Sarcomeric Gene Variations and Phenotypic Plasticity of Cardiomyopathy M. L. Satyanarayana * , S. R. Deepa ** , R. Advithi * , A. Venkateshwari § , C. Narasimhan §§ and N. Pratibha *# * Department of Genetics, Osmania University, Hyderabad 500 007, Andhra Pradesh, India ** Centre for Molecular and Cellular Biology, Habsiguda, Uppal Road, Hyderabad 500 007, Andhra Pradesh, India § Institute of Genetics and Hospital for Genetic Diseases, Begumpet, Hyderabad 500 016, Andhra Pradesh, India §§ Cardiology Unit, CARE Hospital, Road No.1, Banjara Hills, Hyderabad 500 034, Andhra Pradesh, India KEYWORDS Cardiomyopathy. Sarcomeric Genes. Genetic Variations. Phenotypic Plasticity ABSTRACT Hypertrophic Cardiomyopathy (HCM) is a primary cardiac disease characterized by increased thickness of the left ventricular walls in the absence of secondary causes and manifested by mutations in sarcomeric genes. Dilated Cardiomyopathy (DCM) is associated with dilation and impaired contraction of the ventricles and is associated with sarcomeric and cytoskeletal gene mutations. The present study is focused on screening for genetic variations in the sarcomeric genes viz., Myosin Heavy Chain gene (MYH7), Troponin I3 (TNNI3), Troponin T2 (TNNT2), Alpha-Actin (ACTC), Myosin Regulatory Light Chain (MYL2) and Myosin Essential Light Chain (MYL3) by SSCP and sequencing in 100 HCM, 97 DCM and 200 controls to elucidate the phenotypic plasticity associated with cardiomyopathy. Common variations were observed in exons 7, 12, 19 and 20 of MYH7; exon 9 and intron 16 of TNNT2; intron1, intron2, exon 5 and exon 7 of TNNI; exon 1 of MYL3 gene/s in both HCM and DCM cases. This can be explained on the basis of impaired energy compromise or dose effect of the mutant protein or environmental factors wherein a HCM could progress to a DCM phenotype affecting both the right and left ventricles, leading to heart failure. Genotype-phenotype correlations can be best explained by phenotypic plasticity where in mutations/ variations in the same gene and even same variations in a different environmental background may lead to HCM / DCM dispartite phenotypes. # Address for correspondence Dr. Pratibha Nallari, Professor and Head, Department of Genetics, Osmania University, Hyderabad 500 007, Andhra Pradesh, India E-mail: prathinallari@yahoo.com INTRODUCTION Cardiomyopathy is the disease of heart muscle caused by abnormalities in cardiac wall thick- ness, chamber size, contraction and relaxation. Based on the pathophysiology, cardiomyopathy is classified into four major groups viz., Hyper- trophic, Dilated, Restrictive and Arrythmogenic Right Ventricular Dysplasia. Hypertrophic Car- diomyopathy (HCM) and Dilated Cardiomyopa- thy (DCM) are the most frequent forms of cardi- omyopathy. Earlier reports state that a large num- ber of pathogenic mutations in sarcomeric genes are associated with structural changes of the myocardium and pumping efficiency of the HCM and DCM heart (Tayler et al. 2006; Parvari and Levitas 2012; Maron and Maron 2013; Teekakirikul et al. 2013). HCM is characterized by hypertrophy of the left ventricle with the predominant involvement of the interventricular septum and diastolic dys- function, and ventricular chamber volume de- crease and disarray (Varnava et al. 2000). The diastolic dysfunction is responsible for heart fail- ure and sudden cardiac death, with an incidence of 1 in 500 individuals (Maron and Maron 2013). Phenotypic heterogeneity exists in HCM with some individuals being asymptomatic and some symptomatic, exhibiting symptoms of progres- sion like syncope or dyspnea with or without heart failure, and / or sudden cardiac death. The genetic basis of HCM is also characterized by greater inter / intra-allelic heterogeneity. DCM is characterized by systolic dysfunction, which often leads to heart failure with a require- ment of cardiac transplantation. DCM produces a prominent increase in chamber volumes as well as ventricular wall thickening, with the familial prevalence of 20% to 48% (Taylor et al. 2006). Most commonly DCM is inherited as an autoso- mal dominant disorder and exhibits genetic het- erogeneity with the implication of both sarcom- eric, cytoskeletal and calcium regulatory genes. © Kamla-Raj 2013 Int J Hum Genet, 13(4): 177-181 (2013)