ZEB2

Chr 2AD

zinc finger E-box binding homeobox 2

NCBI Gene: 9839 ENSG00000169554 OMIM: 605802

The encoded protein is a DNA-binding transcriptional repressor that interacts with activated SMADs and localizes to the nucleus. Loss-of-function mutations cause Mowat-Wilson syndrome through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variation, consistent with haploinsufficiency as the disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.111 OMIM phenotype

Clinical Summary— ZEB2

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Gene-Disease Validity (ClinGen)

Mowat-Wilson syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 6.03

OE 0.02 (0.01–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.94Z-score

OE missense 0.57 (0.52–0.62)

378 obs / 663.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.57 (0.52–0.62)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 1 / 44.3Missense obs/exp: 378 / 663.9Syn Z: -0.23

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveZEB2-related Mowat-Wilson syndromeLOFAD

This gene — mechanism propensity

0.19100th %ile

GOF

0.1799th %ile

LOF

0.90top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

Literature Evidence

GOFUsing a conditional gain-of-function mouse model, we recently demonstrated that ZEB2 is an oncogenic driver of immature T-cell acute lymphoblastic leukemia (T-ALL), a heterogenic subgroup of human leukemia characterized by a high incidence of remission failure or hematological relapse after conventi1

LOFHaploinsufficiency of the ZEB2 gene may predispose to MWS.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References