Determination of GATA4, GATA5 ve TBX5 gene polymorphisms in turkish children with bicuspid aortic valve disease

Bicuspid aortic valve (BAV) is the most common congenital heart disease characterised by an aortic valve with two leaflets instead of three. Although many genes are known to be effective in the pathogenesis of bicuspid aortic valve disease, there is not yet a single gene model that can explain its inheritance. In this study, we aimed to investigate GATA4, GATA5 and TBX5 gene regions which are thought to have a possible role in bicuspid aortic valve formation. For this purpose, 155 children with bicuspid aortic valve and 152 healthy children with tricuspid aortic valve were included in the study. Valve type, valve function, concomitant coarctation of the aorta and dilatation of the ascending aorta were evaluated by echocardiography in all children included in the study. Valve angulations were classified as superior-inferior (type 1) and right-left (type 2 and type 3). Peripheral blood samples were collected from children in the patient and control groups for GATA4, GATA5 and TBX5 gene isolation. Genetic analyses were performed by Sanger sequence analysis. There was no difference in age and gender between children in the bicuspid aortic valve and control groups (p>0.05). In 54.2% of patients with bicuspid aortic valve, valve angulation was in the superior-inferior direction, whereas it was in the right-left direction in 45.8%. Patients with bicuspid aortic valves were divided into four groups in terms of aortic valve function: patients with normal valve function, patients with isolated aortic stenosis, patients with isolated aortic regurgitation and patients with combined valve dysfunction. Aortic stenosis (p=0.0001) and aortic regurgitation (p=0.008) were more common in patients with right-left valve angulation. In addition, the severity of aortic stenosis (p=0.002) and aortic regurgitation (p=0.002) was more severe. Coarctation of the aorta and dilatation of the ascending aorta were associated with 7.7% and 9% of the patients, respectively. Valve dysfunction was present in all patients with ascending aortic dilatation (p=0.0001). No genetic mutation was found in any of the healthy children with tricuspid aortic valve. Heterozygous mutations were found in the GATA4 rs55980825 gene region in 29 (18.7%) and in the TBX5 rs759976245 gene region in 27 (17.4%) children with bicuspid aortic valve. Having GATA4 rs55980825 heterozygous mutation increased the risk of developing bicuspid aortic valve disease 2.2-fold [p=0.0001 and OR 2.21 (95% CI; 1.94-2.51)], and having TBX5 rs759976245 heterozygous mutation increased the risk of developing bicuspid aortic valve disease 2.2-fold [p=0.0001 and OR 2.19 (95% CI; 1.93-2.49)]. The incidence of isolated aortic stenosis was higher in patients with GATA4 rs55980825 mutation (p=0.003), and the incidence of aortic regurgitation was higher in patients with TBX5 rs759976245 mutation (p=0.044). In addition, the presence of TBX5 rs759976245 mutation was found to reduce the risk of aortic coarctation 1.233-fold in patients with bicuspid aortic valve [(p=0.098 and OR 1.233, 95% CI;(1.139-1.334)]. In conclusion, we found no mutations in GATA4 exon 1, GATA5 exon 1 and TBX5 exon 5, exon 7, exon 8 gene regions, but mutations in GATA4 exon 4 and TBX5 exon 2 gene regions in Turkish children with bicuspid aortic valve disease and these mutations increased the risk of developing BAV. We think that GATA4 rs55980825 mutation and TBX5 rs759976245 mutation, which was found in our study for the first time in the literature, may help in the diagnosis of bicuspid aortic valve disease and prediction of complications that may occur in the later stages in the follow-up. Keywords: Bicuspid aortic valve, Child, Genetics, GATA4, GATA5, TBX5