Hypertrophic cardiomyopathy (HCM) is a condition involving the abnormal thickening of the heart muscle, known as hypertrophy. This thickening occurs without clear external causes, such as long-term high blood pressure. HCM is the most common inherited heart disease, affecting approximately one in every 500 adults. The disorder is caused by genetic mutations that provide instructions for building the heart’s contractile machinery. In the majority of cases, HCM is passed down through families.
The Nature of Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy is defined by the unexplained enlargement of the walls of the left ventricle, the heart’s main pumping chamber. This thickening often occurs unevenly, frequently affecting the interventricular septum, the wall separating the two lower chambers. This excessive muscle growth reduces the space inside the left ventricle.
The primary functional consequence of this hypertrophy is that the heart becomes stiff and less able to relax between beats. This impaired relaxation, called diastolic dysfunction, prevents the ventricle from filling properly with blood. The thickened septum can also obstruct the flow of blood leaving the heart. These abnormalities can cause symptoms like shortness of breath, chest pain, and palpitations, and HCM is the most common cause of sudden cardiac death in some young individuals.
Inheritance Patterns and Risk
HCM transmission follows autosomal dominant inheritance. This means a person only needs to inherit one copy of the mutated gene from either parent to be at risk of developing the condition. A parent with an HCM mutation has a 50% chance of passing that mutation on to each child.
The inheritance pattern is complicated by penetrance and variable expression. Penetrance refers to the likelihood that an individual who inherited the mutated gene will show physical signs of the disease, such as heart wall thickening. For HCM, penetrance is incomplete, meaning not every person with the mutation will develop the condition.
Variable expression describes the wide range of symptoms and disease severity seen among individuals who carry the same mutation, even within the same family. One person might have severe symptoms, while a relative with the identical mutation might have only mild or no noticeable heart changes. This variability is thought to be due to the influence of modifying genes and environmental factors.
The likelihood of developing the disease also increases with age for mutation carriers. For example, characteristic heart changes may only be present in about half of individuals by age 30, but in approximately three-quarters by age 60. Factors such as being male or engaging in high levels of physical activity have been associated with an earlier age of diagnosis.
The Molecular Cause: Specific Gene Mutations
The genetic basis of HCM lies in mutations affecting the sarcomere, the fundamental unit of muscle contraction in the heart. These genes provide the blueprint for the proteins that form the thick and thin filaments responsible for the heart’s pumping action. The resulting defective protein disrupts the balance of contraction and relaxation, leading to excessive muscle growth.
The two most frequently implicated genes are MYH7 and MYBPC3, which account for about 75% of identified pathogenic variants. The MYH7 gene codes for beta-myosin heavy chain, the main motor protein forming the core of the thick filament. MYH7 mutations are associated with an earlier onset of symptoms and more pronounced heart wall thickening.
The MYBPC3 gene codes for cardiac myosin-binding protein C, a regulatory protein located on the thick filament that controls muscle contraction. MYBPC3 mutations are the most common cause of HCM and often result in a loss of function for the protein. Both MYH7 and MYBPC3 mutations alter the efficiency and force of the heart muscle’s contractions.
A significant number of pathogenic variants are unique to a single family, sometimes called “private mutations.” Identifying a specific mutation is challenging in small families or in individuals with no apparent family history, as causality may be less clear. Even with comprehensive testing, a causative gene cannot be identified in approximately 40% of clinically diagnosed HCM cases.
Implications for Family Screening and Genetic Testing
The strong genetic link in HCM makes genetic testing an integral part of the diagnostic and management process. Identifying the specific mutation in the first affected family member, known as the index case, is the first step toward managing the entire family. This testing provides a definitive molecular diagnosis and helps distinguish inherited HCM from other conditions that mimic heart wall thickening.
Once a pathogenic mutation is identified, cascade screening is initiated to systematically identify at-risk relatives. This involves offering genetic testing to first-degree relatives—parents, siblings, and children—of the affected individual. Relatives who test positive can then be monitored closely, even if asymptomatic, allowing for early intervention and risk management.
Genetic counseling plays a fundamental role, providing detailed information about the inheritance pattern and the implications of test results. Relatives who test negative for the family mutation are reassured and eliminate the need for lifelong cardiac screening. Those who test positive but show no clinical signs require regular clinical screening, such as echocardiograms, to detect the onset of heart changes early.