ZFHX3-associated neural tube defect

The zinc finger homeobox 3 (ZFHX3) gene encodes a transcription factor involved in neurodevelopment and organogenesis. ZFHX3 haploinsufficiency is linked to intellectual disability, epilepsy and neurodevelopmental defects, but its potential involvement in neural tube defects (NTDs) and related structural anomalies is unknown. We report a female proband with a de novo heterozygous ZFHX3 variant (NM_006885.3: c.5876 A>C, p.(Gln1959Pro), identified via exome sequencing. She presented with spina bifida occulta, segmental spinal dysgenesis, bilateral clubfeet, bicuspid aortic valve and genital anomaly. This report suggests an expanded phenotypic spectrum of ZFHX3-associated disorders. Given the known interactions of ZFHX3 with Wnt/β-catenin, mTOR and Hippo signalling pathways, we hypothesise that disruptions in these networks could contribute to NTDs and skeletal defects. No functional studies were performed, so causality cannot be established. Further research and reports of similar phenotypes in ZFHX3 variants are needed to confirm its role in NTDs and other congenital structural anomalies.