Garg et al. (2003) identified a large kindred spanning 5 generations in which 16 individuals had congenital heart defects. Detailed clinical evaluations reviewed for all available family members demonstrated an autosomal dominant pattern of inheritance. All affected family ... Garg et al. (2003) identified a large kindred spanning 5 generations in which 16 individuals had congenital heart defects. Detailed clinical evaluations reviewed for all available family members demonstrated an autosomal dominant pattern of inheritance. All affected family members had atrial septal defects. Eight individuals had additional congenital heart defects, including ventricular septal defects (VSD), atrioventricular septal defects (AVSD), pulmonary valve thickening, or insufficiency of the cardiac valves. Ten of the 16 affected members required surgical repair of the heart defect. Unlike the familial cases of cardiac septal defects associated with mutations in NKX2.5 (600584) or TBX5 (601620), neither the cardiac conduction system nor other organs were affected in this kindred, suggesting that the congenital heart defects were isolated and not associated with syndromic disease. Hirayama-Yamada et al. (2005) reported a 4-generation family with ASD in which affected members were found to have the same mutation in the GATA4 gene (600576.0002) as the second family described by Garg et al. (2003). A deceased member of the family in whom the mutation was identified was said to have had dextrocardia rather than ASD.
In a 5-generation pedigree segregating autosomal dominant congenital heart defects, with all affected individuals manifesting ASD, Garg et al. (2003) identified a gly296-to-ser mutation in the GATA4 gene (G296S; 600576.0001). All affected individuals who were clinically evaluated had ... In a 5-generation pedigree segregating autosomal dominant congenital heart defects, with all affected individuals manifesting ASD, Garg et al. (2003) identified a gly296-to-ser mutation in the GATA4 gene (G296S; 600576.0001). All affected individuals who were clinically evaluated had the G296S mutation, suggesting complete penetrance of the disease phenotype. Garg et al. (2003) identified a second family with autosomal dominant transmission of atrial septal defects in which mutation of GATA4 (600576.0002) was found in all available affected family members spanning 4 generations. In affected members of 2 families with isolated ASD, Hirayama-Yamada et al. (2005) found 2 mutations in the GATA4 gene: in 1 family they identified a 1075delG mutation (600576.0002), and in the other they identified an S52F mutation (600576.0003). Tomita-Mitchell et al. (2007) identified 4 missense sequence variants in the GATA4 gene (see, e.g., 600576.0004; 600576.0005) in 5 of 628 patients with cardiac septal or conotruncal defects. One patient had tetralogy of Fallot (187500). The findings indicated that GATA4 mutations are uncommon in patients with septal defects. In an affected father, 2 sons, and grandson from a 3-generation Chinese family segregating autosomal dominant atrial septal defect and pulmonary stenosis, Chen et al. (2010) identified heterozygosity for a missense mutation in GATA4 (600576.0016) that was not found in unaffected family members or in 800 healthy controls. Analysis of GATA4 in 30 additional patients with nonsyndromic congenital heart defects, including 10 with ASD, 10 with VSD, 8 with VSD combined with ASD, and 2 with AVSD, did not reveal any mutations. In 4 affected sisters and 4 affected offspring from a Chinese family with secundum ASD, Chen et al. (2010) identified heterozygosity for a missense mutation in GATA4 (600576.0017). The sisters' unaffected father carried the mutation, which was not found in other unaffected family members, 100 healthy controls, or 70 sporadic patients with congenital heart disease, including 20 with ASD. Three of the 8 affected family members also had pulmonary stenosis.