👪

Inheritance

1

Autosomal Dominant

EZH2-related overgrowth (Weaver syndrome) is inherited in an autosomal dominant manner. Many cases are de novo; some affected individuals have an affected parent. Each child of an affected individual has a 50% recurrence risk.

Show evidence (2 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:22177091 SUPPORT Human Clinical

"Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2)."

Most cases arise from de novo dominant EZH2 variants, consistent with autosomal dominant inheritance.

◈

Mechanistic Hypotheses

2

Dominant-negative interference with PRC2

dominant_negative_prc2

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.

Show evidence (1 reference)

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.

Loss-of-function / reduced PRC2 catalytic activity

loss_of_function_prc2

An alternative (not mutually exclusive) view holds that WS EZH2 variants reduce PRC2 histone methyltransferase activity. In vitro reconstitution of PRC2 with WS-associated EZH2 alterations shows reduced H3K27 methyltransferase function, though methyltransferase activity does not directly correlate with phenotypic severity.

Show evidence (1 reference)

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.

⚙

Pathophysiology

3

EZH2/PRC2 Histone Methyltransferase Dysfunction

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 and impair PRC2 catalytic function. In vitro reconstitution shows WS-associated amino-acid changes reduce EZH2 histone methyltransferase activity, and isogenic stem-cell modeling indicates many variants act through dominant-negative interference with PRC2 even at low expression, lowering global H3K27me2/3 with reciprocal gains in H3K27ac.

embryonic stem cell CL:0002322

PRC2 (PcG protein complex) GO:0031519

peptidyl-lysine (H3K27) methylation GO:0018022 ↓ DECREASED

histone H3K27 methyltransferase activity GO:0046976 ↓ DECREASED

Downstream

Impaired Polycomb Repression and Derepression of Growth Genes

Neuroblastoma Predisposition

Show evidence (3 references)

PMID:22190405 SUPPORT Human Clinical

"We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case."

Establishes EZH2, a histone methyltransferase, as the cause of Weaver syndrome.

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 demonstrate impaired EZH2 methyltransferase activity for WS variants.

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."

Isogenic stem-cell modeling shows WS EZH2 variants reduce H3K27me2/3 and increase H3K27ac.

Impaired Polycomb Repression and Derepression of Growth Genes

Reduced PRC2-mediated H3K27 methylation (with chromatin decompaction and loss of canonical PRC1 occupancy) impairs facultative heterochromatin formation and Polycomb-mediated transcriptional silencing. WS-associated EZH2 variants derepress weakly Polycomb-bound genes, including phenotypically relevant growth control genes, providing a mechanistic link between dysregulated histone modification and human overgrowth.

facultative heterochromatin formation GO:0140718 ↓ DECREASED chromatin organization GO:0006325 ⚠ ABNORMAL

Downstream

Dysregulated Osteoblast Differentiation and Skeletal Overgrowth

Intellectual Disability / Developmental Delay

Low, Hoarse Cry

Abnormal Muscle Tone (Hypotonia / Hypertonia)

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 Skeletal Overgrowth

In bone, perturbed H3K27 methylation balance dysregulates osteoblast differentiation and the BMP signaling pathway, driving excess osteogenesis, skeletal overgrowth, and advanced bone age. A knock-in mouse model of the common EZH2 p.R684C variant shows global H3K27me3 depletion, abnormal bone parameters indicative of skeletal overgrowth, and increased osteogenic activity, with reciprocal balance restorable by inhibiting the opposing H3K27 demethylases KDM6A/KDM6B.

osteoblast CL:0000062 bone marrow mesenchymal stem cell CL:0002540

osteoblast differentiation GO:0001649 ⚠ ABNORMAL BMP signaling pathway GO:0030509 ⚠ ABNORMAL

Downstream

Tall Stature / Overgrowth

Large for Gestational Age (Prenatal Overgrowth)

Accelerated Skeletal Maturation (Advanced Bone Age)

Macrocephaly

Distinctive Craniofacial Appearance

Broad Forehead

Almond-Shaped Palpebral Fissures

Retrognathia

Camptodactyly

Soft, Doughy Skin

Umbilical Hernia

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.

●

Phenotypes

16

Eye 1

Distinctive Craniofacial Appearance Hypertelorism HP:0000316

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."

Describes the recurrent craniofacial gestalt including hypertelorism.

Head and Neck 2

Macrocephaly Macrocephaly HP:0000256

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 Almond-shaped palpebral fissure HP:0007874

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 3

Accelerated Skeletal Maturation (Advanced Bone Age) Accelerated skeletal maturation HP:0005616

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 Camptodactyly HP:0012385

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.

Abnormal Muscle Tone (Hypotonia / Hypertonia) Hypotonia HP:0001252

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.

Nervous System 1

Intellectual Disability / Developmental Delay VERY_FREQUENT Intellectual disability HP:0001249

Show evidence (1 reference)

PMID:24214728 SUPPORT Human Clinical

"Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild."

~80% frequency (VERY_FREQUENT) with predominantly mild severity.

Voice 1

Low, Hoarse Cry Hoarse voice HP:0001609

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 Tall stature HP:0000098

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) Large for gestational age HP:0001520

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 6

Broad Forehead Broad forehead HP:0000337

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 Retrognathia HP:0000278

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 Soft, doughy skin HP:0001027

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 Umbilical hernia HP:0001537

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.

Poor Coordination Incoordination HP:0002311

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 Neuroblastoma HP:0003006

Show evidence (1 reference)

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.

🧬

Genetic Associations

1

EZH2 (Pathogenic Variants)

Gene: EZH2 hgnc:3527 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 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.

💊

Medical Actions

4

Genetic Counseling

Action: Genetic Counseling 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. Once a familial variant is identified, prenatal and preimplantation genetic testing are possible.

Show evidence (1 reference)

PMID:23865096 SUPPORT Human Clinical

"Each child of an individual with EZH2-related overgrowth has a 50% chance of inheriting the pathogenic variant"

GeneReviews supports genetic counseling given autosomal dominant 50% recurrence risk.

Developmental and Physical Therapy

Action: physical therapy MAXO:0000011

Referral for learning/behavior/speech assessment and support for developmental delay and learning disability; physiotherapy for joint pain secondary 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 procedure MAXO:0000004

Toe camptodactyly may occasionally require surgical release.

Target Phenotypes: Camptodactyly HP:0012385

Show evidence (1 reference)

PMID:23865096 SUPPORT Human Clinical

"Occasionally, toe camptodactyly may require surgical release."

GeneReviews notes occasional surgical release for toe camptodactyly.

Neuroblastoma Surveillance

Action: surveillance for malignancies MAXO:0001492

There are no internationally ratified neuroblastoma surveillance guidelines for EZH2 variant carriers, 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.

Target Phenotypes: Neuroblastoma HP:0003006

Show evidence (1 reference)

PMID:23865096 SUPPORT Human Clinical

"US guidelines recommend imaging and urine biochemistry surveillance until age 10 years."

GeneReviews documents the US neuroblastoma surveillance recommendation for EZH2 carriers.

🔬

Biochemical Markers

1

PRC2 DNA Methylation Episignature (PRESENT)

Show evidence (2 references)

PMID:32243864 SUPPORT Human Clinical

"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."

Defines the EZH2/PRC2 DNA methylation episignature and its diagnostic utility.

PMID:37022461 SUPPORT Human Clinical

"DNA methylation signatures, syndrome-specific patterns of DNA methylation alterations, serve as both a research avenue for elucidating disease pathophysiology and a clinical diagnostic tool. The latter is well established, especially for the classification of variants of uncertain significance (VUS)."

Reviews how DNA methylation signatures serve as a clinical diagnostic tool, well established especially for VUS classification, supporting the episignature's diagnostic utility in PRC2 chromatinopathies.

🔀

Differential Diagnoses

1

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

Sotos Syndrome

Overlapping Features Sotos syndrome (NSD1) is the principal differential diagnosis, with considerable phenotypic overlap (overgrowth, advanced bone age, learning difficulties). EZH2 testing or the PRC2 DNA-methylation episignature provides an objective means of distinguishing Weaver from Sotos syndrome; the WS chin crease, increased prenatal growth, and pattern of advanced bone age can also help clinically.

Show evidence (1 reference)

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.

{ }

Source YAML

click to show

name: Weaver Syndrome
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), and EZH2 testing or a PRC2 DNA-methylation episignature can distinguish
  the two. Most EZH2 variants are missense and act, at least in part, through
  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
inheritance:
- name: Autosomal Dominant
  description: >-
    EZH2-related overgrowth (Weaver syndrome) is inherited in an autosomal
    dominant manner. Many cases are de novo; some affected individuals have an
    affected parent. Each child of an affected individual has a 50% recurrence
    risk.
  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:22177091
    reference_title: "Mutations in EZH2 cause Weaver syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Filtering of rare variants in the affected probands against the parental variants identified two different de novo mutations in the enhancer of zeste homolog 2 (EZH2)."
    explanation: Most cases arise from de novo dominant EZH2 variants, consistent with autosomal dominant inheritance.

pathophysiology:
- name: EZH2/PRC2 Histone Methyltransferase Dysfunction
  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 and impair PRC2 catalytic function. In
    vitro reconstitution shows WS-associated amino-acid changes reduce EZH2
    histone methyltransferase activity, and isogenic stem-cell modeling indicates
    many variants act through dominant-negative interference with PRC2 even at low
    expression, lowering global H3K27me2/3 with reciprocal gains in H3K27ac.
  cell_types:
  - preferred_term: embryonic stem cell
    term:
      id: CL:0002322
      label: embryonic stem cell
  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:22190405
    reference_title: "Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case."
    explanation: Establishes EZH2, a histone methyltransferase, as the cause of Weaver syndrome.
  - 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 demonstrate impaired EZH2 methyltransferase activity for WS variants.
  - 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: Isogenic stem-cell modeling shows WS EZH2 variants reduce H3K27me2/3 and increase H3K27ac.
  downstream:
  - target: Impaired Polycomb Repression and Derepression of Growth Genes
    causal_link_type: DIRECT
  - target: Neuroblastoma Predisposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Impaired Polycomb Repression and Derepression of Growth Genes
  description: >-
    Reduced PRC2-mediated H3K27 methylation (with chromatin decompaction and loss
    of canonical PRC1 occupancy) impairs facultative heterochromatin formation and
    Polycomb-mediated transcriptional silencing. WS-associated EZH2 variants
    derepress weakly Polycomb-bound genes, including phenotypically relevant growth
    control genes, providing a mechanistic link between dysregulated histone
    modification and human overgrowth.
  biological_processes:
  - preferred_term: facultative heterochromatin formation
    term:
      id: GO:0140718
      label: facultative heterochromatin formation
    modifier: DECREASED
  - 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: "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 Skeletal Overgrowth
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual Disability / Developmental Delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low, Hoarse Cry
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Abnormal Muscle Tone (Hypotonia / Hypertonia)
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Poor Coordination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Dysregulated Osteoblast Differentiation and Skeletal Overgrowth
  description: >-
    In bone, perturbed H3K27 methylation balance dysregulates osteoblast
    differentiation and the BMP signaling pathway, driving excess osteogenesis,
    skeletal overgrowth, and advanced bone age. A knock-in mouse model of the
    common EZH2 p.R684C variant shows global H3K27me3 depletion, abnormal bone
    parameters indicative of skeletal overgrowth, and increased osteogenic
    activity, with reciprocal balance restorable by inhibiting the opposing H3K27
    demethylases KDM6A/KDM6B.
  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: DIRECT
  - target: Large for Gestational Age (Prenatal Overgrowth)
    causal_link_type: DIRECT
  - target: Accelerated Skeletal Maturation (Advanced Bone Age)
    causal_link_type: DIRECT
  - target: Macrocephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Distinctive Craniofacial Appearance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Broad Forehead
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Almond-Shaped Palpebral Fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Retrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Camptodactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Soft, Doughy Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Umbilical Hernia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

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.
- hypothesis_group_id: loss_of_function_prc2
  hypothesis_label: Loss-of-function / reduced PRC2 catalytic activity
  description: >-
    An alternative (not mutually exclusive) view holds that WS EZH2 variants reduce
    PRC2 histone methyltransferase activity. In vitro reconstitution of PRC2 with
    WS-associated EZH2 alterations shows reduced H3K27 methyltransferase function,
    though methyltransferase activity does 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.

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
  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), a hallmark 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
  severity: MILD
  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: ~80% frequency (VERY_FREQUENT) with predominantly mild severity.
- name: Distinctive Craniofacial Appearance
  category: Physical
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  description: >-
    Characteristic facial gestalt: ocular hypertelorism, broad forehead,
    almond-shaped palpebral fissures, large fleshy ears in early childhood,
    retrognathia, and a pointed "stuck-on" chin with horizontal skin creases.
    Features can be subtle and age-dependent.
  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: Describes the recurrent craniofacial gestalt including hypertelorism.
- 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 with a pointed "stuck-on" chin and horizontal chin crease helps
    distinguish Weaver from Sotos syndrome.
  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
  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 (Hypotonia / Hypertonia)
  category: Neurologic
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  description: >-
    Abnormal tone is common, with both hypotonia and hypertonia reported in the
    EZH2-positive cohort.
  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 frequently reported.
  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; it is the most commonly reported tumor type in Weaver
    syndrome. There is currently no clear evidence of an increased frequency of
    additional malignancies.
  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.

genetic:
- name: EZH2
  gene_term:
    preferred_term: EZH2
    term:
      id: hgnc:3527
      label: EZH2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  frequency: VERY_FREQUENT
  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) is the most common variant. Many variants are de novo, but autosomal
    dominant transmission occurs.
  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.

biochemical:
- name: PRC2 DNA Methylation Episignature
  biomarker_term:
    preferred_term: EZH2/PRC2 DNA methylation signature
  presence: PRESENT
  specificity: HIGH
  notes: >-
    Pathogenic EZH2 variants generate a highly specific and sensitive
    peripheral-blood DNA methylation (episignature) reflecting the Weaver
    phenotype. The signature can distinguish loss-of-function from gain-of-function
    missense variants, detect somatic mosaicism, and also classify variants in the
    other PRC2 core genes EED and SUZ12, supporting its use for VUS classification.
  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: "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 EZH2/PRC2 DNA methylation episignature and its diagnostic utility.
  - reference: PMID:37022461
    reference_title: "DNA methylation signatures for chromatinopathies: current challenges and future applications."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA methylation signatures, syndrome-specific patterns of DNA methylation alterations, serve as both a research avenue for elucidating disease pathophysiology and a clinical diagnostic tool. The latter is well established, especially for the classification of variants of uncertain significance (VUS)."
    explanation: Reviews how DNA methylation signatures serve as a clinical diagnostic tool, well established especially for VUS classification, supporting the episignature's diagnostic utility in PRC2 chromatinopathies.

differential_diagnoses:
- name: Sotos Syndrome
  description: >-
    Sotos syndrome (NSD1) is the principal differential diagnosis, with
    considerable phenotypic overlap (overgrowth, advanced bone age, learning
    difficulties). EZH2 testing or the PRC2 DNA-methylation episignature provides
    an objective means of distinguishing Weaver from Sotos syndrome; the WS chin
    crease, increased prenatal growth, and pattern of advanced bone age can also
    help clinically.
  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.

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. 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"
    explanation: GeneReviews supports genetic counseling given autosomal dominant 50% recurrence risk.
- name: Developmental and Physical Therapy
  description: >-
    Referral for learning/behavior/speech assessment and support for developmental
    delay and learning disability; physiotherapy for joint pain secondary to
    ligamentous laxity or joint contractures.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      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.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: MAXO:0000004
      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: Neuroblastoma Surveillance
  description: >-
    There are no internationally ratified neuroblastoma surveillance guidelines for
    EZH2 variant carriers, 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.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: MAXO:0001492
      label: surveillance for malignancies
  target_phenotypes:
  - preferred_term: Neuroblastoma
    term:
      id: HP:0003006
      label: Neuroblastoma
  evidence:
  - reference: PMID:23865096
    reference_title: "EZH2-Related Overgrowth."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "US guidelines recommend imaging and urine biochemistry surveillance until age 10 years."
    explanation: GeneReviews documents the US neuroblastoma surveillance recommendation for EZH2 carriers.

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.

epidemiology:
- name: Rarity and Cohort Size
  description: >-
    Weaver syndrome is a rare disorder. Robust prevalence/incidence estimates are
    not established; the largest series to date identified 48 individuals with EZH2
    mutations. Most cases are de novo.
  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: Provides the largest reported cohort size, reflecting rarity.

📚

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)

Trigger: Heterozygous pathogenic EZH2 missense variants (often de novo) (tattonbrown2011germlinemutationsin pages 1-2, gibson2012mutationsinezh2 pages 1-3).
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).
Downstream tissue programs: In bone, dysregulated osteoblast differentiation and BMP pathway programs contribute to advanced bone age/skeletal overgrowth (gao2024amousemodel pages 1-2).
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	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	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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.

Artifacts

Edison artifact artifact-00

Ask OpenScientist

OpenScientist Report

Inheritance

Mechanistic Hypotheses

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Differential Diagnoses

Source YAML

References & Deep Research

References

Deep Research

Weaver Syndrome (MIM 277590) — Comprehensive Disease Characteristics Report

Target Disease

Summary (current understanding)

1. Disease Information

1.1 Concise overview

1.2 Key identifiers (from retrieved sources)

1.3 Synonyms / alternative names

1.4 Evidence provenance (individual vs aggregated)

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors / gene–environment interactions

3. Phenotypes (with suggested HPO terms)

3.1 Core phenotype spectrum and frequencies

3.2 Suggested HPO terms (examples; not exhaustive)

3.3 Quality of life impact

4. Genetic / Molecular Information

4.1 Causal gene(s)

4.2 Pathogenic variants (types and examples)

4.3 Functional consequences (LoF vs dominant-negative)

4.4 Epigenetic information / DNA methylation episignatures

5. Environmental Information

6. Mechanism / Pathophysiology

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

6.2 Pathways/processes implicated

6.3 Suggested GO biological process terms (examples)

6.4 Suggested cell types (CL terms; examples)

7. Anatomical Structures Affected

7.1 Organ/system level (with suggested UBERON terms)

7.2 Tissue/cell level

7.3 Subcellular level

8. Temporal Development

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology

10. Diagnostics

10.1 Clinical recognition and differential diagnosis

10.2 Genetic testing approaches (current practice reflected in literature)

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

11. Outcome / Prognosis

12. Treatment

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

12.2 Experimental / emerging therapeutics (preclinical)

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Cancer risk and surveillance (expert opinion and recent consensus)

Structured disease tables (identifiers and phenotypic frequencies)

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

Artifacts