A novel GATA6 mutation associated with congenital ventricular septal defect

Ventricular septal defect (VSD) is the most common form of congenital cardiovascularmalformation and an important contributor to the substantially increased morbidityand mortality in infants. Emerging evidence indicates the genetic basis for thepathogenesis of congenital VSD in a significant proportion of patients. However,congenital VSD is a genetically heterogeneous disease and the genetic defectsresponsible for VSD in the overwhelming majority of cases remain unclear. In thisstudy, the entire coding region of the GATA6 gene, which encodes a zinc-fingertranscription factor crucial to normal cardiogenesis, was sequenced in 130 unrelatedpatients with congenital VSD. The available relatives of the index patient carryingthe identified mutation and 200 unrelated ethnically matched healthy individualsused as controls were subsequently genotyped. The functional characteristics ofthe mutant GATA6 were assessed in contrast to its wild-type counterpart usinga luciferase reporter assay system. As a result, a novel heterozygous missenseGATA6 mutation, p.G220S, was identified in a proband with VSD. The variation wasabsent in 400 control chromosomes and the altered amino acid was highly conservedevolutionarily across species. Genetic analysis of the family members of the mutationcarrier showed that the substitution co-segregated with VSD was inherited as anautosomal dominant trait. Functional analysis demonstrated that the p.G220S mutationof GATA6 was associated with significantly decreased transcriptional activity.The findings provide novel insight into the molecular mechanism involved in VSD,implying the potential clinical implications in the gene-specific prophylaxisand therapy of this common developmental abnormality in neonates.