Human Gene Module / Chromosome 2 / ZEB2

ZEB2zinc finger E-box binding homeobox 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
7 / 8
Rare Variants / Common Variants
14 / 0
Aliases
-
Associated Syndromes
Mowat-Wilson syndrome
Chromosome Band
2q22.3
Associated Disorders
-
Relevance to Autism

Trio-based whole-exome sequencing of 168 patients with low-functioning ASD at Sun Yat-sen Memorial Hospital in Wu et al., 2025 identified a de novo loss-of-function variant in the ZEB2 gene in a patient clinically diagnosed with ASD based on DSM-5 criteria and presenting with global developmental delay/intellectual disability. De novo missense variants in the ZEB2 gene, including one predicted to be deleterious by CADD, REVEL, and MPC, were previously reported in an ASD proband from the Simons Simplex Collection and a proband from the SPARK cohort (Iossifov et al., 2014; Zhou et al., 2022). ZEB2 was identified as a top gene with ASD-associated noncoding de novo mutations (DNMs) in the SPARK cohort, with validation in the SSC cohort, using point-based statistical tests (CADD score > 15) in Zhang et al., 2025. Evans et al., 2012 evaluated the behavioral phenotype in 61 individuals with Mowat-Wilson syndrome (MWS) and found an increased rate of repetitive behaviors compared with those for individuals selected from an epidemiological sample of people with intellectual disability from other causes; the authors also found that 40% of the MWS participants and 42.62% of contrast participants scored above the cut-off score for the DBC-Autism Screening Algorithm.

Molecular Function

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ZEB2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Elizabeth Evans et al. (2012) No Repetitive behavior
2 Support Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Cukier HN , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Support Next-Generation Sequencing in Korean Children With Autism Spectrum Disorder and Comorbid Epilepsy Lee J et al. (2020) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - Ana Karen Sandoval-Talamantes et al. (2023) Yes -
7 Support - Yuan Zhang et al. (2025) Yes -
8 Primary - Ruohao Wu et al. (2025) Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
A>G - intron_variant De novo - - 40894881 Yuan Zhang et al. (2025)
A>T - intron_variant De novo - - 40894881 Yuan Zhang et al. (2025)
C>T - intron_variant De novo - - 40894881 Yuan Zhang et al. (2025)
G>A - intron_variant De novo - - 40894881 Yuan Zhang et al. (2025)
G>C - intron_variant De novo - - 40894881 Yuan Zhang et al. (2025)
T>C - intron_variant De novo - - 40894881 Yuan Zhang et al. (2025)
T>TG - intron_variant De novo - - 40894881 Yuan Zhang et al. (2025)
c.2494G>A p.Ala832Thr missense_variant Unknown - - 32477112 Lee J et al. (2020)
c.1902C>T p.Leu634= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3052A>G p.Lys1018Glu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1526C>T p.Pro509Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1326delG p.Met443TrpfsTer11 frameshift_variant De novo - - 41127290 Ruohao Wu et al. (2025)
c.1276T>A p.Leu426Ile missense_variant Familial - Extended multiplex 24410847 Cukier HN , et al. (2014)
c.1769T>C p.Phe590Ser missense_variant Unknown - - 38003033 Ana Karen Sandoval-Talamantes et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2025
icon
3

Increased from to 3

Krishnan Probability Score

Score 0.49231213644022

Ranking 4607/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99983386672298

Ranking 757/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94416556704971

Ranking 15969/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.14110043105237

Ranking 5338/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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