ZFHX4 is a zinc finger homeobox transcription factor located on chromosome 8.11 that plays crucial roles in neurodevelopment and craniofacial patterning. The gene encodes a 397 kDa protein that binds promoter regions of genes essential for embryonic, neuronal, and axonal development 1. ZFHX4 shows increased expression during human brain development and neuronal differentiation 1, and interacts with the NuRD chr8-remodeling complex member CHD4 to regulate gene expression programs 2. Loss-of-function variants in ZFHX4, including protein-truncating variants, microdeletions, and inversions, cause a neurodevelopmental disorder characterized by developmental delay, intellectual disability, distinctive facial features, hypotonia, short stature, and occasionally cleft palate and anterior segment dysgenesis 31. ZFHX4 is essential for craniofacial development; zebrafish studies demonstrate that zfhx4 disruption results in underdeveloped Meckel's cartilage and ethmoid plates, with behavioral abnormalities including decreased movement frequency 41. ZFHX4 variants are associated with both syndromic and nonsyndromic orofacial clefting 4. Additionally, ZFHX4 mutations correlate with enhanced tumor immunogenicity and improved responses to anti-PD-1/PD-L1 immunotherapy in cancer patients 5.