Novel and functional sequence variants within the TBX2 gene promoter in ventricular septal defects

Congenital heart disease (CHD) is the most common birth defects in humans. To date, genetic causes for CHD remain largely unknown. T-box transcription factor 2 (TBX2) gene is expressed in the myocardium of atrioventricular canal, outflow tract and inflow tract and plays a critical role in heart chamber formation. Genomic deletion and duplication of TBX2 gene have been associated with cardiac defects. As TBX2 acts in a dose-dependent manner, we hypothesized that DNA sequence variants (DSVs) within TBX2 gene promoter may mediate CHD development by changing TBX2 levels. In this study, TBX2 gene promoter was genetically analyzed in large cohorts of patients with ventricular septal defect (VSD) (n = 324) and ethnic-matched healthy controls (n = 328). Four novel and heterozygous DSVs, g.59477201C > T, g.59477347G > A, g.59477353delG and g.59477371G > A were identified in VSD patients, but in none of controls. Functional analyses revealed that all of the four DSVs significantly decreased transcriptional activities of TBX2 gene promoter. Therefore, our data suggested that the DSVs within TBX2 gene promoter identified in VSD patients may contribute to VSD etiology.