GATA5 Loss-of-Function Mutation Responsible for the Congenital Ventriculoseptal Defect

The ventriculoseptal defect (VSD) is the most common form of congenital heart disease and a leading noninfectious cause of infant mortality. Growing evidence demonstrates that genetic defects are associated with congenital VSD. Nevertheless, VSD is genetically heterogeneous, and the molecular basis for VSD in an overwhelming majority of patients remains unknown. In this study, the whole coding region of GATA5, a gene encoding a zinc finger transcription factor crucial for normal cardiogenesis, was sequenced in 120 unrelated patients with VSD. The available relatives of the patient harboring the identified mutation and 200 unrelated individuals used as controls were subsequently genotyped. The causative potential of a sequence variation was evaluated by MutationTaster, and the functional effect of the mutation was characterized using a luciferase reporter assay system. As a result, a novel heterozygous GATA5 mutation, p.L199V, was identified in a patient with VSD, which was absent in 400 control chromosomes. Genetic analysis of the mutation carrier's available family members showed that the substitution co-segregated with VSD transmitted in an autosomal dominant pattern. The p.L199V variation was automatically predicted to be disease causing, and the functional analysis showed that the GATA5 p.L199V mutant protein was associated with significantly reduced transcriptional activation compared with its wild-type counterpart. To the best of the authors' knowledge, this is the first report on the link of functionally compromised GATA5 to human VSD, suggesting potential implications for the early prophylaxis and personalized treatment of VSD.