Background: Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and is a major cause of substantial morbidity and mortality in infants. Accumulating evidence implicates genetic defects, especially in cardiac transcription factors, in the pathogenesis of VSD. However, VSD is genetically heterogeneous and the genetic determinants for VSD in most patients remain to be identified.
Material/Methods: A cohort of 230 unrelated patients with congenital VSD was included in the investigation. A total of 200 unrelated ethnically matched healthy individuals were recruited as controls. The entire coding region of GATA4, a gene encoding a zinc-finger transcription factor essential for normal cardiac morphogenesis, was sequenced initially in 230 unrelated VSD patients. The available relatives of the mutation carriers and 200 control subjects were subsequently genotyped for the presence of identified mutations.
Results: Four heterozygous missense GATA4 mutations of p.Q55R, p.G96R, p.N197S, and p.K404R were identified in 4 unrelated patients with VSD. These mutations were not detected in 200 control individuals nor described in the human SNP database. Genetic analysis of the relatives of the mutation carriers showed that in each family the mutation co-segregated with VSD.
Conclusions: These findings expand the mutation spectrum of GATA4 linked to VSD and provide new insight into the molecular etiology responsible for VSD, suggesting potential implications for the genetic diagnosis and gene-specific therapy for VSD.

Keywords: Molecular Sequence Data, Introns - genetics, Heart Septal Defects, Ventricular - genetics, GATA4 Transcription Factor - genetics, Exons - genetics, DNA Mutational Analysis, Child, Preschool, Base Sequence, Amino Acid Sequence, Mutation - genetics, Pedigree, Phenotype, Sequence Alignment