Congenital heart diseases and their association with the variant distribution features on susceptibility genes

Abstract

Congenital heart disease (CHD), one cause of childhood morbidity and mortality, is mainly triggered by a combination of environmental and genetic factors. Several susceptible genes, such as NKX2-5, GATA4 and TBX5, have been reported as closely related to heart and vessel development. CHD subtypes are classified by diverse clinical phenotypes such as atrial septal defects (ASD), ventricular septal defects (VSD), tetralogy of Fallot (TOF), and Holt-Oram syndrome (HOS). Here, we summarize the associations of the genetic variants in these three genes with CHD subtypes. CHD-associated variants of NKX2-5 locates mainly in the tinman domain and the homeodomain. Mutations in the homeodomain are correlated with ASD and atrioventricular block (AV block) subtypes. VSD-associated variants of GATA4 are mainly at its terminal ends. Variants of TBX5 gene are primarily in exons 3, 4, 5 and 7 and highly associated with HOS subtype. Hence, the variant distribution of NKX2-5, GATA4 and TBX5 are tightly associated with particular CHD subtypes. Further structure modelling analysis revealed that these mutated amino acid residuals are to maintain their DNA binding ability and structural stability. These signify that the structural features of these genes may be used to predict the high risk of CHD subtypes in infants.

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