Introduction: Congenital atrial septal defect (ASD) is the second commonest form of cardiac developmental anomaly, responsible for substantial morbidity and mortality in affected individuals. Previous studies have implicated genetic defects in the pathogenesis of ASD. However, ASD is largely a genetically heterogeneous disease and the genetic determinants for ASD in the majority of patients remain to be identified.
Material and methods: The entire coding region of GATA4, a gene encoding a zinc-finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 220 unrelated patients with ASD. The available relatives of the patients harboring the identified mutations and 200 unrelated ethnicity-matched control individuals were genotyped.
Results: Four heterozygous missense GATA4 mutations, p.P36S, p.H190R, p.S262A, and p.V399G, were identified in four unrelated patients with ASD, respectively. These mutations were neither detected in 200 control individuals nor described in the human SNP database. Alignment of multiple GATA4 protein sequences across species indicated that the affected amino acids were highly conserved evolutionarily. Genetic analysis of the available relatives of the mutation carriers showed that in each family the mutation co-segregated with ASD.
Conclusions: The findings expand the spectrum of mutations in GATA4 linked to ASD and provide new insight into the molecular etiology associated with ASD, suggesting the potential implications for the genetic diagnosis and gene-specific therapy for this prevalent cardiovascular abnormality in humans.