EED

protein-coding

embryonic ectoderm development, the group of Polycomb repressive complex 2|WD repeat domain containing|MicroRNA protein coding host genes

Gene summary

This gene encodes a member of the Polycomb-group (PcG) family. PcG family members form multimeric protein complexes, which are involved in maintaining the transcriptional repressive state of genes over successive cell generations. This protein interacts with enhancer of zeste 2, the cytoplasmic tail of integrin beta7, immunodeficiency virus type 1 (HIV-1) MA protein, and histone deacetylase proteins. This protein mediates repression of gene activity through histone deacetylation, and may act as a specific regulator of integrin function. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003797.5

Inheritance

ClinVar variants

P:15U:84B:32

Top phenotype

Cohen-Gibson syndrome

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr11:86,201,212-86,279,807

External References & Databases

Ensembl (ENSG00000074266)

Transcript & Mutation Effects

hg38 • Region Span ~78.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Cohen-Gibson syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060510

Submitter: ClinGen

*EED* was first reported in relation to autosomal dominant Cohen-Gibson syndrome in 2015 (Cohen et al., PMID: 25787343). Cohen-Gibson syndrome is an overgrowth disorder characterized by increased somatic growth parameters with neonatal onset and variable intellectual disability. Affected individuals have dysmorphic facial features, advanced bone age, and skeletal abnormalities, including flaring of the metaphyses of the long bones, large hands with long fingers and camptodactyly, and often scoliosis or cervical spine anomalies. Other features may include hypotonia, difficulty walking due to skeletal anomalies, and umbilical hernia (PMID: 27868325). Nine variants (8 missense and one insertion-deletion) that primarily arise *de novo* or are assumed *de novo* have been reported in 11 probands in 8 publications (PMIDs: 25787343, 27193220, 27868325, 28229514, 28475857, 29410511, 30793471, 30858506) and are included in this curation. Though all variants reported to date have been missense, loss of function has been postulated as the mechanism of disease as a functional copy of *EED* is essential for proper EZH2-mediated methyltransferase activity at H3K27 via the polycomb repressive complex 2 (PRC2). This was supported by western blotting of H3K27me3 as a marker of PRC2 methyltransferase activity; wild-type *EED* rescued normal levels of H3K27me3 whereas at least two reported missense variants failed to do so (PMID: 28229514). This gene-disease relationship is also supported by biochemical function in the PRC2 which maintains gene silencing to play a role in neurogenesis and embryogenesis, and protein interaction with EZH2 to support methyltransferase activity (PMIDs: 9584199, 15225548, 27578866). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2022 (SOP Version 9).

Cohen-Gibson syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060510

Submitter: PanelApp Australia

Cohen-Gibson syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060510

Submitter: Labcorp Genetics (formerly Invitae)

Cohen-Gibson syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060510

Submitter: G2P

Cohen-Gibson syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060510

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Cohen-Gibson syndromeAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25787343; 27193220; 27868325; 28229514

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EED variants in ClinVar

10 Conditions Cataloged

Cohen-Gibson syndromeTotal: 69

not providedTotal: 41

Inborn genetic diseasesTotal: 36

not specifiedTotal: 18

EED-related disorderTotal: 12

EED-related disordersTotal: 3

Hereditary breast ovarian cancer syndromeTotal: 1

Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003797.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	24 clinvar	3 clinvar	29
missense	5 clinvar	10 clinvar	76 clinvar	3 clinvar	1 clinvar	95
nonsense						0
start loss						0
frameshift			2 clinvar	1 clinvar		3
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	5	10	84	28	4	131

Highest pathogenic variant AF is 0.0000013698349

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003797.5	RefSeq	NP_003788.2	12	MANE Select
ENST00000263360.11	Ensembl	ENSP00000263360.6	12	MANE Select
NM_001308007.2	RefSeq	NP_001294936.1	13	Standard
NM_001330334.2	RefSeq	NP_001317263.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Histone Modifications
Interactome of polycomb repressive complex 2 (PRC2)
Oxidative Stress Induced Senescence
Tumor suppressor activity of SMARCB1
EMT transition in Colorectal Cancer

Biological Process

negative regulation of transcription by RNA polymerase II
chromatin silencing
regulation of gene expression by genetic imprinting
spinal cord development
negative regulation of gene expression, epigenetic

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
protein binding
nucleosome binding
histone methyltransferase activity
identical protein binding

Cellular Component

sex chromatin
nucleus
nucleoplasm
cytosol
ESC/E(Z) complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263360
Coding exons: 12
Length: 34270
Individuals with no LoFs: 125154
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125157
p: 0.0000120

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.73	118	236	0.499	0.0000115	2963
Missense (PolyPhen)		8	71.005	0.11267		916
Synonymous	-0.121	79	77.6	1.02	0.00000392	763
Loss of Function	4.48	1	25.4	0.0394	0.00000132	304

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000028	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Polycomb group (PcG) protein. Component of the PRC2/EED- EZH2 complex, which methylates 'Lys-9' and 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Also recognizes 'Lys-26' trimethylated histone H1 with the effect of inhibiting PRC2 complex methyltransferase activity on nucleosomal histone H3 'Lys-27', whereas H3 'Lys-27' recognition has the opposite effect, enabling the propagation of this repressive mark. The PRC2/EED-EZH2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2/EED-EZH2 complex include HOXC8, HOXA9, MYT1 and CDKN2A. {ECO:0000269|PubMed:10581039, ECO:0000269|PubMed:14532106, ECO:0000269|PubMed:15225548, ECO:0000269|PubMed:15231737, ECO:0000269|PubMed:15385962, ECO:0000269|PubMed:16357870, ECO:0000269|PubMed:18285464, ECO:0000269|PubMed:20974918, ECO:0000269|PubMed:28229514, ECO:0000269|PubMed:9584199}.;
Disease: DISEASE: Cohen-Gibson syndrome (COGIS) [MIM:617561]: An autosomal dominant overgrowth disorder characterized by accelerated osseous maturation, advanced bone age, skeletal abnormalities including flaring of the metaphyses of the long bones, large hands with long fingers and camptodactyly, scoliosis, cervical spine anomalies, dysmorphic facial features, and variable intellectual disability. {ECO:0000269|PubMed:25787343, ECO:0000269|PubMed:27193220, ECO:0000269|PubMed:27868325, ECO:0000269|PubMed:28229514, ECO:0000269|PubMed:28475857}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.149

Intolerance Scores

RVIS EVS: -0.43
RVIS percentile EVS: 25.15

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.972

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium