ZFHX3-associated neural tube defect.

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• The zinc finger homeobox 3 (ZFHX3) gene is crucial for neurodevelopment and organogenesis.
• ZFHX3 haploinsufficiency is associated with intellectual disability, epilepsy, and neurodevelopmental defects.
• The role of ZFHX3 in neural tube defects (NTDs) and related congenital structural anomalies remains uncharacterized.

Purpose of the Study:

• To investigate the potential role of ZFHX3 in NTDs and congenital structural anomalies.
• To report a novel case of a patient with a de novo ZFHX3 variant and associated phenotypic features.

Main Methods:

• Whole exome sequencing was performed to identify genetic variants.
• Clinical phenotyping of the proband was conducted, including assessment of neurological and structural anomalies.

Main Results:

• A de novo heterozygous ZFHX3 variant (c.5876 A>C, p.(Gln1959Pro)) was identified in a female proband.
• The proband presented with a spectrum of congenital anomalies, including spina bifida occulta, segmental spinal dysgenesis, bilateral clubfeet, bicuspid aortic valve, and genital anomaly.
• This case expands the known phenotypic spectrum associated with ZFHX3.

Conclusions:

• The findings suggest a potential role for ZFHX3 in the etiology of NTDs and other congenital structural defects.
• Disruptions in Wnt/β-catenin, mTOR, and Hippo signaling pathways due to ZFHX3 alterations may contribute to these anomalies.
• Further research and case reports are necessary to establish causality and confirm ZFHX3's role in NTDs and congenital anomalies.