Significance of intronic and synonymous MYBPC3 gene variations in hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy is a multifactorial disorder, with mutations implicated in 12 sarcomeric and cytoskeletal genes accounting for genotypic and phenotypic heterogeneity, making genetic and clinical diagnosis much more challenging. The genetics of HCM has been studied for more than two decades in various ethnic and racial groups reporting many novel pathogenic variations. It is interesting to know that the Indian population owing to its varied genetic pool and vast ethnic background is still a potential ground for novel genetic variations. Hence, the present study considered screening of MYBPC3 gene, which is highly implicated in HCM.Molecular screening was carried out by PCR based SSCP analysis in 100 controls and 100 HCM patients. The variations were further confirmed by sequencing. In silico analysis was carried out to analyze the effect of the respective variations.The study revealed seven variations viz.: one missense variation in exon 5 (p.Val158Met), two synonymous variations in exon 17 (p.Ala432=; p.Asp431=), two intronic variations in exon 14 (c.1223+2T>G, c.1091−24C>T), one intronic variation in exon 21 (c.1927+89C>G) and one synonymous variation in exon 26 (p.Val849Val).The synonymous and intronic variations though are non-pathogenic, may still have a regulatory role in the splicing mechanism, resulting in stoichiometry changes mandatory in protein-protein interactions. Their effect may be further influenced by the modifier genes and environmental factors accounting for severe clinical manifestations and phenotypic heterogeneity. Hence, the present study describes the significance of intronic and synonymous variations of MYBPC3 gene in the phenotype.