Inherited cardiomyopathy:
risk for children and screening of family members

Article written and reviewed by Dr Luca Moretti

Cardiomyopathy can be inherited, but not all cardiomyopathies have a demonstrable genetic cause and there is no single risk percentage that applies to every family. When the disease is caused by a pathogenic variant inherited in an autosomal dominant pattern, which is common in several cardiomyopathies, each child generally has a 50% chance of inheriting that variant. This does not mean, however, that the child will definitely develop the disease or have the same age at onset or the same severity as the parent.
Understanding the actual risk requires three elements: a precise cardiac diagnosis, reconstruction of the family history and, when indicated, genetic counseling with genetic testing performed and interpreted appropriately.

The key points to remember are:

• the genetic component is important in many cardiomyopathies, but not to the same extent in all of them;
• the 50% figure applies to specific autosomal dominant forms, not to every cardiomyopathy;
• inheriting a variant does not necessarily mean developing clinically evident cardiomyopathy;
• genetic testing is more informative when it is performed first in an affected member of the family;
• a variant of uncertain significance, or VUS, should not automatically be considered causal;
• first-degree relatives may need ECG, echocardiography and other follow-up even if they feel well.

Inherited forms may involve different phenotypes, including hypertrophic cardiomyopathy, genetic dilated cardiomyopathy and arrhythmogenic cardiomyopathy. Genetics does not replace clinical cardiology: it is used to complete the picture and, above all, to identify which family members may benefit from targeted follow-up.

When cardiomyopathy may be inherited

Suspicion of an inherited form increases when several people in the same family have cardiomyopathy, heart failure without an obvious acquired cause, ventricular arrhythmias, conduction disorders, pacemakers or defibrillators at a young age, heart transplantation or sudden death. However, even a single case can have a genetic origin: the absence of other already diagnosed family members does not exclude it.
This may occur because a variant arose for the first time in the affected person, because some carriers never develop an evident phenotype or develop it only later in life, or because relatives have never undergone the necessary tests.

Inherited cardiomyopathies often show incomplete penetrance and variable expressivity. In practical terms, two people in the same family with the same variant can have very different clinical pictures: one may remain asymptomatic, another may develop mild disease, and another may experience arrhythmias or cardiac dysfunction. Age, sex, other genes and environmental factors may contribute to these differences.

What is the risk for children?

Many genetic cardiomyopathies are inherited in an autosomal dominant pattern. If a parent carries a heterozygous pathogenic variant responsible for the disease, each pregnancy generally carries a 50% chance of transmitting that variant, independently of what happened in previous pregnancies.
The 50% figure refers to the probability of inheriting the variant, not to certainty of developing cardiomyopathy. Penetrance may be incomplete and the age of onset variable, so a child who carries the variant may have normal follow-up examinations for years and may or may not subsequently develop the phenotype.

Not all families follow this pattern. Autosomal recessive, X-linked and mitochondrial forms exist, as do syndromic conditions with different modes of inheritance. It is therefore incorrect to automatically apply the "50%" figure to any diagnosis of cardiomyopathy. If a genetic cause has not been identified, risk is estimated using the type of cardiomyopathy, family history and the results of clinical screening.

How genetic testing works and who should be tested first

Whenever possible, genetic testing is first performed in the proband, meaning an affected person with a well-documented phenotype. This strategy increases the likelihood that any result will be interpretable. Testing should be accompanied by genetic counseling, explaining before the test what it may find, what its limitations are and what consequences it may have for the person and their relatives.
Modern panels analyze genes whose relationship with the specific phenotype is supported by adequate evidence. Indiscriminately broad testing can increase the number of results that are difficult to interpret without necessarily increasing clinical usefulness.

The result may identify a pathogenic or likely pathogenic variant, a benign or likely benign variant, or a VUS, meaning a variant of uncertain significance. A VUS is not a genetic diagnosis: there is currently insufficient evidence to classify it as causal or harmless. For this reason, it should not be used on its own to establish that a relative is "genetically positive" or "negative" and should not be used like a pathogenic variant for predictive cascade screening.

What follow-up should family members undergo?

First-degree relatives, meaning parents, siblings and children, are the group most often involved in screening. Clinical assessment generally includes medical history, physical examination, ECG and echocardiography; in some cardiomyopathies or when findings are uncertain, Holter monitoring, cardiac magnetic resonance imaging or other tests may be indicated.
The age at which follow-up begins and how often it is repeated depend on the phenotype, any gene involved, the family history and the relative's age. There is therefore no single schedule that applies to all cardiomyopathies.

If a pathogenic or likely pathogenic variant consistent with the disease has been identified in the proband, family members may be offered targeted genetic testing for that specific variant. A relative who does not carry it can often be excluded from the surveillance program linked to that familial variant, provided that they do not have a cardiac phenotype or other findings that still require follow-up.
A person who inherits the variant is not necessarily ill, but enters an appropriate surveillance program because the phenotype may develop over time.

What happens if the test is negative or finds a VUS?

A negative genetic test in a person with cardiomyopathy does not prove that the disease is not inherited. The cause may lie in a gene that has not yet been recognized, in a region not adequately analyzed by the test used, or in genetic mechanisms that current clinical tests cannot yet identify. In a family with strong clinical suspicion, relatives may therefore continue to need cardiac follow-up even if testing in the proband does not identify a causal variant.

A VUS also requires caution. Variant classification can change over time as new evidence, family data and database updates become available. In appropriate cases, it may be useful to have the report reassessed periodically at a center with expertise in cardiovascular genetics.
Decisions about exercise, medications, a defibrillator or other therapies should not be based on an isolated VUS, but on the clinical phenotype and documented risk factors.

Frequently asked questions about cardiomyopathy and family history

If I have cardiomyopathy, will my children inherit it?
Not necessarily. The risk depends on the cause. In autosomal dominant forms with a causal variant, each child generally has a 50% chance of inheriting the variant, but not a certainty of developing the disease.

Are all cardiomyopathies inherited?
No. Some have a strong genetic component, whereas others are acquired or result from the interaction between predisposition and environmental factors.

Who should have genetic testing first?
Whenever possible, an affected family member with a well-defined diagnosis.

What does VUS mean?
It means variant of uncertain significance: it has not been shown to be responsible for the disease and should not be treated as a pathogenic variant for predictive testing of relatives.

If genetic testing is negative, can family members avoid follow-up?
Not always. If the genetic cause has not been identified but the family picture remains suspicious, cardiac screening may still be necessary according to specialist recommendations.