Many of the identified risk variants fall near genes where more deleterious mutations have been reported to cause serious heart defects in humans (GATA4, MYH6, NKX2-5, PITX2, TBX5)<sup>1</sup>, or near genes important for striated muscle function and integrity (for example, CFL2, MYH7, PKP2, RBM20, SGCG, SSPN).
The mutations in GATA4 gene induce inherited atrial and ventricular septation defects, which is the most frequent forms of congenital heart defects (CHDs) constituting about half of all cases.
In accordance with previous findings on GATA4 mutation screening and in vitro experiments, this study confirms that GATA4M310V mutation may lead to the development of the congenital heart defect, ASD.
Congenital heart defects also are common in patients with GATA4 mutations and deletions, but the role of GATA4 in the developing human pancreas is unproven.
Mice deficient for one copy of the Gata4 gene have been described with CDH and heart defects suggesting mutations in Gata4 can cause the phenotype in mice.
These findings suggest that C-terminus of GATA4 is critical to maintain DNA binding, and genetic mutations in this region may affect genes important for myocyte apoptosis and differentiation associated with congenital heart defects.
In summary, the Gata4G295S mutation functions as a hypomorph in vivo and leads to defects in cardiomyocyte proliferation during embryogenesis, which may contribute to the development of congenital heart defects in humans.
Mutations in GATA4 are thought to be responsible for the congenital heart defects reported in association with this chromosomal deletion, and several familial point mutations leading to amino acid substitutions have also been identified.
In addition, GATA4 is supposed to be the responsible gene for the CHDs in the chromosomal 8p23 deletion syndrome, which is recognized as a malformation syndrome with clinical symptoms of facial anomalies, microcephaly, mental retardation, and congenital heart defects.
Congenital heart defects are among the most common developmental anomalies, affecting 1% of newborns, and the GATA4 gene is less frequently involved in these disorders.
Duplication of the GATA-binding protein 4 gene (GATA4) in this patient and others with and without heart defects, suggests it is a dosage-sensitive gene with variable penetrance.