Familial hypercholesterolaemia

This is an overview of a condition called “familial hypercholesterolaemia”. This information should not replace assessment and advice from your doctor. Please address any questions or concerns to your doctor.

What is familial hypercholesterolaemia (FH)?

Cholesterol is a naturally-occurring substance in blood. It is important for making cells, and some hormones such as vitamin D. The liver is responsible for making and regulating cholesterol. The level of cholesterol in the blood varies with diet, age, medications, illnesses and inherited (familial) factors. The risk of heart attack and stroke are increased if the level of cholesterol is raised. Having a raised level of cholesterol is called hypercholesterolaemia.

Doctors recommend that the cholesterol levels be checked regularly in adults. Lifestyle changes or medication can be used to keep the level of cholesterol within the low-risk range.

Genes also affect the level of cholesterol in the blood. Most people with raised cholesterol levels have a condition called multifactorial or polygenic hypercholesterolaemia. This is where many genes have changes that impact the way they function. Each of these genetic changes causes a small change in cholesterol, and together these multiple changes cause hypercholesterolaemia.

There are some people who have hypercholesterolaemia because of a change in just one gene that stops the gene from working correctly. Hypercholesterolaemia that is due to an error (variant) in single gene is called “familial hypercholesterolaemia”, or “FH”. It is called familial because this variant is inherited i.e. passed from parent to child.

How common is FH?

FH is one of the most common genetic disorders in our community. It affects 1 in 250 people. This amounts to 100,000 people with FH in Australia. To date,  approximately 90,000 people with FH in Australia are undiagnosed.

Why is FH important?

  • A person with FH requires earlier and stronger treatment to bring the cholesterol level down.
  • A person with FH can receive special drugs on the Pharmaceutical Benefits Scheme (PBS) that may be necessary to control their cholesterol level.
  • A person who is identified with FH and managed accordingly has a much lower chance of developing serious complications e.g. a heart attack.

FH is also important for the patient’s family. The chance that a child, parent, brother or sister of the patient with FH also has FH is up to 50% (1 in 2). There is also a significant risk for other relatives (see below). Diagnosing FH in a relative can mean early and effective treatment to prevent complications.

Why is Familial hypercholesterola important?

What tests are used to diagnose FH?

FH can be clinically diagnosed using a combination of medical history, family history, the doctor’s clinical examination and measurement of cholesterol level in blood. However, genetic testing provides a definitive diagnosis of FH, and helps to define a person’s risk of serious complications such as heart disease or stroke. There are currently over 2,000 different genetic variants that cause FH. Sonic Genetics can identify these using specialised testing.

Who should be tested for FH?

The Australian Department of Health recommends that a person who fulfils one or more of the following conditions be tested for FH:

  1. a person having an LDL-cholesterol level of 6.5 mmol/l or more; or
  2. a person having an LDL-cholesterol level of 5.0 mmol/l plus clinical features suggestive of complications due to FH; or
  3. a person having a combination of clinical features, laboratory results, family history that categorises them as have “probable or definite FH” according to an internationally accepted scoring system known as the Dutch Lipid Clinic Network score; or
  4. a person with a first- or second-degree relative who has a genetic diagnosis of FH.

>Your doctor may also recommend testing of a person who does not fulfil any of these criteria.

What does the genetic test for FH cost?

Medicare covers the cost of genetic testing for FH in the four situations specified above. Sonic Genetics also provides genetic testing for a private fee if you do not meet these criteria. Your doctor will inform you FH is likely and the cost, if any, of genetic testing. 

How can a patient at risk of FH arrange for genetic testing?

Your general practitioner (GP) will check your cholesterol levels, medical history, and family history to assess the possibility of FH. We recommend that patients with a possibility of FH are referred to a doctor specialising in lipid disorders for review and consideration of genetic testing. Medicare rebated genetic testing must be requested by a medical specialist.

Is genetic counselling required for genetic testing for FH?

Genetic testing can raise a number of important issues that should be discussed before testing. Pre-test genetic counselling can give you an opportunity to learn and ask questions about what is involved in the test and how it might impact both you and your family. We recommend that these discussions be managed either by an FH specialist or by a genetic counsellor before you have the test.

Sonic Genetics offers genetic counselling on request by your doctor. This counselling is provided by phone or video link within a few days of the request being received, and at no additional cost.

Sonic Genetics offers post-test genetic counselling on request by your doctor. This, too, is provided by phone or video link after you have received your result and at no additional cost. Post-test genetic counselling can help to understand what the results means for you and your family. It can help you prepare for talking to your family about how the result impacts them. Post-test genetic counselling doesn’t replace your doctor’s management of FH. It is essential that you also discuss these results with your doctor. 

What results could I expect from my genetic test?

The different results you may get from genetic testing for FH will depend on the type of testing you have.

  • If you are the first person in your family having genetic testing because your doctor has suspected FH, this is called diagnostic testing.

Diagnostic test

Diagnostic testing refers to the initial test of the four genes on our panel that is performed for a person with FH.  This test is designed to discover which gene is involved in causing FH in that family.

If the test result is that a pathogenic mutation has been found, this confirms that you have a genetic diagnosis of FH. Your doctor will have clear management guidelines to follow. This genetic diagnosis can be used by your family members for cascade testing.

If no pathogenic mutation is detected, the test report will outline one of the following outcomes:

  • No variation was found in any of the genes that were screened.
  • A variation was found in one or more of the genes, and the current scientific information clearly classifies this variation as being benign i.e. not causing any disease.
  • A variation was found in one or more of the genes, but there is insufficient scientific information to clearly classify this variation as being either benign or pathogenic. This is referred to as a “variant of uncertain significance” or “VUS”. This is a common finding in genetic testing because our understanding of genetics is still developing. Over time, a VUS may be reclassified in the scientific literature as benign or pathogenic. Sonic Genetics does not routinely review the reports of all VUSs and issue amended reports. However, we would be pleased to review the significance of a VUS on request from the patient’s doctor.

These three outcomes (normal gene sequence, benign variation, and VUS) do not identify the underlying cause of the patient’s hypercholesterolaemia. Such a result does not exclude the possibility of there being a single gene mutation responsible for hypercholesterolaemia, but it makes it unlikely. Benign variations or VUSs cannot be used by your family members for cascade testing.

Cascade test/Predictive test

If there has been a genetic diagnosis of FH in your family, a cascade test will determine whether you have the same pathogenic mutation already identified in another family member. A cascade test does not examine the entire gene sequence of the four genes known to cause FH.

Once the abnormal gene has been identified, a direct test for just that gene can be offered to family members. This is called cascade testing. If the relative being tested is unaffected, the cascade test is described as a predictive test. If the relative is already suspected of having FH, the cascade test is described as a confirmatory test. In each case, the cascade test is limited to just the abnormal gene identified in the first family member. 

There are two possible results from this type of testing:

  • You have inherited the family’s mutation. This means that you have a genetic diagnosis of FH. Your doctor can follow clear management guidelines for people with genetically confirmed FH. This may include further tests, lifestyle changes and medications. Your first- and second-degree relatives should also consider cascade testing.
  • You have not inherited the family’s mutation. You do not have a genetic diagnosis of FH. Your doctor may still need to check your cholesterol level, and will advise you if any further tests or treatment are recommended.

What should be done if the FH genetic test does not find an abnormality?

A pathogenic mutation is not identified in up to 10% of people with definite clinical diagnosis of FH. If you have hypercholesterolaemia and we are not able to identify a pathogenic mutation, you may be one of those people. However, it is more likely that you have the more common diagnosis of “polygenic hypercholesterolaemia” i.e. a combination of multiple gene variants which together increase the chance of you developing hypercholesterolaemia.

Your specialist will be able to identify which diagnosis applies to you. Your specialist will also look for other possible causes of hypercholesterolaemia. Your hypercholesterolaemia still needs to be treated, even if a genetic cause is not identified. Your doctor will advise what further tests, lifestyle changes or medications are recommended in your situation.

What should be done if the FH genetic test finds an abnormality?

If the result of your FH genetic test is that a pathogenic mutation has been found, this confirms that you have a genetic diagnosis of FH. All people with a genetic diagnosis of FH develop hypercholesterolaemia if left untreated. Your doctor will advise what further tests, lifestyle changes and medications are recommended for you.

Should family members be tested for FH?

FH runs in the family. It is usually passed on in an “autosomal dominant” pattern; this technical term describes the pattern of inheritance of FH within the family. Once you have a genetic diagnosis of FH,

  • there is a 50% (1 in 2) chance that a first-degree relative has the pathogenic mutation and will develop hypercholesterolaemia. First-degree relatives include parents, brothers, sisters and children
  • there is a 25% (1 in 4) chance that a second-degree relative has the pathogenic mutation and will develop hypercholesterolaemia. Second-degree relatives include grandparents, grandchildren, aunts, uncles, nieces and nephews.

This pattern does not skip generations. If a second-degree relative has the family’s pathogenic mutation, then the person connecting the relatives will also have the mutation and should be tested.

We strongly recommend that your first- and second-degree relatives have a genetic test for FH, preferably by the age of 10 years. We call this process of testing family members “cascade testing”. Sonic Genetics can assist you in discussing cascade testing with family members.

The cost of this test is covered by Medicare.

Can FH affect children?

Yes, children with FH can develop hypercholesterolaemia during childhood. Early treatment has been shown to manage cholesterol levels and reduce the chance of cardiovascular disease in later life. Both national and international guidelines recommend that children in a family with FH be tested by 10 years of age.

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