EDNRB and isolated spina bifida: Previously we reported that the cause eliciting malformation and mortality by VPA involved multi-mechanism, such as inhibition of histone deacetylase (HDAC), suppressed superoxide dismutase (SOD) and glutathione regenerative cycle; enhanced ROS stress, and neural tube defect (NTD) [3]; [5], [6], downregulated gene folr1, IGF2R, RGS2, COL6A3, EDNRB, KLF6, and pax-3 [5].