GATA4 is localised on human chromosome 8p23.1-p22 and codes for a zinc finger transcription factor. Mice lacking Gata4 suffer from defective ventral morphogenesis and heart tube formation.^1,2 This factor therefore targets various genes important for heart development and basic cardiac function. Recently, three GATA4 mutations have been detected in families with congenital heart disease.^3,4 A mutation affecting a residue next to the C-terminal zinc finger has been identified in family members with atrial septal defects, and resulted in the disruption of a physical interaction between Gata4 and TBX5.³ There is growing evidence that the two zinc fingers of Gata4 display distinct functions so as to facilitate protein–DNA and protein–protein interactions.

To further our understanding of the specific role of GATA4 in human congenital heart disease, we searched for mutations in the sequences coding for the zinc fingers in diseased heart tissues of 68 patients with complex heart malformations, encompassing atrial (ASD), ventricular (VSD), and atrioventricular septal defects (AVSD). These patients mostly died in early infancy as a result of the severity of the cardiac abnormalities. We isolated genomic DNA from the formalin fixed malformed hearts, amplified exons 3 and 4 from DNA fragments of about 2 kb, and carried out double strand direct sequencing. Mutations were confirmed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) or cloning and subsequent sequencing to separate alleles (fig 1A–F).