Abstract
BackgroundCongenital heart disease (CHD) is the leading cause of mortality from birth defects. In adult CHD patients with successful surgical repair, cardiac complications including heart failure develop at late stage, likely due to genetic causes. To date, many mutations in cardiac developmental genes have been associated with CHD. Recently, regulatory variants in genes have been linked to many human diseases. Although mutations and splicing variants in GATA4 gene have been reported in CHD patients, few regulatory variants of GATA4 gene are identified in CHD patients.MethodsGATA4 gene regulatory region was investigated in the patients with atrial septal defects (ASD) (n = 332) and ethnic-matched controls (n = 336).ResultsFive heterozygous regulatory variants including four SNPs [g.31360 T>C (rs372004083), g.31436G>A, g.31437C>A (rs769262495), g.31487C>G (rs1053351749) and g.31856C>T (rs1385460518)] were only identified in ASD patients. Functional analysis indicated that the regulatory variants significantly affected the transcriptional activity of GATA4 gene promoter. Furthermore, two of the five regulatory variants have evidently effected on transcription factor binding sites.ConclusionsOur data suggested that GATA4 gene regulatory variants may confer ASD susceptibility by decreasing GATA4 levels.
Highlights
Congenital heart disease (CHD) is the leading cause of mortality from birth defects
Cardiac morphogenesis is spatiotemporally controlled by transcription factors, cofactors, epigenetic regulators, cell signaling molecules and non-coding RNAs [6, 7]
Accumulating evidence has demonstrated that mutations, copy number variation and regulatory variants in cardiac developmental genes cause different types of CHD, such as atrial septal defects (ASD), Ventricular septal defects (VSD)
Summary
Congenital heart disease (CHD) is the leading cause of mortality from birth defects. CHD prevalence is about 1% of live births [1]. Genetic factors play a critical role in the CHD development. Hundreds of gene mutations and variants are implicated in CHD, precise genetic basis for sporadic CHD is largely unclear [2, 3]. In adult CHD patients with successful surgical repair, cardiac complications Disruption in integrity and function of cardiac gene regulatory networks causes CHD. Accumulating evidence has demonstrated that mutations, copy number variation and regulatory variants in cardiac developmental genes cause different types of CHD, such as ASD (atrial septal defects), VSD. Congenital heart disease (CHD) is the leading cause of mortality from birth defects. In adult CHD patients with successful surgical repair, cardiac complications including heart failure develop at late stage, likely due to genetic causes. Mutations and splicing variants in GATA4 gene have been reported in CHD patients, few regulatory variants of GATA4 gene are identified in CHD patients
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