ZEB2

protein-coding

zinc finger E-box binding homeobox 2, the group of ZF class homeoboxes and pseudogenes|Zinc fingers C2H2-type

Gene summary

The protein encoded by this gene is a member of the Zfh1 family of 2-handed zinc finger/homeodomain proteins. It is located in the nucleus and functions as a DNA-binding transcriptional repressor that interacts with activated SMADs. Mutations in this gene are associated with Hirschsprung disease/Mowat-Wilson syndrome. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Jan 2010]

Previous symbols:

ZFHX1B

MANE transcript

NM_014795.4

Inheritance

ClinVar variants

P:426U:543B:557

Top phenotype

Mowat-Wilson syndrome

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr2:144,364,364-144,521,057

External References & Databases

Ensembl (ENSG00000169554)

Transcript & Mutation Effects

hg38 • Region Span ~156.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Mowat-Wilson syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009341

Submitter: ClinGen

*ZEB2* is located on chromosome 2q22.3 and encodes a transcription factor involved in multiple developmental processes. In the nervous system, ZEB2 regulates neuronal specification, migration, and differentiation. *ZEB2* was first reported in relation to autosomal dominant Mowat-Wilson syndrome in 2001 (Wakamatsu et al., PMID: 11279515; Cacheux et al., PMID: 11448942). Mowat-Wilson syndrome is characterized by moderate-to-severe intellectual disability, severe speech impairment, typical facial dysmorphic features, short stature with microcephaly, seizures, and congenital anomalies, including Hirschsprung disease, congenital heart defects, genitourinary abnormalities, and hypoplasia or agenesis of the corpus callosum. Eight variants (4 frameshift, 3 nonsense and 1 missense) that have been reported in eight probands in three publications (PMIDs: 11448942, 16053902, 38351292) are included in this curation. Variants are typically *de novo*. Most patients have truncating variants or gene deletions; pathogenic missense variants are rare and result in a milder clinical presentation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. A specific DNA methylation signature can be observed in individuals with pathogenic variants in *ZEB2* (PMID: 38351292). This gene-disease relationship is also supported by mouse models and functional alteration in non-patient cells. In summary, there is definitive evidence supporting the relationship between *ZEB2* and autosomal dominant Mowat-Wilson syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 23, 2018. It was reevaluated on July 1, 2026 (SOP Version 12). As a result of this reevaluation, the classification did not change.

Mowat-Wilson syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009341

Submitter: Ambry Genetics

Mowat-Wilson syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009341

Submitter: Labcorp Genetics (formerly Invitae)

Mowat-Wilson syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0009341

Submitter: PanelApp Australia

Mowat-Wilson syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009341

Submitter: G2P

Clinical Genomic Database (CGD)

Mowat-Wilson syndromeAD

Manifestation: Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: The condition can include Hirschsprung disease, among other multi-systemic manifestations; 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: 9719364; 11448942; 11279515; 14679597; 15121779; 16088920; 16688751; 16532472; 17203459; 19215041;20301585; 21343952; 21497296; 22246645; 22486326; 23322667; 23427518; 23466526; 23523603; 24029077; 24715670; 27831545

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZEB2 variants in ClinVar

22 Conditions Cataloged

Mowat-Wilson syndromeTotal: 1292

not providedTotal: 427

Inborn genetic diseasesTotal: 206

not specifiedTotal: 187

ZEB2-related disorderTotal: 90

See casesTotal: 5

Neurodevelopmental disorderTotal: 3

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014795.4. 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			8 clinvar	339 clinvar	3 clinvar	350
missense	11 clinvar	36 clinvar	522 clinvar	170 clinvar	45 clinvar	784
nonsense	99 clinvar	17 clinvar	3 clinvar			119
start loss			3 clinvar			3
frameshift	201 clinvar	42 clinvar	5 clinvar			248
splice donor/acceptor (+/-2bp)	12 clinvar	8 clinvar	2 clinvar			22
Total	323	103	543	509	48	1526

Highest pathogenic variant AF is 0.0000020521632

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014795.4	RefSeq	NP_055610.1	9	MANE Select
ENST00000627532.3	Ensembl	ENSP00000487174.1	9	MANE Select
NM_001171653.2	RefSeq	NP_001165124.1	8	Standard
ENST00000303660.8	Ensembl	ENSP00000302501.4	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
zeb2b	Danio rerio	Structure: intrahepatic bile duct Quality: decreased length abnormal

Gene / Model

Organism

Observed Phenotype

zeb2b

Danio rerio

Structure: intrahepatic bile duct

Quality: decreased length

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MicroRNAs in cancer - Homo sapiens (human)
TGF-beta Signaling Pathway
EMT transition in Colorectal Cancer
TGF-beta Receptor Signaling
TGF_beta_Receptor

Biological Process

negative regulation of transcription by RNA polymerase II
neural crest cell migration
somitogenesis
neural tube closure
nervous system development

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
protein binding
phosphatase regulator activity

Cellular Component

nuclear chromatin
nucleus
nucleolus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000558170
Coding exons: 9
Length: 140500
Individuals with no LoFs: 124846
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124847
p: 0.00000400

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.94	378	664	0.569	0.0000377	8112
Missense (PolyPhen)		73	211.53	0.34511		2608
Synonymous	-0.233	264	259	1.02	0.0000165	2239
Loss of Function	6.03	1	44.3	0.0226	0.00000251	583

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcriptional inhibitor that binds to DNA sequence 5'- CACCT-3' in different promoters. Represses transcription of E- cadherin. {ECO:0000269|PubMed:16061479}.;
Disease: DISEASE: Mowat-Wilson syndrome (MOWS) [MIM:235730]: A complex developmental disorder characterized by mental retardation, delayed motor development, epilepsy, microcephaly and a wide spectrum of clinically heterogeneous features suggestive of neurocristopathies at the cephalic, cardiac, and vagal levels. Affected patients show an easily recognizable facial appearance with deep set eyes and hypertelorism, medially divergent, broad eyebrows, prominent columella, pointed chin and uplifted, notched ear lobes. Some patients manifest Hirschsprung disease. {ECO:0000269|PubMed:11448942, ECO:0000269|PubMed:12451214, ECO:0000269|PubMed:15384097, ECO:0000269|PubMed:16688751}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.223

Intolerance Scores

LoFtool: 0.0187
RVIS EVS: -0.91
RVIS percentile EVS: 10.03

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.960

Gene Damage Prediction

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