Novel histone deacetylase 6 gene variant is associated with fetal hydrocephalus and lateral ventriculomegaly.

OBJECTIVES: Congenital hydrocephalus (CH) is a neurological disease that significantly impacts fetal nervous system development and subsequent quality of life. CH pathogenesis may be linked to genetic factors such as defects in the histone deacetylase 6 (HDAC6) gene. However, only one CH family has been reported to date, limiting our comprehension of the relationship between HDAC6 and CH. Here, we investigated a family with an HDAC6-related fetal case of CH and ventriculomegaly, and propose a potential pathogenic mechanism involving the HDAC6 gene in CH development. METHODS: Skin tissue from a fetal-induced abortion as well as peripheral blood samples from both parents were collected for analysis. Whole-exome and Sanger sequencing were used to analyze fetal germline variants, and variant plasmids were constructed for western blot (WB) experiments; cycloheximide (CHX) chase assays with or without MG132 were further performed to assess protein degradation kinetics. RESULTS: In the fetal tissue, a variant of the HDAC6 gene was identified (NM_006044.4: c.206_c.209delTGGG, p.Val69fsTer7) that had not yet been documented in public databases. Both parents had wild-type versions of the HDAC6 gene. WB analysis revealed a significantly lower expression level of the mutant HDAC6 protein compared to that of the wild-type protein in vitro, suggesting that the truncated protein may have reduced structural stability that leads to degradation. CHX chase assays further showed that the mutant protein had a shorter half-life (~14 h) than wild-type (~35 h) and that MG132 blocked its degradation, indicating proteasome-dependent degradation. CONCLUSIONS: The frameshift variant in the HDAC6 gene likely contributed to the development of CH and ventriculomegaly in the fetus. This study underscores the importance of prenatal ultrasound for detecting early signs of CH and ventriculomegaly, and of molecular genetic diagnostic technologies to facilitate timely clinical intervention.