EZH1

protein-coding

enhancer of zeste 1 polycomb repressive complex 2 subunit, the group of Lysine methyltransferases|MicroRNA protein coding host genes|SET domain containing|Myb/SANT domain containing|Polycomb repressive complex 2

Gene summary

EZH1 is a component of a noncanonical Polycomb repressive complex-2 (PRC2) that mediates methylation of histone H3 (see MIM 602812) lys27 (H3K27) and functions in the maintenance of embryonic stem cell pluripotency and plasticity (Shen et al., 2008 [PubMed 19026780]).[supplied by OMIM, Mar 2009]

MANE transcript

NM_001991.5

Inheritance

AR, AD

ClinVar variants

P:5U:90B:5

Top phenotype

complex neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr17:42,700,275-42,745,049

External References & Databases

Ensembl (ENSG00000108799)

Transcript & Mutation Effects

hg38 • Region Span ~44.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

neurodevelopmental disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: LiferaOmics

Genetic evidence – Published: PMID: 37433783 – Reports 4 independent consanguineous families with homozygous truncating (pLOF) EZH1 variants and 1 sporadic individual with compound heterozygous predicted loss-of-function variants (exon deletion plus splice variant with RNA evidence), presenting with global developmental delay, intellectual disability, speech delay, and variable dysmorphism. Case-level (4 homozygous probands with biallelic predicted null variants in AR model; homozygous scored once each; −0.5 consanguinity deduction applied) = 4.0; (1 compound heterozygous proband; each predicted null scored independently; no consanguinity deduction stated) = 3.0; segregation (affected siblings across families; conservative) = 1.0; case-control = 0 PMID: 38814056 – Reports two affected sisters with biallelic loss-of-function EZH1 variants and neurodevelopmental phenotype (developmental delay/intellectual disability; central precocious puberty noted). Case-level (biallelic predicted null in AR model; homozygous/compound scored once as proband; no consanguinity specified) = 1.5; segregation (affected sibling; conservative) = 0.5; case-control = 0 PMID: 29302074 – Reports a consanguineous family with two affected siblings harboring a homozygous frameshift (pLOF) EZH1 variant and neurodevelopmental phenotype. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation (affected sibling; conservative) = 0.5; case-control = 0 Published genetic evidence total = case-level (7.0 + 1.5 + 1.0 = 9.5) + segregation (1.0 + 0.5 + 0.5 = 2.0) = 11.5/12 Genetic evidence – our cases: Family 1 – 1 proband; homozygous; pLOF variant; autosomal recessive inheritance; positive consanguinity; parents confirmed heterozygous carriers. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation (parental carrier confirmation; conservative) = 0.5; case-control = 0 Family 2 – 1 proband (affected sibling); homozygous; pLOF variant; autosomal recessive inheritance; positive consanguinity. Case-level (biallelic predicted null in AR model; homozygous scored once; −0.5 consanguinity deduction applied) = 1.0; segregation (affected sibling; conservative) = 0.5; case-control = 0 Our cases total = case-level (1.0 + 1.0 = 2.0) + segregation (0.5 + 0.5 = 1.0) = 3.0/12. Total genetic evidence (published + our cases) = 11.5 + 3.0 = 14.5 (capped at 12/12) Experimental evidence – Published: PMID: 37433783 – Demonstrates that EZH1 encodes a component of the PRC2 chromatin-modifying complex with an established role in neuronal differentiation (biochemical function/biological plausibility) = 1.0. Functional alteration in patient-derived or engineered systems showing reduced EZH1 expression and impaired histone methylation activity consistent with a loss-of-function mechanism = 2.0. Model systems (human pluripotent stem cell–derived neural cultures, forebrain organoids, and in vivo neural tube models) demonstrating disrupted neurodevelopment consistent with the patient phenotype = 2.0 Experimental evidence total = 5.0/6 Overall score = 17.0/18 First report: PMID: 29302074 (2019) Additional independent families published in subsequent years (2023; 2024).

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EZH1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 55

not providedTotal: 34

EZH1-neurodevelopmental syndromeTotal: 5

EZH1-related disorderTotal: 2

EZH1-associated neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001991.5. 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	4 clinvar		6
missense		2 clinvar	80 clinvar	1 clinvar		83
nonsense		1 clinvar				1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)		2 clinvar	6 clinvar			8
Total	0	5	90	5	0	100

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001991.5	RefSeq	NP_001982.2	19	MANE Select
ENST00000428826.7	Ensembl	ENSP00000404658.1	19	MANE Select
NM_001321079.2	RefSeq	NP_001308008.1	20	Standard
NM_001321081.2	RefSeq	NP_001308010.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Lysine degradation - Homo sapiens (human)
Histone Modifications
Interactome of polycomb repressive complex 2 (PRC2)

Biological Process

anatomical structure morphogenesis
hippocampus development
positive regulation of transcription by RNA polymerase II
histone H3-K27 methylation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
chromatin binding
histone-lysine N-methyltransferase activity

Cellular Component

nucleoplasm
ESC/E(Z) complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000428826
Coding exons: 19
Length: 44779
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 15
Defined: 125747
p: 0.0000596

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.20	179	422	0.425	0.0000228	4980
Missense (PolyPhen)		68	213.99	0.31778		2565
Synonymous	1.95	116	146	0.795	0.00000769	1345
Loss of Function	4.66	12	46.1	0.260	0.00000264	506

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000062	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Polycomb group (PcG) protein. Catalytic subunit of the PRC2/EED-EZH1 complex, which methylates 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. Able to mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively. Required for embryonic stem cell derivation and self-renewal, suggesting that it is involved in safeguarding embryonic stem cell identity. Compared to EZH2-containing complexes, it is less abundant in embryonic stem cells, has weak methyltransferase activity and plays a less critical role in forming H3K27me3, which is required for embryonic stem cell identity and proper differentiation. {ECO:0000269|PubMed:19026781}.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.330
RVIS EVS: -0.45
RVIS percentile EVS: 24.19

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.995

Gene Damage Prediction

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