Submitted: 30 Dec 2018
Accepted: 04 Oct 2019
ePublished: 31 Oct 2019
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J Cardiovasc Thorac Res. 2019;11(4): 287-299.
doi: 10.15171/jcvtr.2019.47
PMID: 31824610
PMCID: PMC6891041
  Abstract View: 291
  PDF Download: 189

Original Article

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

Samira Kalayinia 1, Serwa Ghasemi 2, Nejat Mahdieh 1 * ORCID logo

1 Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Department of Biology, School of Basic Sciences, Islamic Azad University Research Tehran Branch, Tehran, Iran


Introduction: Congenital heart disease (CHD) affects 1% to 2 % of live births. The Nkx2-5 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, Nkx2-5 mutations are investigated to identify the frequency, distribution, functional consequences of mutations by using computational tools.
Methods: A complete literature search was conducted to find Nkx2-5 mutations using the following key words: Nkx2-5 and/or CHD and mutations. The mutations were in silico analyzed using tools which predict the pathogenicity of the variants. A picture of Nkx2-5 protein and functional or structural effects of its variants were also figured using I-TASSER and STRING.
Results: A total number of 105 mutations from 18 countries were introduced. The most (24.1%) and the least (1.49%) frequency of Nkx2-5 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 Nkx2-5 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.
Conclusion: This is the first report of the Nkx2-5 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 Nkx2-5 mutations arise from Germany.
Keywords: Congenital Heart Disease, Nkx2-5, Mutation, Computational Analysis
Please cite this article as: Kalayinia S, Ghasemi S, Mahdieh N. A comprehensive in silico analysis, distribution and frequency of human Nkx2-5 mutations; A critical gene in congenital heart disease. J Cardiovasc Thorac Res 2019;11(4):287-299. doi: 10.15171/ jcvtr.2019.47.
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