Hypertrophic cardiomyopathy: Unlike global cohorts, South Indians carry different pathogenic genetic signatures
Compared with global cohorts (43.23%), South Indian patients had fewer variants (15.77%) in the 12 definitive genes linked to hypertrophic cardiomyopathy, which is a major cause of sudden cardiac deaths in young athletes. Instead, a single gene (MYH6) from the limited and disputed genes category had higher prevalence of pathogenic variants in South Indian patients
Hypertrophic cardiomyopathy (HCM), a common genetic heart muscle disorder, results in thickening of the heart muscle and obstructs blood flow, leading to a range of clinical symptoms and complications. Hypertrophic cardiomyopathy, particularly in young athletes, is the major case of sudden cardiac deaths. It affects over one in 200 to 500 people worldwide, and one in 200 in India (50,000 cases in one million population). A new genetic study of 335 patients from South India has revealed higher prevalence of MYH6 gene variants than in global cohorts. The findings underscore the need for ethnicity-specific and ancestral-specific studies to enhance precision medicine for hypertrophic cardiomyopathy across diverse populations.
Researchers from the Institute for Stem Cell Science and Regenerative Medicine (BRIC-inStem) collected and screened cardiomyopathy patients between 2016 and 2023. A total of 1,558 unrelated patients with mixed cardiomyopathies, including primary hypertrophic cardiomyopathy, secondary hypertrophy, other types of hypertrophies, and dilated cardiomyopathy were screened and narrowed down to 335 patients with primary hypertrophic cardiomyopathy.
“We narrowed down the group to primary hypertrophic cardiomyopathy cases by excluding patients who smoked, consumed alcohol, or had other comorbidities such as hypertension and diabetes which can independently induce hypertrophy. There have been previous studies on Indian patients with hypertrophic cardiomyopathy, but we wanted to concentrate exclusively on patients with no other factors, but genetics, that could have an effect on hypertrophic cardiomyopathy. In this way, we were able to look at the genes and the gene variants to decode the genetic underpinnings of hypertrophic cardiomyopathy, independent of lifestyle or metabolic influences,” explains Dr. Dhandapany Perundurai, Associate Professor at BRIC-inStem and corresponding author of the paper published recently in the Journal of the American Heart Association.
Understanding the genetic landscape of HCM
Most hypertrophic cardiomyopathy (HCM) cases are caused by mutations in genes encoding for sarcomere proteins or the proteins within the sarcomere, which is the basic unit of a muscle fibre, that help in heart muscle contraction and relaxation.
Mutations in sarcomeric proteins such as MYBPC3, MYH7 and TNNT2 are known to cause disruption in the normal muscle contraction. Most genetic research has focused on populations from Europe, North America, and the Middle East and has shown the genetic contributors to the condition.
To bring uniformity to global genetic interpretation, the ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel has categorised hypertrophic cardiomyopathy-associated genes into five levels based on clinical evidence: definitive, strong, moderate, limited, and disputed. However, so far there has not been any examination into how this classification applies to Indian patients.
Different gene variant affects Indian population
DNA studies revealed that the 335 patients included in the study had fewer variants (15.77%) in the 12 definitive genes or those that are most strongly linked to hypertrophic cardiomyopathy, compared with global cohorts (43.23%), suggesting that Indian patients may carry mutations in less-characterised genes.
Interestingly, a gene from the limited and disputed genes category, the MYH6 gene, stood out with a notably higher prevalence of pathogenic or likely pathogenic variants in the Indian cohort compared with global studies.
The MYH6 gene’s role in cardiac development and function has been well studied in fish and frog models. These models showed impairment in the ability of the heart muscle to contract, with the thickening of the muscular tissue in the heart’s lower chambers, which is a hallmark of hypertrophy.
“We are currently carrying out more studies in human organoid models and large pre-clinical models, such as rat to understand the MYH6 gene and its role in detail,” said Dr. Perundurai. “This could help us identify specific genetic mechanisms behind hypertrophic cardiomyopathy in Indian populations and eventually aid in precision medicine.”
Why Indian genome studies matter
India is one of the world’s most genetically diverse populations, yet most of the global databases are dominated by European and American samples. Underrepresentation of the Indian genetic variants can hinder the therapeutic frameworks used on Indian patients. This study provides direct evidence that disease-causing gene variants and their frequencies can be very different between Indian and global populations.
The authors say that is it timely to create a national reference genome database and efforts have been started to create a database that can help in risk prediction for cardiac and other genetic diseases.
According to the authors, precision medicine in cardiology goes beyond the one-size-fits-all model to deliver targeted therapies based on individual gene risk factors and specific mechanisms. For example, the recent mavacamten drug for hypertrophic cardiomyopathy is shown to be effective for only subtypes of mutated patients, not for all. Also, sarcomeric mutations affect implantable cardioverter-defibrillator (ICD) implantation in cardiomyopathies, warranting the need for personalised medicine.
The researchers aim to expand their work to other forms of cardiac disease including coronary artery disease and congenital heart disease.
