First-generation (F1) hybrids of the inbred strains C57BL/6N and FVB/N or A/J were found to have a lower incidence of congenital heart defects than Nkx2-5+/− mice in the C57BL/6N background or the second-generation (F2) offspring of backcrosses to the parental strains or intercrosses (F1×F1). This evidence concerns the gene NKX2-5 and congenital heart disease.