Relevance to Autism

Perez Baca et al., 2025 reported 63 individuals (57 probands and 6 affected family members) with protein-truncating variants (n=41), copy number variants (n=21), or an inversion (n=1) affecting the ZFHX4 gene presenting with a variable neurodevelopmental syndrome characterized by developmental delay and intellectual disability, distinctive facial characteristics, morphological abnormalities of the central nervous system, behavioral abnormalities (of which stereotypies (n=7) and autism (n=10) were the most frequently reported), short stature, hypotonia, and occasionally cleft palate and anterior segment dysgenesis; while ZFHX4 deletions showed a mild methylation profile, protein-truncating variants did not. Moreover, the authors of this study implicated ZFHX4 interactors in transcriptional regulation and development and its target gene in neural development using multi-omics data and also observed that zebrafish zfhx4 crispants displayed craniofacial/medulla oblongata defects and reduced movement frequency. Additional de novo variants in ZFHX4, including two de novo loss-of-function variants and several de novo missense variants, have been identified in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort (Satterstrom et al., 2020; Zhou et al., 2022; Trost et al., 2022).

Molecular Function

Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in chromatin. Predicted to be active in nucleus

External Links

References