Abstract
Congenital heart defect (CHD) is one of the most common cardiovascular diseases, affecting approximately 0.8% of live births. The transcription factor GATA4 has been known to play a key role in cardiac development. In this study, we performed whole exome sequencing in nine unrelated CHD patients and found two rare deleterious missense variants in the GATA4 gene (c.C487T,p.P163S and c.C1223A,p.P408Q) (ExAC <0.001 and CADD >15) in three cases that were confirmed by Sanger sequencing. Subsequently, these two variants were screened for in an additional 226 patients with CHD and 206 healthy controls by Sanger sequencing, and no variants were observed. These two variants were predicted to be damaging to protein function using a functional prediction program. Co-IP indicated that both of the GATA4 variants (P163S and P408Q) blocked heterodimer formation between GATA4 and ZFPM2 protein. Immunofluorescence showed that the two GATA4 variants diminished the colocalization formation between GATA4 and ZFPM2 protein compared to that of WT protein. These findings indicate that the two rare variants of GATA4 might disturb its interaction with ZFPM2 and influence corresponding downstream gene activity, suggesting that the GATA4 variants may be associated with the pathogenesis of CHD.