A novel mutation in GATA4 gene associated with dominant inherited familial atrial septal defect

Atrial septal defect (ASD) is a common congenital heart disease (CHD). Although most cases are sporadic, familial cases have been reported. The transcription factors NKX2.5 and GATA4 play important roles in the pathogenesis of ASD. Mutations in either gene have been identified in familial cases of ASD. Here, we examine a Chinese family with isolated ASD to find out whether there is any mutation in NKX2.5 or GATA4 accounting for the etiology.

We identified kindred spanning 3 generations in which 8 of 31 (38%) individuals had ASD. One hundred seventy unrelated individuals were included as controls. Peripheral blood samples were collected and genomic DNA was extracted from the leukocytes. NKX2.5 and GATA4 were amplified by polymerase chain reaction (PCR) with specific primers. The sequences of PCR products were compared between affected members and unaffected members, as well as controls.

Direct sequencing of NKX2.5 from the genomic DNA of family members failed to identify mutations, whereas sequencing of GATA4 identified an A-to-G transition at nucleotide 928 in exon 5 that predicted a methionine to valine substitution at codon 310 (M310V) in the NLS region. All affected members and a patriarch of the family who was recognized as a carrier exhibited this mutation, whereas the other unaffected family members or control individuals did not. This mutation has not been reported previously in either familial or sporadic cases of CHD.

We identified a novel M310V mutation in GATA4 gene that is located in the NLS region and leads to hereditary ASD in a Chinese family. In this family, we identified a carrier with incomplete penetrance and 8 patients with variable expressivity. However, the mechanism by which this mutation contributes to the development of a congenital heart defect remains to be ascertained.