Abstract Body (Do not enter title and authors here): Background: Mutations in the β-MYH7 gene are a leading cause of unexplained left ventricular hypertrophy with abnormal loading conditions, which progressively increase the risk of heart failure (HF) and sudden cardiac death (SCD) across all age groups. Despite the high morbidity and mortality rates in South Asia, this area remains relatively unexplored, with limited research studies. India, with its large ethnic diversity, presents a unique and intriguing opportunity for a deeper understanding of population-specific genetic variations.
Methods: In our case-control study, we conducted targeted direct sequencing of the β-MYH7 gene to detect the causative variations in 160 patients diagnosed with hypertrophic cardiomyopathy (HCM) through clinical examination, ECG, and echocardiography, along with 178 ethnically matched healthy controls. We also constructed homology protein models for causative mutations to evaluate their impact on the β-MYH7 protein structure in Indian HCMs.
Results: Our study identified a total of 33 variations in the β-myosin heavy chain gene (β-MYH7). We defined six missense mutations (M362L, K367N, E525K, M684R, L725P, and D896N) as causative because they co-segregated with the disease in family pedigrees, altered conserved amino acids, and were absent in the 178 healthy controls. By comparing the homology protein models of each of the six mutants (p.M362L, p.K367N, p.E525K, p.M684R, p.L725P, and p.D896N) to the native protein, we found that each mutant protein uniquely disrupts the structure, and potentially affecting the protein function and the phenotypic expression of the disease. Additionally, several rare compound variations in the β-MYH7 gene were observed in 4 HCM patients, specifically: HCM1, (G354G, M362L & G389K); HCM2, (splice site (SS8) & F244F); HCM3, (E525K & D896N); and HCM4, (A423T, V431M & N602K-fs). Notably, one patient with hypertrophic obstructive cardiomyopathy (HOCM) exhibited rare compound digenic variations in the Myosin (β-MYH7_G354G, A423T, A917A) and Troponin T2 (TNNT2_A28V) genes. Principal component analysis (PCA) and HapMap data indicated that both the cases and controls derived from the same ethnic background.
Conclusion: We identified Novel Mutations in the β-MYH7 Gene that lead to HCM among Indians. We provided valuable insights about causative mutations and their impact on the β-MYH7 protein structure, which may facilitate the development of therapeutic strategies for personalised medicine.