This finding is supported by evidence linking all of the human disease genes for the VATER/VACTERL association identified to date, namely, FGF8, FOXF1, HOXD13, LPP, TRAP1, and ZIC3, with renal malformations.
NMD efficiency is known to vary greatly between transcripts, tissues and individuals and it is possible that differences in survival of PTC-containing transcripts partially explain the striking phenotypic variability that characterizes ZIC3-associated congenital defects.
The birth incidence of heterotaxy-spectrum malformations is significantly higher in males, but our previous work indicated that mutations within ZIC3 did not account for the male over-representation.
These patients occasionally also show spina bifida, indicating that genetic variation in human ZIC3 may contribute to other congenital malformations, including neural tube defects.