Our results demonstrate for the first time that Nkx2.5 acts upstream of GDF1 and the genetic variants in GDF1 promoter may confer genetic susceptibility to sporadic CHD potentially by altering its expression.
Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent-offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot.
A significant difference was noted for the CT phenotype of GDF1rs4808863 between the controls and the fetuses with CHDs using homozygote and heterozygote comparisons.
In summary, our results provide evidence that genetic variations of the Nodal-like factor, GDF1 may be associated with CHD risk, and these variations contribute at least in part to the development of some subtypes of CTD in the Chinese Han population.