In 3 sporadic Chinese patients with congenital heart defects, 2 with atrial septal defect (ASD9; 614475) and 1 with tetralogy of Fallot (TOF; 187500), Lin et al. (2010) identified heterozygosity for a 551G-A transition in exon 2 of the GATA6 gene, resulting in a ser184-to-asn (S184N) substitution at a highly conserved residue in the transcriptional activation domain. Functional analysis in HEK293 cells, using a direct cardiac downstream target, ANF (108780), as a luciferase reporter, demonstrated significantly decreased transcriptional activity and loss of dosage sensitivity for the mutant compared to wildtype. Studies in H9c2 rat cardiomyoblast cells using RT-PCR also showed impaired transcriptional ability of S184N GATA6. One of the ASD patients was a 3-year-old girl with an ostium secundum ASD and mild pulmonary arterial hypertension, whereas the other was a 4-year-old boy with an ostium secundum ASD and mild tricuspid valve disease and pulmonary valve replacement. The third patient was a 7-month-old boy with an overriding aorta (50% override), pulmonary stenosis, ventricular septal defect, and right atrial and ventricular hypertrophy. None of the patients had any other abnormalities. The S184N mutation was detected in the unaffected fathers of the boy with TOF and the girl with ASD, and it was also detected in the clinically unaffected mother of the boy with ASD, who was found to have bicuspid aortic valve on echocardiography. The mutation was not found in 500 ethnically matched controls.
