Hypertrophic cardiomyopathy (HCM) is genetic in the majority of cases. It is one of the most common inherited heart conditions, affecting roughly 1 in 500 people in the general population, and up to 1 in 200 when genetic criteria are included. Most cases follow an autosomal dominant inheritance pattern, meaning a single copy of an altered gene is enough to cause the condition, and each child of an affected parent has a 50% chance of inheriting the mutation.
Which Genes Cause HCM
HCM is caused by mutations in genes that encode proteins in the sarcomere, the basic contractile unit of heart muscle. The two genes most frequently responsible are MYH7, which provides instructions for a key motor protein in the heart, and MYBPC3, which helps regulate how forcefully the heart contracts. Together, mutations in these two genes account for the majority of genetically confirmed cases.
When genetic testing is performed on people with a clinical HCM diagnosis, about 35% test positive for a known disease-causing mutation. That number is higher in certain subtypes of HCM. In the most common form, where the thickening occurs in the septum (the wall between the two lower chambers), roughly 40% of patients carry an identifiable sarcomere gene mutation. In apical HCM, where thickening is concentrated at the tip of the heart, only about 13% test positive. The remaining patients likely have mutations in genes that haven’t been identified yet, or their thickening has a different underlying cause.
How HCM Is Inherited
HCM follows autosomal dominant inheritance. In practical terms, that means only one parent needs to carry the mutation for a child to be at risk, and the odds are essentially a coin flip: 50% per pregnancy. In most cases, an affected person has at least one parent with the condition, though that parent may never have been diagnosed because symptoms can be mild or absent.
Rarely, a person inherits altered copies of the gene from both parents. When this happens, the disease tends to be more severe and appears earlier in life. It’s also possible for HCM to arise from a new (de novo) mutation that neither parent carries, though this is uncommon.
Same Gene, Different Outcomes
One of the most confusing aspects of HCM for families is that two people carrying the exact same mutation can have very different experiences. One sibling might develop significant heart wall thickening in adolescence, while another might show no signs until middle age, or never at all. This phenomenon, called incomplete penetrance and variable expressivity, is a hallmark of the condition.
Several factors influence how the disease manifests. Sex plays a role: men tend to develop detectable thickening earlier than women. Ethnicity, the specific location of the mutation within the gene, and the presence of additional genetic modifiers all contribute to differences in timing and severity. Symptoms can range from none at all to severe heart failure, chest pain, dangerous heart rhythms, or fainting episodes. This wide range is why genetic testing alone can’t predict exactly how the disease will affect any individual person.
Conditions That Mimic HCM
Not every case of unexplained heart muscle thickening is true sarcomeric HCM. Several other genetic conditions produce a similar appearance on an echocardiogram but have different underlying mechanisms and require different treatment. These are called phenocopies, and distinguishing them matters because some have specific therapies available.
- Fabry disease: A metabolic disorder that causes a fatty substance to accumulate in cells throughout the body, including the heart. It often also affects the kidneys, skin, and nervous system.
- Danon disease: A rare condition primarily affecting young men, involving both the heart and skeletal muscles, often with intellectual disability.
- Noonan syndrome: A developmental condition that can include heart thickening alongside distinctive facial features, short stature, and other findings.
- Cardiac amyloidosis: Caused by abnormal protein deposits in the heart, particularly a hereditary form linked to the TTR gene.
Current guidelines recommend that genetic testing panels for HCM include genes for these phenocopies so they aren’t missed. The distinction is particularly important because some of these conditions, like Fabry disease, have enzyme replacement therapies that can slow progression.
When Genetic Testing Is Recommended
HCM is typically diagnosed when imaging reveals a left ventricular wall thickness of 15 mm or greater in adults, or 13 mm or greater in someone with a family history of the condition. Some Asian populations use lower thresholds (10 mm for women, 12 mm for men) to account for differences in body size. Once a clinical diagnosis is established, guidelines from the American Heart Association and American College of Cardiology recommend a consultation with a genetic counselor to discuss the risks and benefits of testing.
Genetic testing serves two main purposes. First, identifying a specific mutation helps confirm the diagnosis and rule out phenocopies. Second, and often more importantly, it enables cascade testing for family members. If a pathogenic mutation is found in the person diagnosed (called the proband), first-degree relatives can be tested for that specific mutation. Those who don’t carry it can be reassured and released from ongoing cardiac surveillance. Those who do carry it can be monitored closely, even before symptoms or thickening appear.
Screening for Family Members
First-degree relatives of someone with HCM, meaning parents, siblings, and children, are recommended to undergo screening that includes a medical and family history review, a physical exam, an electrocardiogram (ECG), and an echocardiogram. Additional tests like cardiac MRI, exercise testing, or heart rhythm monitoring may be added based on what the initial evaluation shows.
For relatives who carry the family’s known mutation but haven’t yet developed thickening, periodic imaging is recommended because the condition can emerge at any age. Children of an affected parent may be screened starting in adolescence, with repeat evaluations over time. One recent study found that among relatives from families where no genetic mutation could be identified, a wall thickness below 10 mm at baseline screening made it very unlikely (0.4%) that they would go on to develop HCM during follow-up. This kind of finding helps clinicians identify which relatives can safely be screened less frequently.
Does Genotype Affect Risk of Sudden Cardiac Death
One of the most feared complications of HCM is sudden cardiac death, particularly in young athletes. Research has clarified that carrying a positive genotype does influence this risk, though it is only one piece of the puzzle. In a large study, patients who tested positive for a sarcomere mutation had roughly 1.5 times the risk of sudden cardiac death compared to those who tested negative. A family history of sudden cardiac death raised the risk by about 1.8 times.
The combination of these factors matters. Among patients whose only risk marker was a family history of sudden death, those who also tested genotype-positive had a 6.4% risk of a sudden cardiac event over five years, while genotype-negative patients had a 2.6% risk. This difference is significant enough that it can influence decisions about whether a preventive implantable defibrillator is appropriate. For genotype-negative patients with a family history of sudden death but no other risk markers, the data suggest the risk may not be high enough to warrant a defibrillator on its own.