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.

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