Congenital heart disease (CHD) is one of the most common birth defects in humans. Mutations in cardiac transcription factor genes, such as GATA4, NKX2-5 and TBX5 genes, have been associated to a small portion of familial and isolated CHD cases. NKX2-5, a highly conserved homeobox gene, is expressed in the developing heart. During embryonic development, NKX2-5 plays pivotal roles in specifying cardiac progenitors, cardiac morphogenesis, cardiomyocyte differentiation and conduction system development. Numerous mutations in NKX2-5 gene have been reported in CHD patients, including atrial septal defect, ventricular septal defect (VSD) and tetrology of Fallot. We have previously identified the sequence variants within the NKX2-5 gene promoter in VSD patients. As several studies have revealed that the NKX2-5 gene is regulated by a complex module involving promoter and multiple independent cardiac enhancers, one of which is located between -3500 bp and -2500 bp upstream to the transcription start site, we hypothesized that the variants within the cardiac enhancer may contribute to CHD. In this study, we genetically analyzed the enhancer of NKX2-5 gene in large cohorts of VSD patients (n=322) and controls (n=336). The results showed that three novel variants, g.1467G>A, g.1487 Ins with a 13 bp insertion and g.1515 Ins with a 6 bp insertion, were identified within the enhancer element in both VSD patients and controls with similar frequencies (P>0.05). Therefore, our data suggested that the enhancer of NKX2-5 gene may not be a contributor to the VSD etiology. Other regulatory elements of the NKX2-5 gene will be further analyzed in CHD patients.
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