Hypertrophic Cardiomyopathy (HCM) is a condition where the heart muscle, particularly the walls of the left ventricle, becomes abnormally thick (hypertrophy). This thickening occurs without obvious causes like high blood pressure. The result is a stiff heart that struggles to relax and fill with blood between beats, impairing its ability to pump effectively. While the clinical presentation is complex, the underlying cause for the vast majority of individuals is a change in their genetic code, meaning HCM is typically passed down through generations.
Understanding Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is defined by thickened heart muscle, often occurring asymmetrically and commonly affecting the septum (the wall separating the lower chambers). This thickening can sometimes block or reduce blood flow from the left ventricle into the aorta, known as obstructive HCM. The thickened muscle tissue becomes stiff, impairing the heart’s ability to relax and fill with blood effectively during diastole.
This impaired filling often causes symptoms like shortness of breath, especially during physical activity. Other common symptoms include chest pain, palpitations, dizziness, or fainting spells. Structural changes, such as a disorganized arrangement of heart muscle cells, can also create electrical instability, potentially leading to life-threatening abnormal heart rhythms.
The severity of HCM is highly variable; some individuals remain asymptomatic, while others face serious complications like heart failure or sudden cardiac death. Diagnosis typically relies on imaging techniques, such as an echocardiogram, to visualize the abnormal thickening of the ventricular walls. For adults, a wall thickness of 15 millimeters or more, absent other causes, is a common diagnostic threshold.
The Primary Role of Genetics
HCM is the most common genetic heart condition, affecting about one in every 500 people. In most familial cases, the disease is inherited in an autosomal dominant pattern. This means inheriting only one copy of the altered gene from one parent is sufficient to potentially develop the condition.
A child of an affected parent has a 50% chance of inheriting the altered gene. However, HCM displays variable expression, meaning individuals inheriting the identical mutation can have vastly different clinical outcomes. For example, one person might develop severe symptoms while a relative with the same gene change may have only mild or no detectable heart changes.
The likelihood that a person carrying the mutation will show clinical signs is called penetrance. HCM demonstrates age-dependent penetrance, as heart thickening may not be detectable until adolescence, early adulthood, or later in life. While primarily inherited, 30-40% of diagnosed patients lack a known family history, suggesting spontaneous new mutations or unidentified genetic causes are also factors.
Key Genes and Molecular Mechanisms
The genetic changes responsible for HCM primarily involve genes that encode for the sarcomere, the basic contractile unit of the heart muscle cell. These mutations disrupt the machinery allowing the heart muscle to contract and relax. The vast majority of identified gene mutations occur in two main genes: MYH7 and MYBPC3.
The MYH7 gene provides instructions for making beta-myosin heavy chain, a major component of the thick filament. Mutations in MYH7 disrupt filament interaction, leading to impaired function and often a more severe clinical presentation. The MYBPC3 gene codes for cardiac myosin-binding protein C, which regulates muscle contraction and stability. MYBPC3 mutations are the most common cause of HCM and typically result in a truncated, non-functional protein.
When these sarcomeric proteins are altered, heart muscle cells experience increased mechanical stress and abnormal contractility. This stress triggers a compensatory response, leading to the excessive growth and disorganization of the cells, resulting in characteristic hypertrophy. Mutations in other sarcomeric genes, such as TNNT2 (Troponin T) and TNNI3 (Troponin I), also contribute to HCM but are less frequent causes.
Genetic Screening and Counseling
Genetic testing is a recommended component of the diagnostic process for all individuals with confirmed or suspected HCM. The primary purpose is to identify the specific gene mutation responsible for the condition in the affected person (the proband). Testing typically involves DNA sequencing from a blood or saliva sample to check for known pathogenic variants.
Genetic counseling should take place both before and after the test. A genetic counselor helps patients understand the benefits and limitations of testing, the potential for identifying a variant of uncertain significance, and the autosomal dominant inheritance pattern. They also provide support in navigating the complex emotional and family implications of a genetic diagnosis.
If a pathogenic or likely pathogenic gene variant is identified in the proband, this result becomes the target for testing in the rest of the family. The diagnostic yield of genetic testing in patients with a clear family history is higher, ranging from 40% to 60%. Genetic testing also plays a role in distinguishing HCM from phenocopies, which are other conditions that can cause heart thickening but have a different underlying cause and require different management strategies.
Implications for Family Members and Ongoing Care
Once a specific gene mutation is identified in a person with HCM, a systematic approach known as cascade screening is initiated for all first-degree relatives, including parents, siblings, and children. This process involves offering targeted genetic testing for the known family mutation to these at-risk, asymptomatic individuals. If a family member tests negative for the specific gene variant, they are not at risk for developing HCM or passing it on to their own children, and they can be discharged from further routine cardiac screening.
Conversely, if an asymptomatic relative tests positive for the family’s mutation, they are considered genotype-positive and at risk, even if their heart appears structurally normal at the time of testing. These individuals require regular cardiac surveillance, including periodic physical examinations, electrocardiograms, and echocardiograms, to monitor for the development of hypertrophy. Screening is often recommended annually during adolescence and early adulthood, and then every three to five years thereafter.
Identifying the precise genetic cause can also influence personalized medical management. For example, some gene mutations, such as those in TNNT2, have been associated with a higher risk of sudden cardiac death, even in the absence of severe heart thickening, which may prompt earlier consideration for an implantable cardioverter-defibrillator (ICD). This genetic information provides a clearer picture of individual risk and allows for early intervention and tailored care, which is particularly beneficial as the disease is progressive.