Abstract
Introduction: Congenital heart disease (CHD) is the most common congenital abnormality and the main cause of infant mortality worldwide. Some of the mutations that occur in the GATA4 gene region may result in different types of CHD. Here, we report our in silico analysis of gene variants to determine the effects of the GATA4 gene on the development of CHD. Methods: Online 1000 Genomes Project, ExAC, gnomAD, GO-ESP, TOPMed, Iranome, GME, ClinVar, and HGMD databases were drawn upon to collect information on all the reported GATA4 variations.The functional importance of the genetic variants was assessed by using SIFT, MutationTaster, CADD,PolyPhen-2, PROVEAN, and GERP prediction tools. Thereafter, network analysis of the GATA4protein via STRING, normal/mutant protein structure prediction via HOPE and I-TASSER, and phylogenetic assessment of the GATA4 sequence alignment via ClustalW were performed. Results: The most frequent variant was c.874T>C (45.58%), which was reported in Germany.Ventricular septal defect was the most frequent type of CHD. Out of all the reported variants of GATA4,38 variants were pathogenic. A high level of pathogenicity was shown for p.Gly221Arg (CADD score=31), which was further analyzed. Conclusion: The GATA4 gene plays a significant role in CHD; we, therefore, suggest that it be accorded priority in CHD genetic screening.
Highlights
Congenital heart disease (CHD) is the most common congenital abnormality and the main cause of infant mortality worldwide
Contains 2 transcriptional activation domains (TAD1 and TAD2); 2 zinc finger domains: 1 at the c-terminal region (CZF) and the other at the n-terminal region (NZF); and 1 nuclear localization signal domain (NLS). Variants in the GATA-binding factor 4 (GATA4) gene are highly associated with different types of CHD, including tetralogy of Fallot, ventricular septal defect, atrial septal defect, atrioventricular septal defect, patent ductus arteriosus, dilated cardiomyopathy, and pulmonary valve stenosis. 14, 16-21 The current literature lacks in silico analysis on the variants of the GATA4 transcription factor and their critical role in the different levels of cardiovascular development
Materials and Methods For the detection of genetic variants in the GATA4 gene, the following methodology was utilized in the present study: Data Collection The amino acid sequence of the human GATA4 gene was obtained from the National Center for Biotechnology Information (NCBI; https://www.ncbi.nlm.nih.gov/), based on the human genome assembly GRCh37
Summary
Congenital heart disease (CHD) is the most common congenital abnormality and the main cause of infant mortality worldwide. We report our in silico analysis of gene variants to determine the effects of the GATA4 gene on the development of CHD. CHD can be caused by variants in different genes whose roles have evolved. 5 Some CHD-associated genes encode transcription factors such as GATA4, NKX2-5, and TBX5, and a number of gene variants identified in these genes have been associated with cardiac structure and functional impairment. Variants in the GATA4 gene are highly associated with different types of CHD, including tetralogy of Fallot, ventricular septal defect, atrial septal defect, atrioventricular septal defect, patent ductus arteriosus, dilated cardiomyopathy, and pulmonary valve stenosis. 14, 16-21 The current literature lacks in silico analysis on the variants of the GATA4 transcription factor and their critical role in the different levels of cardiovascular development. For the first time, we aimed to conduct a comprehensive in silico analysis of the effects of GATA4 alterations associated with CHD
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