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Background: Infantile hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder. Apart from registries in high-income nations, there is a shortage of data on the aetiological basis of infantile HCM in low- and middle-income nations. This study attempts to characterise the phenotypic expression, genetic architecture and short-term clinical outcomes of infantile HCM from a South Asian tertiary referral centre., Methods: This study includes all infants from the Amrita HCM cohort between January 2011 and July 2021. Clinical history, ECG, echocardiographic data, and genetic analyses were evaluated., Results: 34 patients with infantile HCM were diagnosed at a median age of 3.7 months (IQR 1-6 months). Underlying aetiologies were RASopathy (n=13; 38%), non-syndromic (n=12; 35%) and inborn errors of metabolism (n=9; 27%). Genetic analysis was done in 20 patients (59%) with a yield of 90%. Clinical presentation included failure to thrive (n=29; 85%), dyspnoea on exertion (n=23; 68%) and clinical heart failure (n=24; 71%). Echo showed concentric left ventricular hypertrophy in 22 patients (65%), obstructive HCM in 11 patients (32%) and left ventricular systolic dysfunction in 6 patients (18%). The mortality rate was 10.0 deaths per 100 patient years over a median follow-up period of 3.1 years. The main risk markers for mortality were the age at diagnosis, gender and concentric Left ventricular hypertrophy., Conclusions: This cohort demonstrates the morphological, functional and genetical heterogeneity of infantile HCM, enunciating the need for integration of cardiology, metabolic and genetic services to achieve optimum outcomes in these patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

HCM is a monogenic cardiac disorder with a high risk of sudden cardiac death, heterogeneous phenotypic expression and genetic profile. HCM is expressed as autosomal dominant in fashion with the prevalence of 1:500 in the general population. The main objective of the current study was to unravel the mutation status in sarcomeric genes in urbanizing Pune population. HCM patients were recruited from Bharti hospital and Poona hospital and research centre, Pune after being screened by 2-D echocardiography. DNA was extracted from whole blood samples and PCR amplification was performed for selected exons from pre-selected genes, amplimers of >300 b.p were restriction digested and the SSCP technique was optimized for maximum result output. HCM patients shows the maximum prevalence of mitral regurgitation (23.3%) while the minimum prevalence was left auricular diameter (10%). Maximum variation spectrum was present in MYBPC3 genes as most of them were "benign" type as per Polyphen-2 tool status. Mutations in the MYH7 gene produce a prominent impact on splicing by the creation of a new SRP40 binding site (Exon Splicing Enhancer) as predicted by Human Splicing Finder 3.1. I736T mutation in the MYH7 gene results in replacement of β-strand by α-helix upstream from mutation site which may have a profound impact on protein tertiary structure as predicted by Polyphen-2 tool (probably damaging-1.00). Also, two 'novel' mutations and one 'novel' variation were reported in the present study. Thus, the MYBPC3 gene shows maximum mutation load among other sarcomeric genes. Double gene mutations do not represent much severe pathophysiology as compared to single gene mutated and genotypic negative HCM patients.

Background: Myosin is a hexameric contractile protein composed of 2 heavy chains associated with 4 light chains of 2 distinct classes - 2 regulatory light chains (MYL2) and 2 essential light chains (MYL3). The myosin light chains stabilize the long alpha helical neck of the myosin head and regulate the myosin ATPase activities., Objectives: Mutations in MYL2 and MYL3 are reported to be associated with cardiomyopathies. However, there is no study available on these genes in Indian cardiomyopathies, and therefore we planned to study them., Method: For the first time we sequenced MYL2 and MYL3 genes in a total of 248 clinically well-characterized cardiomyopathies consisting of 101 hypertrophic and 147 dilated cases along with 207 healthy controls from south India., Results: Our study revealed a total of 10 variations - 7 in MYL2 and 3 in MYL3, of which 3 are novel variations observed exclusively in cases. However, the 15 causative missense mutations previously reported are totally absent in our study, which showed that the sequences of MYL2 and MYL3 are highly conserved in Indian cases/controls., Conclusions: MYL2 and MYL3 mutations are rare and the least cause of cardiomyopathies in Indians., (© 2019 S. Karger AG, Basel.)

Hypertrophic cardiomyopathy (HCM) is a primary disorder, characterized by unexplained hypertrophy of the left ventricle that frequently involved in the inter-ventricular septum. Mitochondrial DNA (mtDNA) mutations and haplogroups have been found to be associated with several diseases. Therefore, in the present study, we have sequenced the complete mtDNA of 114 clinically well-characterized HCM patients to look for the role of mtDNA variations and haplogroups in HCM phenotype among Indian patients. Complete mtDNA analysis revealed 28 novel variations, 25 disease-associated and 50 private mutations. We found 13 (11.40%) HCM patients having novel non-synonymous and/or MT-tRNA variations, of which two (m.4797C>M and m.8728T>Y) were in heteroplasmic condition. In silico prediction showed that a few mutations are pathogenic, which may affect the energy production in the heart. Unlike some of the other studies, we did not find association of mitochondrial haplogroup with HCM., (Copyright © 2013 © Elsevier B.V. and Mitochondria Research Society. All rights reserved. Published by Elsevier B.V. All rights reserved.)

Hypertrophic Cardiomyopathy (HCM) is an autosomal dominant disorder of the myocardium which is hypertrophied resulting in arrhythmias and heart failure leading to sudden cardiac death (SCD). Several sarcomeric proteins and modifier genes have been implicated in this disease. Troponin I, being a part of the Troponin complex (troponin I, troponin C, troponin T), is an important gene for sarcomeric function. Four mutations (1 novel) were identified in Indian HCM cases, namely, Pro82Ser, Arg98Gln, Arg141Gln and Arg162Gln in Troponin I protein, which are in functionally significant domains. In order to analyse the effect of the mutations on protein stability and protein-protein interactions within the Troponin complex, an in silico study was carried out. The freely available X-ray crystal structure (PDB ID: 1JIE) was used as the template to model the protein followed by loop generation and development of troponin complex for both the troponin I wild type and four mutants (NCBI ID: PRJNA194382). The structural study was carried out to determine the effect of mutation on the structural stability and protein-protein interactions between three subunits in the complex. These mutations, especially the arginine to glutamine substitutions were found to result in local perturbations within the troponin complex by creating/removing inter/intra molecular hydrogen bonds with troponin T and troponin C. This has led to a decrease in the protein stability and loss of important interactions between the three subunits. It could have a significant impact on the disease progression when coupled with allelic heterogeneity which was observed in the cases carrying these mutations. However, this can be further confirmed by functional studies on protein levels in the identified cases.

Background: Troponin I (TNNI3) is the inhibitory subunit of the thin filament regulatory complex Troponin, which confers calcium-sensitivity to striated muscle actomyosin ATPase activity. Mutations (2-7%) in this gene had been reported in hypertrophic cardiomyopathy patients (HCM). However, the frequencies of mutations and associated clinical presentation have not been established in cardiomyopathy patients of Indian origin, hence we have undertaken this study., Methods: We have sequenced all the exons, including the exon-intron boundaries of TNNI3 gene in 101 hypertrophic cardiomyopathy patients (HCM), along with 160 healthy controls, inhabited in the same geographical region of southern India., Results: Our study revealed a total of 16 mutations. Interestingly, we have observed Arginine to Glutamine (R to Q) mutation at 3 positions 98, 141 and 162, exclusively in HCM patients with family history of sudden cardiac death. The novel R98Q was observed in a severe hypertrophic obstructive cardiomyopathy patient (HOCM). The R141Q mutation was observed in two familial cases of severe asymmetric septal hypertrophy (ASH++). The R162Q mutation was observed in a ASH++ patient with mean septal thickness of 29 mm, and have also consists of allelic heterogeneity by means of having one more synonymous (E179E) mutation at g.4797: G → A: in the same exon 7, which replaces a very frequent codon (GAG: 85%) with a rare codon (GAA: 14%). Screening for R162Q mutation in all the available family members revealed its presence in 9 individuals, including 7 with allelic heterogeneity (R162Q and E179E) of which 4 were severely affected. We also found 2 novel SNPs, (g.2653; G → A and g.4003 C → T) exclusively in HCM, and in silico analysis of these SNPs have predicted to cause defect in recognition/binding sites for proteins responsible for proper splicing., Conclusion: Our study has provided valuable information regarding the prevalence of TNNI3 mutations in Indian HCM patients and its risk assessment, these will help in genetic counseling and to adopt appropriate treatment strategies.

We sought to determine the frequency of the genetic variations in the Troponin T (TNNT2) gene and its association in Indian cardiomyopathy patients. Sequencing of the entire TNNT2 gene in 162 hypertrophic cardiomyopathy (HCM) patients, along with 179 healthy controls, revealed a total of 15 variants. These included an A28V missense mutation, a novel single-nucleotide polymorphism (SNP) (g.7239;G→A) predicted to disturb the splicing significantly, three SNPs, rs3729547 (C→T), rs3729843 (G→A), rs3729842 (C→T), which were in high linkage disequilibrium, and a 5 bp polymorphism that skipped exon 4 during splicing, which was found to be significantly higher in HCM patients (del/del genotype, p=0.00011; deletion allele, p=0.00008). Further studies on the 5 bp polymorphism in 2092 randomly selected individuals belonging to 39 ethnic and endogamous populations from 19 states of India, and representing the major linguistic Indian families, revealed that the South and the Northwest Indians have a high frequency of 5 bp deletions. The missense mutations in TNNT2 are responsible for 15%-20% of familial HCM by impairing the function of the heart muscle. However, other than the 5 bp polymorphism, our comprehensive study on the Indian HCM patients have lowered the occurrence and overall prevalence of supposedly more aggressive and worst disease causing percentage of missense mutations in TNNT2 dramatically.

Introduction: Hypertrophic cardiomyopathy (HCM) is a complex disorder and genetically transmitted cardiac disease with a diverse clinical course. The objective of the present study was to examine the association of the T704C polymorphism of exon 2 of the angiotensinogen (AGT) gene with HCM in a South Indian population from Andhra Pradesh. Subjects and methods. One-hundred and fifty HCM (90 sporadic hypertrophic cardiomyopathy [SHCM] and 60 familial hypertrophic cardiomyopathy [FHCM]) patients and 165 age- and sex-matched normal healthy controls without known hypertension and left ventricular hypertrophy were included in the study. DNA was isolated from peripheral leukocytes and the region of interest in the AGT gene bearing a missense mutation methionine to threonine substitution at codon 235 (M235T) of exon 2, was amplified by polymerase chain reaction (PCR). The PCR products were subjected to restriction digestion with the enzyme SfaNI., Results: Significant differences were detected in genotypic distribution (p = 0.04) as well as the allelic frequency (p = 0.003) between the SHCM patients and controls. The polymorphism did not show any association with FHCM., Conclusion: Our results suggest that the T allele of the AGT gene is significantly associated with SHCM in a South Indian population from Andhra Pradesh. However, we did not find significant association of this polymorphism with FHCM.

Both idiopathic restrictive cardiomyopathy (IRCM) and hypertrophic cardiomyopathy (HCM) are part of the same disease spectrum and are due to sarcomeric gene mutations. A patient with restrictive physiology without left ventricular hypertrophy (LVH) would be diagnosed as IRCM, while one with LVH would be diagnosed as HCM with restrictive physiology. We studied a group of patients with restrictive physiology for mutations in beta-myosin heavy chain (MYH7) and troponin I (TNNI3) gene. Consecutive probands in the HCM and IRCM cohort over a 4-year period were considered for this study. These included 10 IRCM and 102 HCM patients. All were Asian Indians. Among the 17 patients who had restrictive physiology 10 were IRCM patients and seven were HCM patients. Of the HCM patients, seven (6.9%) had restrictive physiology. Mean age of these 17 patients was 40.1 +/- 19.2 years (range: 15-67 ), six (35.3%) were males. Maximal left ventricular wall thickness of the seven HCM probands was 20.7 +/- 5.2 mm (range: 16-31), while it was normal in the IRCM probands. Ten probands (58.8%) were in NYHA class III or IV. Seven patients (41.2%) had atrial fibrillation. All the probands were screened for mutations in selected exons of MYH7 and TNNI3 genes. One IRCM patient was found to have p.Arg721Lys mutation in the MYH7 gene. She died due to progressive congestive cardiac failure at the age of 47 years. One HCM proband with a maximal left ventricular wall thickness of 17 mm had p.Arg192His mutation in the TNNI3 gene. She had features consistent with restrictive physiology. Her father and sister had died of restrictive cardiomyopathy. IRCM and HCM with restrictive physiology, both are part of the clinical expression of MYH7 and TNNI3 mutations and lead to worse clinical onset and progression of the disease.

The aim of the current study was to determine the frequency of mutations in the beta-myosin heavy chain gene (MYH7) in a cohort of hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and their families, and to investigate correlations between genotype and phenotype. About 130 consecutive patients diagnosed with HCM or DCM (69 with HCM and 61 with DCM) attending the cardiology clinic of Post Graduate Institute of Medical Education and Research were screened for mutations in the MYH7 gene. The control group for genetic studies consisted of 100 healthy subjects. We report 14 mutations in 6 probands (5 probands in HCM and 1 proband in DCM) and their family members. Out of these 6 mutations, 3 are new and are being reported for the first time. One known mutation (p.Gly716Arg) was found to be "de novo" which resulted in severe asymmetric septal hypertrophy (31 mm) and resulted in the sudden cardiac death (SCD) of the proband at the age of 21 years. Further, a DCM causing novel mutation p.Gly377Ser was identified which resulted in the milder phenotype. The present study shows that there is genetic and phenotypic heterogeneity of cardiomyopathies in Indian population. Further, the location and type of mutation in a given sarcomeric gene determines the severity and phenotypic plasticity in cardiomyopathies.

Hypertrophic cardiomyopathy is characterized by massive ventricular hypertrophy, reduced diastolic function, and excessive ventricular contraction. The human leukocyte antigens HLA-A, HLA-B, and HLA-DR were studied in 14 hypertrophic cardiomyopathy patients with left ventricular obstruction from South India. They were compared with 81 normal age- and sex-matched individuals from the same ethnic background. The human leucocyte antigens were identified using the standard serological assay with a longer incubation for DR antigens. The odds ratio, frequency, chi-squared value, p-value, etiological fraction, preventive fraction, and haplotype frequency estimates were calculated. The HLA-B51 and HLA-DR2 levels were significantly increased in hypertrophic cardiomyopathy patients compared to controls, whereas HLA-A19, HLA-B7, and HLA-DR4 were decreased when compared to the controls. It was noticed that haplotype B51-DR2-DQ3 was significantly associated with hypertrophic cardiomyopathy patients from South India. Hypertrophic cardiomyopathy may be associated with genes in the human leukocyte antigen region, and immunogenetic factors linked to human leukocyte antigens appear to play a major role in the pathogenesis.