As Hypertrophic Cardiomyopathy (HCM) is a genetic disease, understanding of its genetics is crucial in diagnostics, treatment and eventually prevention of the disease. A new article by Dr. Luis R. Lopes, Prof. Carolyn Y. Ho, and Prof. Perry M. Elliott in the August 2024 issue of the European Heart Journal gives a great overview of the implications of genetic findings now and in the future. You can find the full text of the article here.

We will try to summarize for patients and caregivers the key findings of the article in a less scientific language. Before we start, let us clarify that a sarcomere is the basic contractile unit of muscle fiber. Each sarcomere is composed of two main protein filaments—actin and myosin—which are the active structures responsible for muscular contraction. According to the results of genetic screening, HCM patients are currently categorized in two main sub-populations: sarcomeric-positive (Sarc+) patients, in whom the causal mutation is identified in a sarcomeric gene; and sarcomeric-negative (Sarc−) patients, in whom a causal mutation has not been identified. In rare cases, Sarc− HCM cases may be caused by pathogenic variants in non-sarcomeric genes. You can read more about the differences between Sarc+ and Sarc- patients in this article.

Coming back to our task

• The article states that “there have been attempts to describe HCM solely as a disease of the sarcomere, but the fact that >50% of patients with a clinical diagnosis have no discernible sarcomeric gene variant has led to inconsistency in terminology and disease management. Fortunately, rapid developments in clinical diagnostic tools and genetic testing are driving a new approach, in which the phenotype of increased LV wall thickness is only the first step towards an aetiological diagnosis and tailored treatment.” In other words, LV wall thickness is a convenient marker for the presence of HCM but it is not the only one. It is also not easy to determine whether a patient carries a sarcomere or non-sarcomere gene disease causing gene.
• Genetic testing is predicted in all international guidelines and can bring many benefits for patients. The frequency of screening for patients with detected pathogenic or likely pathogenic variant is age-dependent and should be performed more often (e.g. annually) during adolescence and early adulthood and every 3-5 years later in adulthood.
• It is possible to estimate the risk of developing a phenotype (in other words, that HCM will express itself) but the way it expresses in different genes and its severity are more challenging to predict. The article states “In a recently published cohort including adults at start of follow-up, the penetrance of disease in a 10–15-year timespan (median 8 years) was substantial (46%). Male sex and ECG abnormalities were associated with higher penetrance. TNNI3 had the lowest risk of penetrance when compared with MYBPC3 (HR 0.19). Importantly, no episodes of sudden cardiac death (SCD) occurred in individuals who did not fulfil conventional HCM diagnostic criteria”. In other words, if you are male, have abnormalities in your ECG and carry a certain gene as compared to others, you are more likely to develop the disease. It is also very unlikely that you will suffer an SCD if you have not displayed HCM in some way.
• Genetics can be very effectively used for fertility planning to eliminate the HCM gene from future generations. As stated in the article, “In a reproductive medicine context, identifying a pathogenic variant allows for preimplantation genetic testing (PGT). In this process, embryos are generated by in vitro fertilization and those not carrying the pathogenic variant are selected for subsequent implantation and pregnancy. Cardiomyopathies are one of the conditions for which PGT can be considered. This usually takes place in specialized referral centres, where counselling and discussion with the prospective parents takes place, emphasizing the rare potential risk of transferring abnormal embryos due to false negative genetic testing results. Confirmatory genetic testing either during pregnancy (chorionic villus sampling or amniocentesis) or after delivery is typically recommended to be sure of the actual genotype. These techniques can also be used to test in the context of natural conception.” Note that this topic is very well covered in the novel The Green Tunnel by the Foundation’s general manager Emil Tsenov. The novel is centered around the story of people living with HCM. You can buy the book on this Amazon link.
• Studies show some specifics for different genes: TNNT2 tend to cause lesser maximal LV wall thickness but greater arrhythmic risk. MYBPC3 has a later disease penetrance than MYH7, but the later gene has a higher incidence of atrial fibrillation. Compared to sarcomere-negative individuals, sarcomere-positive have an earlier age at presentation by 5–10 years, more severe hypertrophy (1–2 mm on average), less frequent LV outflow tract (LVOT) obstruction, greater myocardial scar burden, and an increased (two-fold) incidence of arrhythmic and heart failure outcomes.
• HCM genetics should not be oversimplified, e.g. variants of the same gene can produce different outcomes.
• There are differences between the modes of inheritance of different genes. “Autosomal dominant inheritance is characterized by the presence of affected individuals in all generations and male-to-male transmission, whereas X-linked transmission is defined by the absence of male–male transmission and is typified by milder or absent phenotypes in females.”
• Sarcomere gene-related disease ususally presents from adolescence to middle age (presentation in younger children also occurs).
• Analysis has shown a particularly strong association of diastolic blood pressure to the risk of HCM in sarcomere-negative individuals. New data points that the development of sarcomere-negative HCM may be influenced by environmental and polygenetic effects and that these individuals may have a less severe phenotype compared to sarcomere-positive HCM, suggest that family screening strategies should be more tailored. Relatives of a sarcomere-negative carrier, in the absence of family history—a concept recently referred to as ‘non- familial HCM’—may not need to be screened as frequently as sarcomere- positive families.
• New genetic therapies targeting specific genes are emerging and fast-developing but they do have their challenges. One of them is the risk of mutations, leading to increased risk of cancer. Other challenges are related to the way of optimum delivery of the medicine so as not to cause the neutralization of antibodies from previous adenovirus exposure. Still, if proven safe and well-tolerated, these new therapies may delay progression or even prevent disease emergence.

Genetics is a complex topic, even more so in the context of HCM. Still, patients and their caretakers should aim to be better acquainted with key genetic terms and developments in order to be able to take an active position in the discussion about their diagnostic and treatment options.