Familial hypercholesterolaemia

Clinicians will be familiar with the lifestyle factors that contribute to hypercholesterolaemia and can be modified to reduce the level of cardiovascular risk.

However, multiple studies have shown that clinicians may be less familiar with the potential genetic basis of hypercholesterolaemia and its relevance in the management of cardiovascular risk. This is especially relevant for familial hypercholesterolaemia (FH), the most common autosomal dominant lipid disorder.

Genetic testing has a key role in the management of hypercholesterolaemia and, in certain circumstances, it can now be rebated by Medicare.

This page provides an overview of the use of genetic testing in the management of hypercholesterolaemia, and references to more detailed information. We also provide two video presentations about familial hypercholesterolaemia, a short general overview and a more detailed presentation, at the bottom of this page.

What is familial hypercholesterolaemia?

There are multiple genes that influence serum cholesterol concentration. Some of these genes have a direct role in cholesterol metabolism, while others have an indirect relationship with hypercholesterolaemia.

For most patients with hypercholesterolaemia, the genetic component of their disorder reflects the relatively small and indirect contributions of multiple genes. This is called “polygenic hypercholesterolaemia”. Because of the number of genes involved, this genetic predisposition does not carry strong clinical implications for relatives i.e. a relative is unlikely to have the same combination of gene variants as the affected patient. Nonetheless, the relatives will still warrant testing for raised cholesterol profile in their own right simply because the frequency of this condition.

However, some patients will have familial hypercholesterolaemia due to a mutation in a single gene that is directly involved in low-density lipoprotein cholesterol (LDL-c) catabolism. Because this disorder is caused by a single gene, the diagnosis in a patient has significant implications for close relatives.

How common is FH?

FH is one of the most common autosomal dominant disorders, affecting 1 in 250 people. This amounts to around 100,000 people in Australia. The frequency is higher in certain ethnic groups.

Approximately 90% of people with FH in Australia remain undiagnosed (~90,000 people).

Why is FH important?

The diagnosis of FH is important for the patient because

  • patients with FH require earlier and more aggressive therapy to control their hypercholesterolaemia and reduce the risk of heart disease
  • patients with FH are eligible for selected medications on the PBS that may be necessary to achieve that control, and
  • patients who are identified as having FH and managed accordingly achieve better clinical outcomes than patients with comparable cholesterol levels who are not identified as having FH

FH is also important for the patient’s family because, in many cases the disorder is inherited as an autosomal dominant disorder, meaning that it is due to a single mutation in a gene. The children, siblings and parents of the index patient are at 50% risk of having the same mutation and developing hypercholesterolaemia. A genetic diagnosis of FH provides an opportunity to intervene and manage hypercholesterolaemia before irreversible cardiovascular damage has occurred.

Studies have documented that diagnosing and managing FH results in better outcomes for patients and families, and saves costs for the healthcare system. For that reason, Medicare now rebates genetic testing for FH.

What tests are used to diagnose FH?

FH can be clinically diagnosed using various combinations of clinical, biochemical and genetic information, although genetic testing is regarded as the gold standard.

The combination of personal and family history of early cardiovascular events, the patients LDL-c and clinical evidence of cholesterol accumulation e.g. tendon xanthomata or corneal arcus, may be sufficient to make a clinical diagnosis of FH.

Elevated LDL-c may be suggestive of FH, depending on the degree of elevation after excluding secondary causes of hypercholesterolaemia such as nephrosis, hypothyroidism and cholestasis. It is important to note that the biochemical features of FH may be masked by treatment with statins.

The combination of family history, clinical features, and biochemistry can be integrated using an algorithm such as the Dutch Lipid Clinic Network (DLCN) score that provides a measure of the likelihood that the patient has FH.

Genetic testing is conclusive in diagnosing FH by identifying a pathogenic mutation in a single gene that is known to cause the disorder. Comprehensive genetic testing for FH includes analysis of the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. Mutations in these genes cause autosomal dominant FH. We also screen patients for mutations in LDLRAP1, a rare cause of autosomal recessive FH. The turnaround for testing is 4 - 6 weeks.   

Who should be tested for FH?

Medicare rebates genetic testing for FH requested by a specialist in patients with

  • a Dutch Lipid Clinic Network score of 6 or more; or
  • an LDL-c concentration of 6.5 mmol/L or more in the absence of secondary causes; or
  • an LDL-c concentration of 5.0 mmol/L or more and signs of premature/accelerated atherogenesis.

Once a mutation has been identified in a patient, Medicare also rebates genetic testing for the variant identified in the family member in their first- and second-degree relatives (cascade testing). Cascade testing may be requested by any doctor caring for the person being tested.

Testing of patients who do not fulfil these criteria may be available for a private fee; please refer to our test summary for current pricing. Clinicians may consider genetic testing for a patient who does not meet the Medicare criteria but could be at high risk of FH; this may be relevant if family history is not available.

How does a patient get tested for FH?

Medicare-rebated diagnostic genetic testing for an index case (the first person to be tested for FH in a family/kindred) is only available on request by a specialist. Patients who fulfil one or more of the Medicare criteria listed above should be referred to a physician with expertise in lipid disorders such as a cardiologist, endocrinologist or other appropriate specialist. To assist, please provide the result of recent testing of fasting total cholesterol, LDL-c, HDL-c and triglycerides and indicate the Medicare criteria that the patient fulfils. In addition, we recommend measurement of fasting lipoprotein a (Lp(a)), as abnormalities in this can both mimic FH and increases the cardiovascular disease (CVD) risk in patients with FH. Testing of Lp(a) is currently not rebated by Medicare.

For patients who do not fulfil the Medicare criteria, or who do not wish to be referred to a specialist, we provide testing for a private fee; please refer to our test summary for current pricing.

When requesting genetic testing for FH, please specify the Dutch Lipid Clinic Network score, LDL-c concentration and any relevant clinical features. You may use a standard request form or a specific Familial hypercholesterolaemia request form. If the requester has provided pre-test genetic counselling (see below), please include a signed copy of the Sonic Genetics consent form.

Is genetic counselling required when genetic testing for FH?

Genetic testing for a familial disorder can raise clinical, psychological, social, and financial issues that merit careful pre-test discussion. We recommend that such pre-test discussions be managed either by a specialist experienced in the management of FH or by a genetic counsellor.

If pre-test counselling is provided by the requesting doctor, please confirm the patient’s consent by using the Sonic Genetics consent form. Other request forms may not necessarily be accepted as we require consent for specific matters that are detailed on our form.

Sonic Genetics can also provide pre-test genetic counselling on request. This is provided by a certified genetic counsellor by phone or video conference, usually within a few days of the request being received, and at no additional cost to the patient (conditions apply). Please refer to the test summary for details about arranging genetic counselling.

What should be done if the FH genetic test does not find a mutation?

The absence of a definite mutation in LDLR, APOB, PCSK9 and LDLRAP1 makes it much less likely that the patient has FH. However, a clinical diagnosis of FH is not necessarily excluded because ~10% of patients with clinically definite FH have normal genetic studies. For patients with a Dutch Lipid Clinic Network score less than six, the lack of an identified mutation means that it is more likely that they have a combination of multiple variants in different genes i.e. polygenic hypercholesterolaemia, elevated Lp(a) and/or environmental factors. These patients should be managed as per their absolute CVD risk as determined by the treating specialist.

Despite the absence of a definite mutation, the patient’s hypercholesterolaemia needs to be managed in its own right. If not already tested, we recommend analysis of the Lp(a) level as this is an independent inherited risk factor for CVD and can both mimic FH and elevate the CVD risk further in patients with FH. Knowing the Lp(a) level can inform therapy. For further advice about the subsequent management of such patients, please contact us. Screening of immediate family members for hypercholesterolaemia by measuring LDL-c levels is recommended.




What should be done if the FH genetic test result is abnormal?

The presence of a definite mutation in LDLR, APOB, or PCSK9, or of two mutations in LDLRAP1, is sufficient to make a genetic diagnosis of FH. Almost all patients with such a genetic diagnosis will have or will develop clinically significant hypercholesterolaemia that requires substantial intervention.

The patient’s hypercholesterolaemia needs to be managed in its own right. If not already tested, we recommend analysis of the fasting Lp(a) level as the result can inform therapy. For further advice about the subsequent management of such patients, please contact us.

Should family members be tested for FH?

Mutations in in LDLR, APOB and PCSK9 are inherited in an autosomal dominant fashion. The first- and second-degree relatives of the index patient are at 50% and 25% risk (respectively) of inheriting the abnormal gene and developing clinically significant hypercholesterolaemia.

Testing of first- and second-degree relatives for the family’s mutation is rebated by Medicare, and treatment for those with the mutation is both effective and provided through the Pharmaceutical Benefits Scheme. It is recommended that these relatives be tested, preferably by the age of 10 years.

With the consent of the index patient, and the approval of the patient’s doctor, Sonic Genetics will assist in notifying relatives of the availability of this testing. This service is provided at no charge and without obligation.

As noted above, cascade testing of first- and second-degree relatives for the family’s mutation is rebated by Medicare. Genetic counselling can be provided by Sonic Genetics by telephone, and at no cost to the patient. Requests can be made by either a general practitioner or specialist.

To request testing, you may use a standard request form or the specific Familial hypercholesterolaemia request form. Please include a copy of the index patient’s laboratory report or other documentation regarding the specific details of the family’s mutation.

Can FH affect children?

Yes, children who have inherited a mutation which causes FH can develop hypercholesterolaemia during early childhood. Prompt identification and treatment has been shown to reduce the risk of cardiovascular disease in later life.

Australian guidelines recommend that children at risk of inheriting a mutation responsible for FH be tested by 10 years of age.

What is homozygous FH?

In rare instances, a person may inherit an autosomal dominant FH mutation from each parent resulting in “homozygous FH”. This causes a more severe form of hypercholesterolaemia, and is not considered further in this document.  


Other resources for doctors, patients, and families



For more training videos on this subject and other genetic tests, please visit our Doctor Education website