A comprehensive in silico analysis, distribution and frequency of human Nkx2-5 mutations; A critical gene in congenital heart disease

Abstract

<i><b>Introduction:</b></i> Congenital heart disease (CHD) affects 1% to 2 % of live births. The <i>Nkx2-5</i> gene, is known as the significant heart marker during embryonic evolution and it is also necessary for the survival of cardiomyocytes and homeostasis in adulthood. In this study, <i>Nkx2-5</i> mutations are investigated to identify the frequency, distribution, functional consequences of mutations by using computational tools. <i><b>Methods:</b></i> A complete literature search was conducted to find <i>Nkx2-5</i> mutations using the following key words: <i>Nkx2-5</i> and/or CHD and mutations. The mutations were in silico analyzed using tools which predict the pathogenicity of the variants. A picture of <i>Nkx2-5</i> protein and functional or structural effects of its variants were also figured using I-TASSER and STRING. <i><b>Results:</b></i> A total number of 105 mutations from 18 countries were introduced. The most (24.1%) and the least (1.49%) frequency of <i>Nkx2-5</i> mutations were observed in Europe and Africa, respectively. The c.73C>T and c.533C>T mutations are distributed worldwide. c.325G>T (62.5%) and c.896A>G (52.9%) had the most frequency. The most numbers of <i>Nkx2-5</i> mutations were reported from Germany. The c.541C>T had the highest CADD score (Phred score = 38) and the least was for c.380C>A (Phred score=0.002). 41.9% of mutations were predicted as potentially pathogenic by all prediction tools. <i><b>Conclusion:</b></i> This is the first report of the <i>Nkx2-5</i> mutations evaluation in the worldwide. Given that the high frequency of mutation in Germany, and also some mutations were seen only in this country, therefore, presumably the main origin of <i>Nkx2-5</i> mutations arise from Germany.