Hypertrophic cardiomyopathy (HCM) is a condition where the heart muscle, particularly the walls of the left ventricle, becomes abnormally thick. This thickening can make it harder for the heart to pump blood effectively throughout the body. The enlarged muscle can also stiffen, reducing the heart’s ability to relax and fill with blood between beats. This condition may affect various parts of the heart, most commonly the septum which separates the ventricles. Symptoms can range from mild or absent to more severe, including shortness of breath, chest pain, and fatigue.
Understanding the Genetic Basis of HCM
Hypertrophic cardiomyopathy is predominantly a genetic disorder, resulting from inherited changes in a person’s DNA. A significant majority of HCM cases are linked to mutations in specific genes that play a role in heart muscle development and function. Approximately 60% of individuals diagnosed with HCM have an identifiable genetic mutation.
This genetic predisposition means that the condition frequently runs in families, often being passed down through generations. Defects within these genes disrupt the normal architecture and contractility of the heart, fundamentally altering how the heart muscle is formed and behaves.
Inheritance Patterns and Associated Genes
Hypertrophic cardiomyopathy is typically inherited in an autosomal dominant pattern. Each child of an affected parent has a 50% chance of inheriting the altered gene and therefore the potential to develop HCM.
The genetic mutations responsible for HCM primarily affect genes that encode sarcomere proteins. Sarcomeres are the fundamental contractile units of heart muscle cells, responsible for the heart’s pumping action. The two most commonly implicated genes are MYH7, which codes for the beta-myosin heavy chain, and MYBPC3, which codes for cardiac myosin-binding protein C. Together, mutations in these two genes account for a significant portion, approximately 50% to 70%, of familial HCM cases. These proteins are crucial for muscle contraction and maintaining sarcomere integrity.
Despite inheriting the same genetic mutation, individuals within the same family can experience different symptoms or disease severity due to phenomena known as variable expression and incomplete penetrance. Variable expression means that the signs and symptoms of HCM can differ widely among affected individuals, even with the identical mutation. Incomplete penetrance indicates that not everyone who inherits the mutated gene will develop clinically detectable HCM. This variability can sometimes make it appear as though the condition has skipped a generation.
Genetic Testing and Family Screening
Genetic testing plays a significant role in the diagnosis and management of hypertrophic cardiomyopathy. Individuals diagnosed with HCM are typically offered genetic testing to identify the specific genetic mutation causing their condition. This process involves analyzing a sample to identify changes in genes linked to HCM. Identifying a pathogenic gene variant provides a molecular diagnosis and can help distinguish HCM from other conditions that might mimic its symptoms.
Once a genetic mutation is identified in a person with HCM, it becomes important to screen their close blood relatives, including parents, siblings, and children. This family screening, often called cascade testing, involves testing relatives for the specific mutation. If a relative tests positive for the mutation, they are at risk of developing HCM, even if they show no symptoms, and can benefit from regular cardiac monitoring. Conversely, if they test negative for the familial mutation, they typically do not need ongoing specialized HCM screenings.
Genetic counseling is an integral part of this process, both before and after testing. Genetic counselors explain the testing procedure, potential results, and implications for both the individual and their family, also guiding decisions related to family planning.
When HCM Isn’t Inherited
While hypertrophic cardiomyopathy is primarily a genetic condition, not every individual with thickened heart muscle has an identifiable inherited mutation. Approximately 20% to 40% of HCM cases occur without a clear genetic cause or family history, often termed “sporadic.” Some of these arise from “de novo” mutations, which are new genetic changes occurring spontaneously in the individual, rather than being inherited.
In other instances, the genetic cause simply remains undiscovered due to limitations in current testing or incomplete knowledge of all relevant genes. Furthermore, various conditions can cause heart muscle thickening that closely resembles HCM, known as “phenocopies.” These include metabolic disorders like Fabry disease, infiltrative diseases such as cardiac amyloidosis, or even effects from long-term hypertension or intense athletic training. Accurately differentiating these phenocopies from true HCM is important for appropriate diagnosis and tailored treatment.