Genetic variants have been implicated, including CRELD1 mutations, but no previous study has examined the candidate genes, NKX2-5 and GATA4, in DS patients with secundum atrial defects (ASDII) and ventricular septal defects (VSD).
In the present study, we further genetically and functionally analyzed an upstream enhancer of the NKX2-5 gene in large cohorts of VSD patients (n=340) and controls (n=347).
In this study, the entire coding region of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor crucial to cardiogenesis, was initially sequenced in 136 unrelated patients with VSD.
None of the VSD patients had this mutation; yet 14/29 had at least one mutation in the third helix leading to either inactivation or reduction of NKX2-5 transactivation.