About Cascade Testing for Familial Hypercholesterolemia (FH)

What it is and why it's important

Although more than 1 million people in the US have familial hypercholesterolemia (FH), only about 30% know they have it. People with FH have increased blood levels of low-density lipoprotein (LDL) cholesterol, sometimes called "bad cholesterol." Having too much blood LDL cholesterol increases the risk for developing coronary artery disease or having a heart attack.

If you have FH, your LDL cholesterol levels are high starting at birth, unlike people who develop high LDL cholesterol later due to behaviors such as smoking or an unhealthy diet. This means that heart disease starts to develop earlier, making you more likely to have a heart attack at a younger age. The sooner a person with FH is identified, the quicker they can start taking medicine to lower their LDL cholesterol levels and reduce their risk of getting heart disease in the future.

How it works

If you have been diagnosed with FH, your parents, sisters, brothers, and children are at higher risk of having it too. Since FH is an inherited disorder, testing family members is an effective way of finding more cases of FH. The good news is they can be tested for FH through genetic testing, a blood cholesterol test, or both. This method of tracing FH through family members is called cascade testing.

Common questions

What are my family members’ chances of having FH?

If you have FH, the chance that your family member has FH depends on what kind of genetic change is found in your family and how closely related you are to your family member. If your genetic test results show that you have a known genetic change, family members who get genetic testing should be checked for the same genetic change. For every new person identified with FH, this process of testing family members is repeated.

FH can be caused by different genetic changes:

FH is most often caused by genetic changes in the LDLR, APOB, or PCSK9 genes. If you have a genetic change in one of these genes, you have heterozygous FH, the most common form of FH:

• Your mother, father, children, and siblings have a 1 in 2 (50%) chance of having FH.
• Your half-siblings, aunts, uncles, grandmother, and grandfather have a 1 in 4 (25%) chance of having FH.
• Your cousins and other more distantly related family members have a 1 in 8 (12.5%) or smaller chance of having FH.

Homozygous FH is a rare, more severe form of FH and is most often caused by genetic changes in both copies of the APOB, LDLR, or PCSK9 genes. If you have this form of homozygous FH:

• Your parents and children have heterozygous FH.
• Your siblings have a 1 in 2 (50%) chance of having heterozygous FH and a 1 in 4 (25%) chance of having homozygous FH.
• Your half-siblings, aunts, uncles, grandmother, and grandfather have a 1 in 2 (50%) chance of having heterozygous FH.
• Your cousins and other more distantly related family members have a 1 in 4 (25%) or smaller chance of having heterozygous FH.

Genetic changes in both copies of the LDLRAP1 gene can also cause homozygous FH, but people with the genetic change in only one copy of the LDLRAP1 gene will not have FH. If you have this form of homozygous FH:

• Family members such as your parents, children, and more distant relatives can have one copy of the genetic change but will not have FH (unless they inherit a genetic change in the other copy of the gene).
• Your siblings have a 1 in 4 (25%) chance of having FH.
• Family members with one copy of the genetic change could have a child with FH if the other parent also has a genetic change in one (or both) copies of the LDLRAP1 gene.

A healthcare provider such as a genetic counselor can help with personalized risk estimates for each person in your family. In addition to the genetic changes listed above, researchers have found other rarer genetic changes. Genetic testing might find one of these genetic changes in your family.

For some people with FH, genetic testing will not find a genetic change in any of the genes known to cause FH. This is because not all genetic changes that cause FH are known. Their family members may still be at increased risk for FH. In other people, many genetic changes together cause FH. In these cases, family members usually will not be at increased risk for FH.

Who should get tested?

Early diagnosis of FH can prevent heart attacks and death. Because people with FH have high LDL cholesterol starting from birth, genetic testing is recommended for family members of all ages. Genetic testing is the preferred method for diagnosis. Another option is blood work to check LDL cholesterol levels. This can be done even when the genetic cause of FH is unknown.

It is usually best to start testing family members who are most closely related to the person who was diagnosed with FH, such as their mother, father, siblings, and children. However, if a family member is not available for testing (for example, if a family member does not want to be tested or has died), then moving to more distant family members is also appropriate.

How do family members get genetic testing?

The genetic counselor or healthcare provider who diagnosed you might be able to help schedule genetic counseling and testing for your family members. Provide your genetic test report to any genetic counselor or healthcare provider who orders testing for your family. If free or discounted cascade testing for family members is limited to a certain amount of time from the first genetic test report, they might need a copy of your report to show the date of your test. Some insurance companies will cover genetic testing for families if a known genetic change is found. A genetic counselor or healthcare provider can give more information on coverage with your specific insurance.