Why Your Doctor May Recommend Genetic Testing If They Suspect Cardiomyopathy

Cardiomyopathy is a group of heart muscle diseases that affect people of all ages and fitness levels, with a prevalence of one in 500 in the general population.

There are several types of cardiomyopathy, with many possible causes. Some CMs are acquired, caused by other underlying diseases (like diabetes mellitus), viral infection or viruses.

Cardiomyopathy can also be caused by mutations in genes, in which case a person is born with it. ​However, many people carrying those genes don't develop cardiomyopathy until adolescence or later in life. This is why many are unaware that they have a significant risk of cardiomyopathy. That's where genetic testing comes into play. 

How can gene mutations cause cardiomyopathy?

It’s fascinating how the foundation of all life rests only on two macromolecules: proteins and the nucleic acids (DNA and RNA). Proteins are carriers of almost all functions in the cell and the organism: from enzymes and receptors on the cells to carriers of important molecules and the building blocks of many structures, like muscles. In other words, they are the ones that do all the work. All proteins are variations of twenty amino acids arranged in different ways. While they’re certainly a hallmark of life, they can’t exist without DNA. DNA has densely packed codes for every protein in our bodies, which forms one’s genetic material.

Both proteins and DNA are dynamic molecules that depend on their environment and constantly adjust to it. Many factors can cause changes in our genetic material. Even a very small change in the part of the DNA that codes for the protein can have a drastic effect on that protein. Those changes can have different effects, from beneficial ones, like for example causing resistance to disease, to neutral and harmful mutations that cause different diseases or disorders. 

When it comes to cardiomyopathy, most frequent mutations that lead to it are related to the proteins that build the heart muscle. Heart muscle is made up of cardiomyocytes (heart muscle cells) that are joined together by different proteins. These proteins are important for normal muscle contraction and the heart’s structure.

A harmful mutation in the part of the DNA that codes for the protein of the heart muscle tissue can cause the protein to be dysfunctional (due to changes in its structure) or it might not be created at all. For example, mutations in genes for myosin-binding protein and myosin heavy chain have been linked with hypertrophic cardiomyopathy (HCM). HCM is the most common inherited heart condition, and it’s characterized by abnormally thick heart muscle walls. There are more than 1,500 known mutations in 11 genes that can lead to HCM.

Genetics of cardiomyopathy: What are your odds of inheriting cardiomyopathy?

You know that we inherit our genes from our parents. But how exactly and what are the odds of inheriting a mutated gene that can cause cardiomyopathy?

In each cell, genes exist in two copies. Those copies are called alleles. They are genes for the same thing, just two different copies: one from your mother and one from your father. For example, if you have brown eyes, it doesn’t mean you don’t also have the genes for blue eyes — it’s just that they’re not "active" (expressed). Alleles that are always expressed are called dominant (in the example above, those would be genes coding for brown eyes).

We have 23 chromosomes: one is the sex chromosome (X for women and Y for men), and the other 22 are called autosomes. Based on how a trait is inherited, it can be:

• Autosomal dominant — linked to autosomes and with a 50 percent chance of being inherited. This is how familial hypertrophic cardiomyopathy is passed from parents to children.
• Autosomal recessive — linked to autosomes and with a 25 percent chance of being inherited.
• X-linked — linked to sex chromosome rather than autosome. Men are more likely to suffer from X-linked disorders, while women are usually only carriers. This is because women have two X chromosomes (their sex chromosomes are XX), which means that the other X chromosome could be carrying a normal copy of the same gene. On the other hand, men have only one X chromosome (their sex chromosomes are XY). Mutations in the DMD gene (that is on the X chromosome) cause a particularly serious form of dilated cardiomyopathy that results in death in the first 20 years of life. 
• Mitochondrial — the “power houses of the cell” also carry genetic material. One of the most important processes in the cell is oxidative phosphorylation, the last phase of cellular respiration in which energy is produced. Cardiomyopathies linked to mitochondrial DNA are mostly due to mutations in the oxidative phosphorylation system in the heart muscle. Hypertrophic CM and mixed hypertrophic-dilated CM have been linked with this type of mutations. 

How does genetic testing work?

More than 1,000 genetic tests are currently in use, bringing us to a new era of diagnostics and disease prevention. Genetic testing for CM is done by comparing your DNA (taken from a mouth swab or blood) with a panel of normal or mutated genes known to cause CM (more often). They can be used to confirm that a disorder has a genetic origin or to assess your risk for developing the disease (to see if you’re carrying a mutation).

You might see the limitations of this type of test right away: we can only test for mutations we know of. One condition can have a great number of mutations, many of which are unknown. For example, hypertrophic cardiomyopathy alone is linked to more than 1500 mutations.

This way the result of your test result can’t claim that you’re not carrying CM-causing genes, but only that you’re not carrying those specific CM-genes it looks for. Even if your test is positive for CM-causing gene, that doesn’t necessarily mean that you’ll develop cardiomyopathy. It means that you have a higher risk of developing it. 

However, genetic testing can have an important impact on both you and your family. If you already have CM diagnosed, you might be tested to see if it is caused by a genetic mutation. If it is, your first degree relatives (parents and full siblings) could also have it. That’s why it’s advised for first degree relatives to go through screening for cardiomyopathy (including physical exams and other diagnostic tests a doctor might order).

Benefits and limitations of genetic testing

Genetic testing can sometimes be life-saving.

For example, scientists found that mutations in gene TNNT2 in hypertrophic CM, as well as the A/C gene in dilated CM, have been linked with a significantly higher risk of sudden death. Meaning that if those mutations are found, extra measures can be undertaken to prevent such complications — measures that normally wouldn’t be considered in an asymptomatic healthy individual.

An even more obvious impact can be seen on the example of rare disorders like Fabry disease and Noonan syndrome, which have certain risks that can be treated as soon as they’re recognized (since they don’t just affect the heart but other organs as well.

Genetic testing might also be useful if you’re planning to start a family. It can be used to see if you could pass CM-linked genes to your child, but it can also lead some people to opt for in vitro fertilization to make sure that the eggs carrying mutations are not implanted in the womb. 

However, like everything, genetic testing does have limitations. The first one is that it doesn't exclude the possibility of carrying CM-linked genes. In addition, many studies emphasize the importance of the psychological effect of testing, with many patients having episodes of depression and anxiety.