The genetics of hypertrophic cardiomyopathy 

A gene is the basic unit of heredity. Genes are made up of DNA. DNA (Deoxyribonucleic acid) is the molecule that carries genetic information. Genes are packaged in structures called chromosomes. The gene is a specific section of DNA within a chromosome. There are hundreds of genes on each chromosome. Each of our genes has a specific code which provides the instructions for building a protein. In the case of HCM these proteins are related to heart muscle structure. An alteration in the code of a gene is called a mutation when it has been proven to cause disease. Mutations in one of several genes can cause familial hypertrophic cardiomyopathy; the most commonly involved genes are MYH7, MYBPC3, TNNT2,  TNNI3 TPM1, ACTC1, MYL7 and MYL2. Other genes, including some that have not yet been identified, may also be involved in this condition.

Inheritance and family history

Hypertrophic Cardiomyopathy (HCM) is usually caused by abnormal genes (gene mutations) that cause the heart muscle to grow abnormally thick. This condition is most commonly inherited in an autosomal dominant inheritance pattern. In a dominant condition only one copy of a gene pair needs to be altered in order for the person to be at risk for developing the condition. 

Every person has two copies of each gene. One we have inherited from our mother and one we have inherited from our father. When we have our children, we pass half of our genetic information onto our children. Each child you have can inherit either copy of your gene pair. This means that each first degree relative (parents, siblings, children) of a person who has HCM has a 50% chance of inheriting the altered copy of the gene.

Like other dominantly inherited genetic disorders there is reduced penetrance and variable expressivity of this condition in families. Reduced penetrance means that not everyone who inherits the genetic mutation will show signs or symptoms of HCM. People talk about conditions skipping generations. The genetic mutations do not skip generations, but the expression of the disease sometimes does. Some people can carry the genetic mutation but never show signs of HCM.

Variable expressivity means the condition can look different in different family members. Some may be mildly affected and other family members with the same genetic mutation may have significant symptoms. This is because the rest of their genetic makeup is different and their environments are different. 

Reviewing a person’s family history is an important part of the genetic counselling process as it allows us to determine if there are other affected family members as well as identify at risk family members who may wish to have screening for HCM. In addition to isolated cases of HCM there are genetic syndromes in which HCM may be a feature (e.g., Noonan syndrome, Fabry disease). Review of the family history, genetic counselling and genetic testing can be helpful in identifying if a genetic syndrome is the cause of the HCM in the family.

Genetic Testing

Genetic testing is offered to people diagnosed with HCM to see if the genetic mutation that is the cause of their HCM can be identified. If so, we have an accurate way to test unaffected family members who wish to know if they too have inherited a genetic predisposition that could cause them to develop HCM.

In some family’s hypertrophic cardiomyopathy is caused by identifiable gene mutations However, not all people who have a clinical diagnosis of HCM will have an identifiable genetic mutation. We currently identify the genetic cause in less than 50% of people affected with HCM.  Sometimes the cause is not clear. It maybe multifactorial, meaning there are genetic and non-genetic causes combined. In these cases, the risk to other family members would be lower but as we currently have no way to test for this, we recommend cardiac screening for all first-degree relatives. 

Family Screening

Early identification of HCM provides the best opportunity to implement clinical and lifestyle management strategies improving clinical outcomes for people and potentially reducing mortality. It is therefore important that at risk family members are made aware that this is an inherited condition. 

Cardiac hypertrophy can begin in adolescence or young adulthood, but it can develop at any time throughout life and is most often picked up later in life with the average age of diagnosis being 39. HCM is usually more severe if diagnosed during childhood. Generally, we recommend screening children in an HCM family around the age of 10-12 years old. Screening can be offered to younger children especially is there is a family history of sudden death or if the child is involved in competitive sports. 

In families with an identified familial mutation, at risk family members can be offered genetic testing. This is done by either a blood or saliva test. Inheriting the genetic mutation does not mean a person will develop HCM but it does mean they are at increased risk and require appropriate cardiac surveillance. If the individual has not inherited the familial mutation, they do not require cardiac screening and their children are also not at increased risk to develop HCM. 

In families that do not have an identifiable familial mutation we recommend first degree relatives have cardiac screening to look for clinical signs of HCM. Cardiac screening should include an echocardiogram, a Holter monitor and an ECG. This should be done every 3-5 years as this condition can develop at any age.