed in the Ezh2 p.R684C knock-in mouse
    generalize to the diverse heterozygous EZH2 variants and developing human
    bone represented in Weaver syndrome?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Dysregulated Osteoblast Differentiation and Excess Osteogenesis
  rationale: >-
    The p.R684C mouse provides coherent molecular, cellular, and bone-level
    evidence for excess osteogenesis, but it models one recurrent allele. Its
    H3K27me3 readout was measured in homozygous mouse embryonic fibroblasts,
    whereas its skeletal phenotype was measured in heterozygous mice and
    osteoblasts. Human disease is heterozygous and genetically heterogeneous,
    and no cited study directly measures osteoblast differentiation or advanced
    bone age in human variant-bearing skeletal cells. The model therefore
    supports a candidate skeletal mechanism without establishing pan-allelic
    human generality.
  proposed_experiments:
  - experiment_id: weaver-human-osteoblast-allelic-series
    name: Isogenic human osteoblast allelic-series study
    description: >-
      Generate heterozygous p.R684C and several structurally diverse
      Weaver-associated EZH2 variants in the same human iPSC background,
      differentiate them through mesenchymal progenitors into osteoblasts, and
      compare them with corrected isogenic controls across matched time points.
    readouts:
    - name: H3K27me2/3 abundance, BMP-pathway transcription, and osteogenic differentiation kinetics by allele
      target: "pathophysiology#Dysregulated Osteoblast Differentiation and Excess Osteogenesis"
    decision_criterion: >-
      Concordant H3K27 loss and excess osteogenesis across variant classes, with
      correction after restoration of wild-type EZH2 dosage, would support a
      general human skeletal mechanism. Absent, opposite, or allele-restricted
      effects would confine the mouse result to p.R684C or identify mechanistic
      subgroups.
  evidence:
  - reference: PMID:38015625
    reference_title: "A mouse model of Weaver syndrome displays overgrowth and excess osteogenesis reversible with KDM6A/6B inhibition."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated a mouse model for the most common Weaver syndrome missense variant, EZH2 p.R684C. Ezh2R684C/R684C mouse embryonic fibroblasts (MEFs) showed global depletion of H3K27me3. Ezh2R684C/+ mice had abnormal bone parameters, indicative of skeletal overgrowth, and Ezh2R684C/+ osteoblasts showed increased osteogenic activity."
    explanation: Establishes both the strength and the allele-, organism-, and zygosity-specific boundaries of the current skeletal model.
- discussion_id: weaver_neuroblastoma_mechanistic_bridge
  prompt: >-
    By what developmental and cell-type-specific mechanism does a germline
    heterozygous EZH2 pathogenic variant increase neuroblastoma frequency in
    Weaver syndrome?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - phenotypes#Neuroblastoma Predisposition
  - pathophysiology#Impaired Polycomb Repression and Gene Derepression
  rationale: >-
    The human association with neuroblastoma is recognized, but the curated
    molecular studies establish PRC2/H3K27 disruption and growth-gene
    derepression in stem-cell systems rather than a transformation mechanism in
    the sympathoadrenal lineage from which neuroblastoma arises. Connecting
    these observations without lineage-specific evidence would overstate the
    pathograph. Resolving the bridge matters both for biological interpretation
    and for determining whether surveillance should eventually be stratified by
    variant or molecular phenotype.
  proposed_experiments:
  - experiment_id: weaver-neural-crest-neuroblastoma-model
    name: Isogenic human sympathoadrenal-lineage tumor-predisposition model
    description: >-
      Differentiate isogenic human iPSCs carrying representative heterozygous
      Weaver EZH2 variants and corrected controls through neural crest into
      sympathoadrenal progenitors, then follow chromatin state, differentiation,
      proliferation, and transformation-associated phenotypes longitudinally.
    readouts:
    - name: Variant-dependent H3K27/cPRC1 state and sympathoadrenal differentiation trajectory
      target: "pathophysiology#Impaired Polycomb Repression and Gene Derepression"
    - name: Persistent proliferative or transformation-associated phenotype in sympathoadrenal progenitors
      target: "phenotypes#Neuroblastoma Predisposition"
    decision_criterion: >-
      A reproducible variant-dependent chromatin defect that precedes impaired
      sympathoadrenal differentiation and persistent proliferative behavior,
      and is reversed by isogenic correction, would support a mechanistic bridge.
      Normal lineage behavior despite the expected H3K27 defect would argue that
      additional developmental, somatic, or environmental events are required.
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuroblastoma occurs at an increased frequency in individuals with a heterozygous EZH2 pathogenic variant."
    explanation: Establishes the human tumor association whose molecular bridge remains unresolved.

epidemiology:
- name: 2013 EZH2-Positive Cohort Size
  description: >-
    A 2013 series identified 48 individuals with EZH2 mutations. This is a
    historical case-series count rather than a population prevalence estimate and
    should not be interpreted as the current worldwide number of affected people.
  evidence:
  - reference: PMID:24214728
    reference_title: "Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, we have identified 48 individuals with EZH2 mutations."
    explanation: Records the cohort size as reported in 2013 without converting it into a prevalence estimate or a time-stable worldwide case count.
📚

References & Deep Research

References

1
PMID:23865096
EZH2-Related Overgrowth.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Weaver Syndrome (MIM 277590) — Comprehensive Disease Characteristics Report
Edison Scientific Literature 32 citations 2026-06-04T15:35:16.231668

Weaver Syndrome (MIM 277590) — Comprehensive Disease Characteristics Report

Target Disease

  • Disease name: Weaver syndrome (WS) (gibson2012mutationsinezh2 pages 1-3, tatton‐brown2013weaversyndromeand pages 1-2)
  • Category: Mendelian (autosomal dominant overgrowth/intellectual disability syndrome) (kendirdemirkol2024expandingthephenotypic pages 1-2, gibson2012mutationsinezh2 pages 1-3)
  • MONDO ID: Not identified in the retrieved primary texts used for this report (limitation of current tool-retrieved corpus).

Summary (current understanding)

Weaver syndrome is a rare congenital anomaly/overgrowth syndrome characterized by pre- and/or postnatal generalized overgrowth, markedly advanced bone age (accelerated osseous maturation), characteristic craniofacial gestalt (e.g., hypertelorism, broad forehead, retrognathia with “stuck-on” chin crease), and variable developmental delay/intellectual disability (gibson2012mutationsinezh2 pages 1-3, tatton‐brown2013weaversyndromeand pages 3-4). Since 2011–2012, heterozygous germline pathogenic variants in EZH2 (encoding the catalytic subunit of Polycomb Repressive Complex 2, PRC2) have been established as the primary cause (tattonbrown2011germlinemutationsin pages 1-2, gibson2012mutationsinezh2 pages 1-3).

Recent mechanistic work (2024–2025) supports that many WS-associated EZH2 missense alleles can act through dominant-negative interference with PRC2, producing global reductions in H3K27me2/3, increases in H3K27ac, and chromatin decompaction (deevy2024dominantnegativeeffects pages 1-2, deevy2025dominantnegativeeffectsof pages 1-2). A 2024 knock-in mouse model (Ezh2 p.R684C) recapitulates skeletal overgrowth/excess osteogenesis and demonstrates pharmacologic reversibility of osteogenic phenotypes by inhibiting the opposing H3K27 demethylases KDM6A/KDM6B (gao2024amousemodel pages 1-2).

1. Disease Information

1.1 Concise overview

Weaver syndrome (MIM 277590) was originally described in 1974 and is now recognized as an EZH2-related overgrowth syndrome with characteristic craniofacial features and variable intellectual disability (tatton‐brown2013weaversyndromeand pages 1-2, gibson2012mutationsinezh2 pages 1-3).

Primary literature abstract quote (2011 discovery): - “Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features.” (Tatton-Brown et al., 2011; published 2011-12-21; URL: https://doi.org/10.18632/oncotarget.385) (tattonbrown2011germlinemutationsin pages 1-2)

1.2 Key identifiers (from retrieved sources)

  • OMIM/MIM disease: Weaver syndrome MIM 277590 (Gibson et al., AJHG, 2012-01-13; DOI: 10.1016/j.ajhg.2011.11.018; URL: https://doi.org/10.1016/j.ajhg.2011.11.018) (gibson2012mutationsinezh2 pages 1-3)
  • Causal gene: EZH2 (Enhancer of Zeste Homolog 2) (gibson2012mutationsinezh2 pages 1-3)
  • EZH2 gene identifier: MIM #601573 (Cohen et al., Human Mutation, published online 2015-12-23; DOI: 10.1002/humu.22946; URL: https://doi.org/10.1002/humu.22946) (cohen2016weaversyndrome‐associatedezh2 pages 1-2)

Not found in retrieved texts: ICD-10/ICD-11 codes, MeSH terms, MONDO ID.

1.3 Synonyms / alternative names

  • “EZH2-related overgrowth syndrome” (descriptor used in contemporary literature) (kendirdemirkol2024expandingthephenotypic pages 1-2)

1.4 Evidence provenance (individual vs aggregated)

  • Aggregated cohort-level phenotyping is available from the large EZH2-mutation positive series (n=48) (Tatton-Brown et al., 2013) (tatton‐brown2013weaversyndromeand pages 1-2), and from mechanistic/biomarker studies that aggregate multiple WS cases (Choufani et al., 2020) (choufani2020dnamethylationsignature pages 1-2).
  • Many additional details come from individual case reports/series and experimental models (e.g., Gao et al., 2024 mouse model) (gao2024amousemodel pages 1-2).

2. Etiology

2.1 Disease causal factors

Primary cause (genetic): heterozygous germline pathogenic variants in EZH2 (gibson2012mutationsinezh2 pages 1-3, tattonbrown2011germlinemutationsin pages 1-2). - Gibson et al. used trio-based whole-exome sequencing and identified de novo EZH2 mutations, concluding “mutations in EZH2 cause Weaver syndrome” (AJHG, 2012-01-13; URL: https://doi.org/10.1016/j.ajhg.2011.11.018) (gibson2012mutationsinezh2 pages 1-3).

2.2 Risk factors

  • For this Mendelian disorder, the dominant “risk factor” is carrying a pathogenic EZH2 variant; most cases are sporadic/de novo, with rare familial autosomal dominant transmission (tattonbrown2011germlinemutationsin pages 1-2, gibson2012mutationsinezh2 pages 1-3).

2.3 Protective factors / gene–environment interactions

  • No protective genetic variants or gene–environment interactions were identified in the retrieved primary literature for Weaver syndrome specifically.

3. Phenotypes (with suggested HPO terms)

3.1 Core phenotype spectrum and frequencies

The best quantitative frequencies in the retrieved corpus come from Tatton-Brown et al. (2013), an EZH2-positive cohort (tatton‐brown2013weaversyndromeand pages 3-4). Key findings: - Tall stature (postnatal height ≥ +2 SD): 41/45 (91%) (tatton‐brown2013weaversyndromeand pages 3-4) - Intellectual disability/developmental delay: 37/45 (82%); often mild (21/37 mild) (tatton‐brown2013weaversyndromeand pages 3-4) - Camptodactyly/contractures: 45% (tatton‐brown2013weaversyndromeand pages 3-4) - Soft/doughy skin: 49% (tatton‐brown2013weaversyndromeand pages 3-4) - Umbilical hernia: 43% (tatton‐brown2013weaversyndromeand pages 3-4) - Hoarse, low-pitched cry: 37% (tatton‐brown2013weaversyndromeand pages 3-4) - Poor coordination/clumsiness: 28/35 (80%) (tatton‐brown2013weaversyndromeand pages 3-4) - Hypotonia: 44%; hypertonia: 28% (tatton‐brown2013weaversyndromeand pages 3-4)

Birth metrics in the same cohort: - Birth length > +2 SD: 12/18 - Birth weight > +2 SD: 15/39 (38%) (tatton‐brown2013weaversyndromeand pages 3-4)

Craniofacial gestalt is described as sometimes subtle and age-dependent but classically includes hypertelorism, broad forehead, almond-shaped palpebral fissures, large fleshy ears in early childhood, retrognathia, and a pointed “stuck-on” chin with a horizontal crease (tatton‐brown2013weaversyndromeand pages 3-4).

3.2 Suggested HPO terms (examples; not exhaustive)

Below are phenotype-to-HPO suggestions aligned to the retrieved descriptions: - Overgrowth / tall stature: Tall stature (HP:0000098) (tatton‐brown2013weaversyndromeand pages 3-4) - Prenatal overgrowth/macrosomia: Large for gestational age (HP:0001520) (supported by prenatal/postnatal overgrowth descriptions) (gibson2012mutationsinezh2 pages 1-3) - Macrocephaly: Macrocephaly (HP:0000256) (gibson2012mutationsinezh2 pages 1-3, tatton‐brown2013weaversyndromeand pages 3-4) - Advanced bone age: Advanced bone age (HP:0005616) (gibson2012mutationsinezh2 pages 1-3) - Intellectual disability: Intellectual disability (HP:0001249) (tatton‐brown2013weaversyndromeand pages 3-4) - Hypotonia: Hypotonia (HP:0001252); Hypertonia: Hypertonia (HP:0001276) (tatton‐brown2013weaversyndromeand pages 3-4) - Hypertelorism: Hypertelorism (HP:0000316) (gibson2012mutationsinezh2 pages 1-3) - Retrognathia/micrognathia: Retrognathia (HP:0000278) (gibson2012mutationsinezh2 pages 1-3) - Camptodactyly: Camptodactyly (HP:0012385) (tatton‐brown2013weaversyndromeand pages 3-4) - Umbilical hernia: Umbilical hernia (HP:0001537) (tatton‐brown2013weaversyndromeand pages 3-4) - Hoarse cry: Hoarse cry (HP:0001609) (tatton‐brown2013weaversyndromeand pages 3-4) - Clumsiness/coordination: Motor delay / impaired coordination (e.g., HP:0002311 for abnormal coordination) (tatton‐brown2013weaversyndromeand pages 3-4)

3.3 Quality of life impact

Formal QoL instruments were not reported in the retrieved sources; however, developmental delay/intellectual disability (82%), hypotonia/hypertonia, and contractures/camptodactyly plausibly affect function and require early intervention/therapy (tatton‐brown2013weaversyndromeand pages 3-4).

4. Genetic / Molecular Information

4.1 Causal gene(s)

  • EZH2 is the primary causal gene for classic Weaver syndrome (gibson2012mutationsinezh2 pages 1-3, tattonbrown2011germlinemutationsin pages 1-2).
  • PRC2-related overlapping overgrowth syndromes exist for EED and SUZ12; these are clinically overlapping OGID syndromes and share a peripheral blood DNAm signature with WS (gao2024amousemodel pages 1-2, choufani2020dnamethylationsignature pages 1-2).

4.2 Pathogenic variants (types and examples)

  • Variant spectrum is predominantly missense and many cases are de novo (tattonbrown2011germlinemutationsin pages 1-2, tatton‐brown2013weaversyndromeand pages 1-2).
  • Truncating variants are uncommon and in the Tatton-Brown 2013 cohort were only identified in the final exon after the SET domain (tatton‐brown2013weaversyndromeand pages 1-2).
  • A recurrent hotspot variant p.Arg684Cys (R684C) is described in early discovery cohorts and used for model organism work (tattonbrown2011germlinemutationsin pages 1-2, gao2024amousemodel pages 1-2).

4.3 Functional consequences (LoF vs dominant-negative)

Canonical EZH2/PRC2 function: EZH2 is the catalytic subunit of PRC2 and mediates methylation of histone H3 lysine 27 (H3K27), which is linked to chromatin compaction and repression (cohen2016weaversyndrome‐associatedezh2 pages 1-2, choufani2020dnamethylationsignature pages 1-2).

In vitro LoF evidence: Cohen et al. report WS-associated EZH2 amino-acid changes reduce EZH2 histone methyltransferase function in an in vitro PRC2 assay (DOI: 10.1002/humu.22946; published online 2015-12-23) (cohen2016weaversyndrome‐associatedezh2 pages 1-2).

Recent (2024–2025) dominant-negative model: Deevy et al. modeled 10 WS-associated EZH2 variants in isogenic ESCs and found global reductions in H3K27me2/3, increased H3K27ac, and chromatin decompaction consistent with dominant-negative interference with PRC2 activity (preprint posted 2023-06-01, cited here in 2024 posting; URL: https://doi.org/10.1101/2023.06.01.543208) (deevy2024dominantnegativeeffects pages 1-2). The peer-reviewed extension similarly concludes “dominant-negative interference” and reports derepression of weak Polycomb-bound growth control genes (Genes & Development, 2025-08; URL: https://doi.org/10.1101/gad.351884.124) (deevy2025dominantnegativeeffectsof pages 1-2).

4.4 Epigenetic information / DNA methylation episignatures

Choufani et al. reported a highly specific and sensitive peripheral-blood DNA methylation (DNAm) signature for EZH2/WS and showed it can distinguish LoF vs GoF missense variants and detect mosaicism (AJHG, 2020-05-07; DOI: 10.1016/j.ajhg.2020.03.008; URL: https://doi.org/10.1016/j.ajhg.2020.03.008) (choufani2020dnamethylationsignature pages 1-2).

Abstract quote (2020): - “Using genome-wide DNA methylation (DNAm) data… pathogenic variants in EZH2 generate a highly specific and sensitive DNAm signature … [that] can be used to distinguish loss-of-function from gain-of-function missense variants and to detect somatic mosaicism.” (choufani2020dnamethylationsignature pages 1-2)

A 2024 perspective emphasizes clinical use of DNAm signatures for VUS classification and warns that classifier scores should be complemented with additional analyses (Human Genetics; published online 2023-04-06; DOI: 10.1007/s00439-023-02544-2; URL: https://doi.org/10.1007/s00439-023-02544-2) (awamleh2024dnamethylationsignatures pages 1-2).

5. Environmental Information

No specific environmental contributors, lifestyle factors, or infectious triggers for Weaver syndrome were identified in the retrieved primary literature; the disorder is primarily monogenic (EZH2) (gibson2012mutationsinezh2 pages 1-3).

6. Mechanism / Pathophysiology

6.1 Causal chain (genotype → epigenome → transcription → phenotype)

  1. Trigger: Heterozygous pathogenic EZH2 missense variants (often de novo) (tattonbrown2011germlinemutationsin pages 1-2, gibson2012mutationsinezh2 pages 1-3).
  2. Primary molecular lesion: Reduced and/or dominantly perturbed PRC2 catalytic activity altering H3K27 methylation balance (H3K27me2/3 depleted; H3K27ac increased), with chromatin decompaction and derepression of Polycomb-regulated gene sets (deevy2024dominantnegativeeffects pages 1-2, deevy2025dominantnegativeeffectsof pages 1-2).
  3. Downstream tissue programs: In bone, dysregulated osteoblast differentiation and BMP pathway programs contribute to advanced bone age/skeletal overgrowth (gao2024amousemodel pages 1-2).
  4. Clinical manifestations: Overgrowth/tall stature, advanced bone age, craniofacial phenotype, neurodevelopmental impairment (tatton‐brown2013weaversyndromeand pages 3-4, gibson2012mutationsinezh2 pages 1-3).

6.2 Pathways/processes implicated

  • Polycomb repression / chromatin organization: PRC2-mediated H3K27 methylation and downstream PRC1 recruitment (chromatin compaction) (deevy2024dominantnegativeeffects pages 1-2).
  • Bone morphogenetic protein (BMP) pathway and osteoblast differentiation: dysregulated in Ezh2R684C/+ osteoblasts by RNA-seq (gao2024amousemodel pages 1-2).

6.3 Suggested GO biological process terms (examples)

  • Histone H3-K27 methylation (GO:0051568)
  • Chromatin organization (GO:0006325)
  • Transcriptional regulation by Polycomb group proteins (broadly captured under chromatin silencing terms)
  • Osteoblast differentiation (GO:0001649)
  • BMP signaling pathway (GO:0030509)

6.4 Suggested cell types (CL terms; examples)

  • Osteoblast (CL:0000062) and mesenchymal stem/stromal cell (MSC)-like populations (bone marrow MSCs) are mechanistically implicated in the mouse model (gao2024amousemodel pages 1-2).

7. Anatomical Structures Affected

7.1 Organ/system level (with suggested UBERON terms)

  • Skeletal system / bone (advanced bone age; skeletal overgrowth) (UBERON:0001434 “skeleton”) (gibson2012mutationsinezh2 pages 1-3, gao2024amousemodel pages 1-2)
  • Brain / nervous system (developmental delay, variable intellectual disability) (UBERON:0000955 “brain”) (tatton‐brown2013weaversyndromeand pages 3-4)
  • Craniofacial structures (distinct facial gestalt, retrognathia/chin crease) (UBERON craniofacial terms as appropriate) (tatton‐brown2013weaversyndromeand pages 3-4)

7.2 Tissue/cell level

  • Bone-forming lineages: osteoblasts and bone marrow MSC-derived osteoblast differentiation programs (gao2024amousemodel pages 1-2).

7.3 Subcellular level

  • Nucleus / chromatin (PRC2 is a chromatin-modifying complex; H3K27 modifications regulate compaction) (deevy2024dominantnegativeeffects pages 1-2, choufani2020dnamethylationsignature pages 1-2).

8. Temporal Development

  • Onset: commonly prenatal and/or early postnatal overgrowth (gibson2012mutationsinezh2 pages 1-3, tatton‐brown2013weaversyndromeand pages 3-4).
  • Course: overgrowth is often present from birth/early childhood; facial features may become more subtle with age, complicating adult recognition (tatton‐brown2013weaversyndromeand pages 1-2, tatton‐brown2013weaversyndromeand pages 3-4).

9. Inheritance and Population

9.1 Inheritance

  • Primarily de novo, but autosomal dominant inheritance is supported by rare parent-to-child transmission (gibson2012mutationsinezh2 pages 1-3, tattonbrown2011germlinemutationsin pages 1-2).

9.2 Epidemiology

Robust prevalence/incidence estimates were not found in the retrieved primary texts used here. Available quantitative statements are limited to reported-case counts in specific publications (e.g., “Approximately 40 cases are known from the literature” in 2012; and “48 individuals with EZH2 mutations” in a 2013 cohort) (gibson2012mutationsinezh2 pages 1-3, tatton‐brown2013weaversyndromeand pages 1-2).

10. Diagnostics

10.1 Clinical recognition and differential diagnosis

Clinical overlap with Sotos syndrome is emphasized; distinguishing features for Weaver syndrome include retrognathia with prominent chin crease (“stuck-on” chin), increased prenatal growth, and a carpal bone age disproportionately advanced relative to metacarpal/phalangeal bone age (gibson2012mutationsinezh2 pages 1-3).

10.2 Genetic testing approaches (current practice reflected in literature)

  • Trio-based WES and confirmatory Sanger sequencing were used in the discovery paper to identify de novo EZH2 variants (gibson2012mutationsinezh2 pages 1-3).
  • Chromosomal microarray (CMA) was used to exclude submicroscopic CNVs in discovery cases, and NSD1 sequencing was performed to exclude Sotos-like etiologies (gibson2012mutationsinezh2 pages 1-3).

10.3 Omics-based diagnostics: DNA methylation episignatures (real-world implementation)

  • Clinical implementation concept: DNAm episignatures are used as syndrome-specific biomarkers and are “well established… especially for the classification of variants of uncertain significance (VUS)” (Awamleh et al., Human Genetics; published online 2023-04-06) (awamleh2024dnamethylationsignatures pages 1-2).
  • Weaver/PRC2-specific evidence: an EZH2 DNAm signature for WS supports functional classification of EZH2 variants and can also classify variants in EED and SUZ12 (Choufani et al., AJHG 2020-05-07) (choufani2020dnamethylationsignature pages 1-2).

11. Outcome / Prognosis

Quantitative long-term outcomes (life expectancy, validated QoL, survival curves) were not present in the retrieved primary literature. Available evidence supports: - Intellectual disability is common but “highly variable and frequently mild” in the large 2013 series (tatton‐brown2013weaversyndromeand pages 1-2). - Clinical management is typically supportive and multidisciplinary (no disease-modifying therapy established in humans in the retrieved literature) (gao2024amousemodel pages 1-2).

12. Treatment

12.1 Current applications / real-world implementations (supportive care)

Disease management in the retrieved sources is largely symptomatic and supportive; MDEMs in general “still only consist of symptomatic management and preventative screening for known complications” (Gao et al., JCI Insight, 2024-01-09) (gao2024amousemodel pages 1-2).

Suggested MAXO terms (examples): - Genetic testing (MAXO term for genetic diagnostic procedure; mapping depends on MAXO version) - Physical therapy / occupational therapy / speech therapy (supportive developmental therapies) - Orthopedic management (for contractures/camptodactyly)

12.2 Experimental / emerging therapeutics (preclinical)

A key 2024 advance is a genetically faithful mouse model for the common EZH2 p.R684C variant, which shows excess osteogenesis reversible by inhibiting KDM6A/KDM6B (gao2024amousemodel pages 1-2).

Abstract quote (2024 JCI Insight): - “Inhibition of the opposing H3K27 demethylases KDM6A and KDM6B substantially reversed the excessive osteogenesis…” (Gao et al., 2024-01-09; DOI: 10.1172/jci.insight.173392; URL: https://doi.org/10.1172/jci.insight.173392) (gao2024amousemodel pages 1-2)

This provides a mechanistic rationale for considering epigenetic modulating agents in PRC2-related overgrowth disorders, though there is no clinical trial evidence for such agents in Weaver syndrome in the retrieved clinicaltrials.gov search results.

13. Prevention

Primary prevention is not applicable for a monogenic, typically de novo disorder. Practical prevention focuses on: - Genetic counseling for recurrence risk and reproductive planning (autosomal dominant; most de novo) (tattonbrown2011germlinemutationsin pages 1-2, gibson2012mutationsinezh2 pages 1-3). - Secondary/tertiary prevention via anticipatory guidance and monitoring for complications (developmental supports; orthopedic issues; malignancy vigilance) (tatton‐brown2013weaversyndromeand pages 3-4).

14. Other Species / Natural Disease

No naturally occurring veterinary Weaver-syndrome analogs were identified in the retrieved texts.

15. Model Organisms

A 2024 knock-in mouse model of the common EZH2 p.R684C variant demonstrates: - molecular phenotype (global H3K27me3 depletion in homozygous MEFs), - organismal phenotype (skeletal overgrowth in heterozygotes), - cellular phenotype (increased osteogenic activity), - pathway dysregulation (BMP pathway and osteoblast differentiation transcriptome changes), - and pharmacologic reversibility (KDM6A/6B inhibition) (gao2024amousemodel pages 1-2).

Cancer risk and surveillance (expert opinion and recent consensus)

A 2024 AACR Childhood Cancer Predisposition Workshop update notes Weaver syndrome is associated with germline EZH2 variants and reports multiple cancers including neuroblastoma, germ cell tumors, leukemias, and lymphomas; neuroblastoma is described as the most common reported tumor type among Weaver cases (Clinical Cancer Research, 2024-06; DOI: 10.1158/1078-0432.CCR-24-0237; URL: https://doi.org/10.1158/1078-0432.ccr-24-0237) (kamihara2024neuroblastomapredispositionand pages 1-2). The same source describes a threshold framework for recommending neuroblastoma surveillance (≥1% neuroblastoma prevalence among carriers or segregation in multiple pedigrees) but the provided excerpt does not state a finalized surveillance recommendation for Weaver syndrome (kamihara2024neuroblastomapredispositionand pages 1-2).

Structured disease tables (identifiers and phenotypic frequencies)

Category Field Value Source year Journal DOI / URL PMID Citation
Identifier Disease name Weaver syndrome 2012 The American Journal of Human Genetics https://doi.org/10.1016/j.ajhg.2011.11.018 (gibson2012mutationsinezh2 pages 1-3)
Identifier MIM / OMIM MIM 277590 2012 The American Journal of Human Genetics https://doi.org/10.1016/j.ajhg.2011.11.018 (gibson2012mutationsinezh2 pages 1-3)
Identifier Abbreviation WS 2024 Molecular Syndromology https://doi.org/10.1159/000533733 (kendirdemirkol2024expandingthephenotypic pages 1-2)
Nomenclature Synonyms / descriptors Rare congenital overgrowth disorder; autosomal dominant overgrowth disorder; EZH2-related overgrowth syndrome 2024 Molecular Syndromology https://doi.org/10.1159/000533733 (kendirdemirkol2024expandingthephenotypic pages 1-2)
Genetics Primary causal gene EZH2 (enhancer of zeste homolog 2) 2011 Oncotarget https://doi.org/10.18632/oncotarget.385 (tattonbrown2011germlinemutationsin pages 1-2)
Genetics EZH2 MIM / OMIM MIM #601573 2016 Human Mutation https://doi.org/10.1002/humu.22946 (cohen2016weaversyndrome‐associatedezh2 pages 1-2)
Genetics Molecular class Germline heterozygous pathogenic / likely pathogenic EZH2 variants, usually missense; many de novo 2011 Oncotarget https://doi.org/10.18632/oncotarget.385 (tattonbrown2011germlinemutationsin pages 1-2, tattonbrown2011germlinemutationsin pages 2-4)
Inheritance Inheritance pattern Autosomal dominant 2024 Molecular Syndromology https://doi.org/10.1159/000533733 (kendirdemirkol2024expandingthephenotypic pages 1-2)
Diagnostic descriptor Typical diagnostic basis Characteristic overgrowth/facial phenotype plus heterozygous pathogenic EZH2 variant on genetic testing 2024 Molecular Syndromology https://doi.org/10.1159/000533733 (kendirdemirkol2024expandingthephenotypic pages 1-2, tatton‐brown2013weaversyndromeand pages 1-2)
Clinical feature Frequency / quantitative detail Cohort / source detail Source year Journal DOI / URL PMID Citation
Tall stature / height ≥ +2 SD 41/45 (91%) Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Very tall stature / height ≥ +4 SD 16 individuals Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Tall stature ~90% Review summary in case report 2024 Molecular Syndromology https://doi.org/10.1159/000533733 (kendirdemirkol2024expandingthephenotypic pages 1-2)
Intellectual disability / developmental delay 37/45 (82%), usually mild (21/37 mild) Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Intellectual disability / developmental delay ~80% Review summary in case report 2024 Molecular Syndromology https://doi.org/10.1159/000533733 (kendirdemirkol2024expandingthephenotypic pages 1-2)
Camptodactyly / contractures 45% Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Umbilical hernia 43% Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Soft / doughy skin 49% Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Hoarse, low-pitched cry 37% Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Poor coordination / clumsiness 28/35 (80%) Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Hypotonia 44% Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Hypertonia 28% Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Birth length > +2 SD 12/18 Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Birth weight > +2 SD 15/39 (38%) Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Macrocephaly / enlarged head circumference Median +1.8 SD; range up to +5.5 SD Tatton-Brown et al. EZH2-positive cohort 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Broad forehead, hypertelorism, almond-shaped palpebral fissures, retrognathia, pointed “stuck-on” chin, large fleshy ears Qualitative recurrent craniofacial gestalt Summarized clinical phenotype 2013 American Journal of Medical Genetics Part A https://doi.org/10.1002/ajmg.a.36229 (tatton‐brown2013weaversyndromeand pages 3-4)
Broad thumbs, large hands, prominent digit pads, deep palmar creases, overriding toes Qualitative recurrent skeletal/digital findings Review summary in case report 2024 Molecular Syndromology https://doi.org/10.1159/000533733 (kendirdemirkol2024expandingthephenotypic pages 1-2)

Table: These tables summarize key disease identifiers and nomenclature for Weaver syndrome and compile core clinical features with reported frequencies, prioritizing Tatton-Brown 2013 and Kendir-Demirkol 2024. They are useful for rapid knowledge-base extraction of ontology-ready identifiers, inheritance, and phenotype prevalence.

Key limitations of this report (based on tool-accessible full text)

  • MONDO/ICD/MeSH identifiers were not present in the retrieved texts used here.
  • Prevalence/incidence estimates were not found; available data are mainly reported-case counts and cohort sizes.
  • PMIDs were not retrievable from the tool outputs for several papers; DOIs/URLs and publication dates are provided where available in-text.

References

  1. (gibson2012mutationsinezh2 pages 1-3): William T. Gibson, Rebecca L. Hood, Shing Hei Zhan, Dennis E. Bulman, Anthony P. Fejes, Richard Moore, Andrew J. Mungall, Patrice Eydoux, Riyana Babul-Hirji, Jianghong An, Marco A. Marra, David Chitayat, Kym M. Boycott, David D. Weaver, and Steven J.M. Jones. Mutations in ezh2 cause weaver syndrome. The American Journal of Human Genetics, 90:110-118, Jan 2012. URL: https://doi.org/10.1016/j.ajhg.2011.11.018, doi:10.1016/j.ajhg.2011.11.018. This article has 346 citations.

  2. (tatton‐brown2013weaversyndromeand pages 1-2): Katrina Tatton‐Brown, Anne Murray, Sandra Hanks, Jenny Douglas, Ruth Armstrong, Siddharth Banka, Lynne M. Bird, Carol L. Clericuzio, Valerie Cormier‐Daire, Tom Cushing, Frances Flinter, Marie‐Line Jacquemont, Shelagh Joss, Esther Kinning, Sally Ann Lynch, Alex Magee, Vivienne McConnell, Ana Medeira, Keiichi Ozono, Michael Patton, Julia Rankin, Debbie Shears, Marleen Simon, Miranda Splitt, Volker Strenger, Kyra Stuurman, Clare Taylor, Hannah Titheradge, Lionel Van Maldergem, I. Karen Temple, Trevor Cole, Sheila Seal, and Nazneen Rahman. Weaver syndrome and ezh2 mutations: clarifying the clinical phenotype. American Journal of Medical Genetics Part A, 161:2972-2980, Dec 2013. URL: https://doi.org/10.1002/ajmg.a.36229, doi:10.1002/ajmg.a.36229. This article has 181 citations.

  3. (kendirdemirkol2024expandingthephenotypic pages 1-2): Yasemin Kendir-Demirkol, Burcu Yeter, and Laura A. Jenny. Expanding the phenotypic and genotypic spectrum of weaver syndrome: a missense variant of the ezh2 gene. Molecular Syndromology, 15:161-166, Sep 2024. URL: https://doi.org/10.1159/000533733, doi:10.1159/000533733. This article has 5 citations and is from a peer-reviewed journal.

  4. (tatton‐brown2013weaversyndromeand pages 3-4): Katrina Tatton‐Brown, Anne Murray, Sandra Hanks, Jenny Douglas, Ruth Armstrong, Siddharth Banka, Lynne M. Bird, Carol L. Clericuzio, Valerie Cormier‐Daire, Tom Cushing, Frances Flinter, Marie‐Line Jacquemont, Shelagh Joss, Esther Kinning, Sally Ann Lynch, Alex Magee, Vivienne McConnell, Ana Medeira, Keiichi Ozono, Michael Patton, Julia Rankin, Debbie Shears, Marleen Simon, Miranda Splitt, Volker Strenger, Kyra Stuurman, Clare Taylor, Hannah Titheradge, Lionel Van Maldergem, I. Karen Temple, Trevor Cole, Sheila Seal, and Nazneen Rahman. Weaver syndrome and ezh2 mutations: clarifying the clinical phenotype. American Journal of Medical Genetics Part A, 161:2972-2980, Dec 2013. URL: https://doi.org/10.1002/ajmg.a.36229, doi:10.1002/ajmg.a.36229. This article has 181 citations.

  5. (tattonbrown2011germlinemutationsin pages 1-2): Katrina Tatton-Brown, Sandra Hanks, Elise Ruark, Anna Zachariou, Silvana Del Vecchio Duarte, Emma Ramsay, Katie Snape, Anne Murray, Elizabeth R Perdeaux, Sheila Seal, Chey Loveday, Siddharth Banka, Carol Clericuzio, Frances Flinter, Alex Magee, Vivienne McConnell, Michael Patton, Wolfgang Raith, Julia Rankin, Miranda Splitt, Volker Strenger, Clare Taylor, Patricia Wheeler, I Karen Temple, Trevor Cole, Jenny Douglas, and Nazneen Rahman. Germline mutations in the oncogene ezh2 cause weaver syndrome and increased human height. Oncotarget, 2:1127-1133, Dec 2011. URL: https://doi.org/10.18632/oncotarget.385, doi:10.18632/oncotarget.385. This article has 195 citations.

  6. (deevy2024dominantnegativeeffects pages 1-2): Orla Deevy, Craig Monger, Francesca Matrà, Ellen Tuck, Eric Conway, Mihaly Badonyi, Darragh Nimmo, Simona Rodighiero, Qi Zhang, Chen Davidovich, Joseph A. Marsh, Diego Pasini, and Adrian P. Bracken. Dominant negative effects on h3k27 methylation by weaver syndrome-associated ezh2 variants. bioRxiv, May 2024. URL: https://doi.org/10.1101/2023.06.01.543208, doi:10.1101/2023.06.01.543208. This article has 5 citations.

  7. (deevy2025dominantnegativeeffectsof pages 1-2): Orla Deevy, Jingjing Li, Craig Monger, Francesca Matrà, Ellen Tuck, Molly Davies, Mihaly Badonyi, Maeve Boyce, Emma J. Doyle, Karsten Hokamp, Darragh Nimmo, Simona Rodighiero, Qi Zhang, Chen Davidovich, Joseph A. Marsh, Diego Pasini, Eric Conway, and Adrian P. Bracken. Dominant-negative effects of weaver syndrome-associated ezh2 variants. Genes & Development, 39:1355-1376, Aug 2025. URL: https://doi.org/10.1101/gad.351884.124, doi:10.1101/gad.351884.124. This article has 7 citations and is from a highest quality peer-reviewed journal.

  8. (gao2024amousemodel pages 1-2): Christine W. Gao, WanYing Lin, Ryan C. Riddle, Priyanka Kushwaha, Leandros Boukas, Hans T. Björnsson, Kasper D. Hansen, and Jill A. Fahrner. A mouse model of weaver syndrome displays overgrowth and excess osteogenesis reversible with kdm6a/6b inhibition. JCI Insight, Jan 2024. URL: https://doi.org/10.1172/jci.insight.173392, doi:10.1172/jci.insight.173392. This article has 14 citations and is from a domain leading peer-reviewed journal.

  9. (cohen2016weaversyndrome‐associatedezh2 pages 1-2): Ana S.A. Cohen, Damian B. Yap, M.E. Suzanne Lewis, Chieko Chijiwa, Maria A. Ramos‐Arroyo, Natália Tkachenko, Valentina Milano, Mélanie Fradin, Margaret L. McKinnon, Katelin N. Townsend, Jieqing Xu, M.I. Allen, Colin J.D. Ross, William B. Dobyns, David D. Weaver, and William T. Gibson. Weaver syndrome‐associated ezh2 protein variants show impaired histone methyltransferase function in vitro. Human Mutation, 37:301-307, Jan 2016. URL: https://doi.org/10.1002/humu.22946, doi:10.1002/humu.22946. This article has 102 citations and is from a domain leading peer-reviewed journal.

  10. (choufani2020dnamethylationsignature pages 1-2): Sanaa Choufani, William T. Gibson, Andrei L. Turinsky, Brian H.Y. Chung, Tianren Wang, Kopal Garg, Alessandro Vitriolo, Ana S.A. Cohen, Sharri Cyrus, Sarah Goodman, Eric Chater-Diehl, Jack Brzezinski, Michael Brudno, Luk Ho Ming, Susan M. White, Sally Ann Lynch, Carol Clericuzio, I. Karen Temple, Frances Flinter, Vivienne McConnell, Tom Cushing, Lynne M. Bird, Miranda Splitt, Bronwyn Kerr, Stephen W. Scherer, Jerry Machado, Eri Imagawa, Nobuhiko Okamoto, Naomichi Matsumoto, Guiseppe Testa, Maria Iascone, Romano Tenconi, Oana Caluseriu, Roberto Mendoza-Londono, David Chitayat, Cheryl Cytrynbaum, Katrina Tatton-Brown, and Rosanna Weksberg. Dna methylation signature for ezh2 functionally classifies sequence variants in three prc2 complex genes. The American Journal of Human Genetics, 106:596-610, May 2020. URL: https://doi.org/10.1016/j.ajhg.2020.03.008, doi:10.1016/j.ajhg.2020.03.008. This article has 98 citations.

  11. (awamleh2024dnamethylationsignatures pages 1-2): Zain Awamleh, Sarah Goodman, Sanaa Choufani, and Rosanna Weksberg. Dna methylation signatures for chromatinopathies: current challenges and future applications. Human Genetics, 143:551-557, Apr 2024. URL: https://doi.org/10.1007/s00439-023-02544-2, doi:10.1007/s00439-023-02544-2. This article has 23 citations and is from a peer-reviewed journal.

  12. (kamihara2024neuroblastomapredispositionand pages 1-2): Junne Kamihara, Lisa R. Diller, William D. Foulkes, Orli Michaeli, Yoshiko Nakano, Kristian W. Pajtler, Melissa Perrino, Sarah R. Scollon, Douglas R. Stewart, Stephan Voss, Rosanna Weksberg, Jordan R. Hansford, and Garrett M. Brodeur. Neuroblastoma predisposition and surveillance-an update from the 2023 aacr childhood cancer predisposition workshop. Clinical cancer research : an official journal of the American Association for Cancer Research, 30:OF1-OF7, Jun 2024. URL: https://doi.org/10.1158/1078-0432.ccr-24-0237, doi:10.1158/1078-0432.ccr-24-0237. This article has 29 citations.

  13. (tattonbrown2011germlinemutationsin pages 2-4): Katrina Tatton-Brown, Sandra Hanks, Elise Ruark, Anna Zachariou, Silvana Del Vecchio Duarte, Emma Ramsay, Katie Snape, Anne Murray, Elizabeth R Perdeaux, Sheila Seal, Chey Loveday, Siddharth Banka, Carol Clericuzio, Frances Flinter, Alex Magee, Vivienne McConnell, Michael Patton, Wolfgang Raith, Julia Rankin, Miranda Splitt, Volker Strenger, Clare Taylor, Patricia Wheeler, I Karen Temple, Trevor Cole, Jenny Douglas, and Nazneen Rahman. Germline mutations in the oncogene ezh2 cause weaver syndrome and increased human height. Oncotarget, 2:1127-1133, Dec 2011. URL: https://doi.org/10.18632/oncotarget.385, doi:10.18632/oncotarget.385. This article has 195 citations.

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