Novel missense mutation in NKX2.6 gene (c.389 G > C, Arg130Pro) as a potentially pathogenic variant in pediatric patients with congenital heart disease

Abstract

Congenital heart diseases (CHD) are the most common anomalies that occur during heart embryogenesis and are associated with significant mortality and morbidity in infants. It has been found that genomic alterations in cardiac-specific transcription factor genes play an important role in the pathogenesis of CHD. However, the prevalence of point mutations in these genes has not yet been determined. The aim of this research was to investigate the relationship of NKX2.6 gene mutations as a candidate gene in patients with congenital heart diseases. In the present study, two coding exons and flanking introns of the NKX2.6 gene, encoding a homeodomain-containing transcription factor, were sequenced in a cohort of patients. Five heterozygous NKX2.6 missense mutations, Ser37Cys, Glu54Val, Ala129Glu, Arg130Pro, Ser232Thr, and a synonymous variation, Asp68Asp, were identified in patients. They were not observed in controls, and the altered amino acids were evolutionarily highly conserved across species. The structural and functional consequences of missense mutations were assessed using various prediction servers. The consensus results showed that the Arg130Pro mutation is pathogenic/deleterious and likely to significantly affect protein function. To our knowledge, this is the first study on the association of NKX2.6 missense mutations with susceptibility to CHD in Iranian patients; our results present the spectrum of NKX2.6 mutations associated with patients and suggest that these missense mutations could be important as an uncommon cause of CHD.