Hypertrophic Cardiomyopathy (HCM) is the most common inherited heart condition worldwide. This disorder is characterized by the abnormal thickening of the heart muscle, known as hypertrophy. In most cases, HCM is passed down through families due to a mutation in one of several specific genes. Understanding this genetic basis is key to managing the condition and identifying at-risk relatives.
What Hypertrophic Cardiomyopathy Does to the Heart
The physical manifestation of Hypertrophic Cardiomyopathy is the enlargement and stiffening of the myocardium, the muscular wall of the heart. This thickening most often affects the interventricular septum, the wall separating the heart’s two lower chambers, or ventricles. The abnormal muscle growth reduces the size of the left ventricle’s cavity, which pumps oxygenated blood to the body.
The thickened, stiff walls hinder the heart muscle’s ability to contract and relax efficiently. The heart struggles to fully relax and fill with blood between beats, a problem known as diastolic dysfunction. This stiffness increases pressure inside the heart, potentially causing fluid to back up into the lungs.
In some patients, the thickened septum partially blocks the left ventricular outflow tract, a condition called obstructive HCM. This obstruction forces the heart to work harder to pump blood, straining the compromised muscle. The abnormal arrangement of heart muscle cells, known as myocyte disarray, is a hallmark of HCM. This disarray can disrupt the heart’s electrical signaling, raising the risk of dangerous, erratic heart rhythms and sudden cardiac death, particularly in younger individuals.
Inheritance Patterns of HCM
The genetic transmission of Hypertrophic Cardiomyopathy follows Autosomal Dominant inheritance. This means a person needs to inherit only one altered copy of the gene from one parent to be at risk of developing the condition. Since the affected gene is located on a non-sex chromosome (autosome), the presence of a single variant is sufficient to introduce the disease trait.
A child born to a parent with genetically proven HCM has a 50% chance of inheriting the pathogenic gene variant, regardless of the child’s or parent’s sex. However, inheriting the gene variant is not the sole determinant of the disease’s physical expression.
HCM genetics involves variable penetrance, meaning not every person who inherits the mutation will develop the physical symptoms (phenotype). The condition also exhibits variable expressivity: even within the same family, severity can range from mild, late-onset hypertrophy to severe, life-threatening disease early in life. This variability suggests that other factors, including other genes and environmental influences, play a significant role in determining the disease’s severity and age of onset.
Primary Genes Responsible for HCM
Most genetic Hypertrophic Cardiomyopathy cases result from mutations in genes that encode components of the cardiac sarcomere, the fundamental contractile unit of heart muscle cells. These sarcomeric gene variants cause dysfunctional proteins, altering the mechanics of heart contraction and relaxation. This dysfunction leads to the muscle overgrowth characteristic of HCM.
Two genes account for approximately 70% of identified sarcomeric HCM cases. The first is MYBPC3, which codes for Myosin-binding protein C, a protein regulating muscle contraction and providing structural support. MYBPC3 mutations are often associated with a later onset of symptoms and a less severe initial presentation.
The second major gene is MYH7, which provides instructions for the beta-myosin heavy chain, a primary component of the sarcomere’s thick filament responsible for generating contraction force. MYH7 mutations are sometimes linked to earlier disease onset and more pronounced hypertrophy. Other sarcomeric genes, such as TNNT2 and TNNI3, also cause HCM, though less frequently.
Up to 50% of individuals clinically diagnosed with HCM do not have an identifiable pathogenic variant using current genetic testing panels. This “genetically negative” status suggests the mutation lies in a gene not yet associated with HCM, or in a region of a known gene not routinely tested. Ongoing research continues to identify new genes and non-sarcomeric variants to close this diagnostic gap.
Clinical Genetic Testing and Family Screening
Identifying a specific pathogenic gene variant in a patient with HCM (the proband) allows for a proactive approach to family health. Genetic counseling provides the patient and family members a clear understanding of the inheritance pattern, risk, and implications of testing. This process aims to establish a diagnosis and inform cascade screening.
Cascade screening is the systematic process of testing first-degree relatives—parents, siblings, and children—of the diagnosed individual. If the exact gene variant is known, a simple blood test determines which family members have inherited the mutation. Those who test negative for the familial variant are typically released from further routine cardiac surveillance.
Individuals who test positive for the gene variant but show no physical signs of the disease are considered “genotype-positive, phenotype-negative.” These individuals require regular cardiac screening, including electrocardiograms (ECG) and echocardiograms, to monitor for the first signs of heart muscle thickening. This early identification allows for timely medical intervention before symptoms become severe.
Genetic testing also holds utility for reproductive planning, allowing couples to understand the risk of passing the mutation to future children. Integrating genetic testing with clinical cardiac imaging provides the most comprehensive strategy for managing HCM, shifting the focus from treating advanced disease to preventing its most serious complications.