Genetic Testing for Hypertrophic Cardiomyopathy (HCM)
- HCM follows an autosomal dominant inheritance pattern. This simply means that it only takes one mutated copy of the gene to develop HCM. There is a 50% chance that someone with HCM will pass on a mutated copy of the gene to their child.
- Genetic testing is done with a focus on the genes already known to cause the disease. It requires either a blood or saliva sample. The sample is then analyzed and compared to a database of known genetic sequences that cause the disease.
- Early diagnosis improves the prognosis of HCM. Genetic testing can help to confirm a patient's diagnosis, as well as identify family members who may also be affected so that interventions can be started as soon as possible
What is Hypertrophic Cardiomyopathy?
Hypertrophic cardiomyopathy (HCM) is considered a progressive and chronic disease state that results in the heart muscle becoming enlarged and thick, typically ≥ 15 millimeters (mm). This typically occurs in the walls of the left ventricle. When the walls of the heart become too thick, they stiffen, which limits the heart's ability to bring blood into the left ventricle and pump it back out through the aorta properly. When blood flow is reduced or blocked entirely, it is referred to as obstructive HCM. This type of disease is more common than nonobstructive.This thickening of the heart muscle is typically caused by one or more genetic mutations. HCM is considered the most common inherited genetic heart condition, affecting approximately 1 out of every 500 people. However, the condition may be considerably underdiagnosed due to many patients being asymptomatic or only symptomatic with exertion.
Read MoreHow is HCM Inherited?
The science behind the genetic mutations that lead to the hypertrophy (enlargement) of the heart muscle is still relatively new, with the first genetic mutation sequence being identified in 1989. Currently, there are at least 9 genes that, if mutated, are known to cause hypertrophic cardiomyopathy. Some people may have mutations in several of these genes. HCM genes are the focus of genetic testing as more disease-causing mutations continue to be discovered.These genetic mutations follow an autosomal dominant inheritance pattern. This simply means that it only takes one mutated copy of the gene to develop HCM. However, the penetrance of the condition is incomplete, which suggests the presence of the gene mutation does not always lead to the expression of the disease.
This can also be described using the terms genotype and phenotype. The genotype refers to the existence of the genetic mutation itself, whereas the phenotype describes whether or not the condition is being expressed. This complicates the ability to predict family patterns. There is a 50% chance that someone with HCM will pass on a mutated copy of the gene to their child. But due to the variable expression of the condition, some people will have the inherited genotype of the disease but never show any signs of the condition, or remain phenotype negative.
Even if a person is phenotype negative, as long as they are genotype positive for a mutation, they carry the same risk of passing the mutation on to their children. Dr. Philip Weintraub, a cardiologist at NYU Langone Health, recommends genetic testing, especially in a young person who has hypertrophic cardiomyopathy. He explains this is necessary " because of the fact that the young person has family members that may not have symptoms and may be carrying the particular trait for HCM".
Hypertrophic Cardiomyopathy Genetic Testing Guidelines
Who should undergo genetic testing? Although the sudden death rate of young athletes with undiagnosed HCM has increased the awareness of the disease, this genetic condition can affect people of all ages. In general, the condition begins to develop in adolescence and the average age of first diagnosis is ~39 years old.
Since the condition may be diagnosed at any age, anyone with clinical signs or symptoms should undergo genetic testing in addition to other diagnostic tests, such as an echocardiogram or echocardiogram. Genetic testing is done with a focus on the genes already known to cause the disease. It is estimated that between 60-70% of people with HCM would have an identifiable gene mutation suspected to cause the disease.
Anytime genetic testing is recommended, people are also advised to meet with a genetic counselor. These specialists are trained to help guide people through the decision process of having testing done, how it impacts their treatment, and how it may affect their future.
Dr. Dwivedi says "if you are lucky that your family has a gene that’s been identified, it can be used to screen your first degree family members like your brother, your sister. If you’re planning to start a family in the future, identifying a gene can be very helpful in risk stratification of your offspring as well, and can help to also, uh, counsel during pregnancy."
Screening Recommendations for First-Degree Relatives
When someone is being evaluated for HCM, a thorough family history of all heart conditions is collected for at least three generations. It is recommended that first-degree relatives of someone with a new HCM diagnosis should undergo testing, if feasible. This includes parents, siblings, and children. This is also sometimes referred to as cascade screening. Testing will be focused on the specific gene mutation(s) that were identified with their family member.
If first-degree relatives are not willing or able to undergo genetic testing, or they have had testing done and are genotype positive but asymptomatic, clinical screening recommendations are provided in the 2020 guidelines developed by the American Heart Association (AHA) and American College of Cardiology (ACC).
For those who are genotype positive but phenotype negative, the concern is that the condition may start to be expressed later in life, so routine screening should be continued based on their age. Routine clinical screening typically includes a medical history, physical exam, echocardiogram, and electrocardiogram.
Surveillance recommendations include, not are limited to, the following:
- Adults should be screened when a relative is first diagnosed, then approximately every 3-5 years thereafter.
- Children or adolescents whose family member had a positive genetic test, or was diagnosed early with HCM, should be screened at the time of the family member's diagnosis, and then every 1-2 years thereafter.
- In the previously published 2003 guidelines, children were rarely recommended to be screened before puberty, but the more recent 2020 guidelines stress the importance of screening high-risk children because there have been HCM cases found in children prior to puberty.
- Children and adolescents, whose family members did not have a positive genetic test or were diagnosed with HCM later in life, should be screened at least by puberty, and continue every 2-3 years.
How is Genetic Testing Performed?
Genetic testing requires either a blood or saliva sample. The sample is then analyzed and compared to a database of known genetic sequences that cause the disease. The genes that make up the majority of the cases of genotype-positive HCM are the focus of genetic testing. They can be tested all at once using a panel test.
If someone has a relative who has had a positive test, a single gene test will likely be used instead. Although the phenotype (expression of the disease) may vary, the genotype (specific gene mutation) should be the same amongst affected first-degree family members.
Benefits of Genetic Testing
Early diagnosis improves the prognosis of HCM. Genetic testing can help to confirm a patient's diagnosis, as well as identify family members who may also be affected so that interventions can be started as soon as possible.
Dr. Weintraub explains that genetic testing is helpful as " itis very important to identify those at risk and to intervene and protect those from what could happen, if things go wrong". If identified early in disease progression, many patients can successfully manage their condition with lifestyle changes and have a normal life expectancy. The earlier the condition is identified, the more treatment options will be available.
Genetic testing is also beneficial to patients of reproductive age who may be planning to have children. People with HCM may choose to meet with a reproductive specialist, prior to conceiving, to discuss the likelihood that the condition is passed along to their offspring.
Genetic testing also helps improve our overall understanding of HCM. Discoveries on which specific mutations lead to the disease help cardiologists successfully screen patients. An understanding of the mutations that cause disease could also help to guide new novel treatment ideas for the future.
Moving Forward Questions to Ask Your Doctor
- Should I undergo genetic testing?
- Should I meet with a genetic counselor if I am planning to have children?
- Do I need to start treatment if I am positive for an HCM gene?
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