Diagnostic Use
This test includes analysis for three genes where mutations can cause lifelong high cholesterol:
– Low density lipoprotein receptor (LDLR)
– Apolipoprotein B (relevant exons)
– PCSK9 (proprotein convertase secretase kexin 9) (relevant exons)
Note: requests for LDL and apolipoprotein B quantitation (apoB) are different non-genetic tests, and these do not require pathologist approval.
Interpretation
This test is vetted by a pathologist.
Monogenic mutations in one of three important genes in cholesterol metabolism can lead to lifelong elevation of cholesterol, predisposing to early development of atherosclerosis and CVD. The three genes tested for are the LDL receptor (LDLR), apolipoprotein B and PCSK9 (relevant exons). The condition has autosomal co-dominant inheritance, with population frequency estimated around 1:250.
Many, but not all FH carrier patients have very high LDL. A strong family history of high LDL cholesterol and early CVD are important ‘alerts’ to the possibility. Other ‘tell tale’ signs include tendon xanthomas and early development of arcus senilis in the cornea (underage 45yr), although these are less often present in children. Presence of high triglycerides is not a typical feature. While other CVD risk factors may be present, these are often less prominent for the degree of atherosclerosis identified clinically compared with patients of similar age 32 .
Genetic testing for familial hypercholesterolaemia (FH) is a very expensive test and the frequency of identification depends on the prior likelihood of finding a genetic cause. Several scoring systems to identify risk of FH have been used internationally, but the one commonly used in Australasia is based on the Dutch Lipid Clinic Score 33 . For Children the European Atherosclerosis Society guidelines are used. Only requests where this score shows a high probability of FH are performed 34 .
FH genetic tests will be approved if:
- The request is made by, or discussed with, an approved specialist (Cardiologist, Endocrinologist, Metabolic Physician, Chemical Pathologist), AND
- The patient has no identified likely secondary cause (hypothyroidism, significant liver (hepatobiliary disease), nephrotic syndrome, steroid treatment (pharmacological doses), AND
- No familial genetic mutation has already been identified (risk management of such patients should be based on their lipid profile), AND
- The patient is an adult with Dutch Lipid Clinic Score (DLCS) of at least 6, or a child meeting the guidelines of the European Atherosclerosis Society.
All requestors must complete the approval form (can be downloaded as pdf document – see link below) . Both the first page AND completed scoring chart (either Adult on page 2, or Child on page 3) with full clinical details are required. (TWO PAGES TOTAL). For help with DLCS score, refer to Australasian Atherosclerosis FH calculator tool,
A. The completed approval form should preferably accompany the standard laboratory request form (which should state? Familial Hypercholesterolaemia (FH) Gene Test?) at the time of blood collection.
B. Alternatively, the completed approval form can be scanned (as pdf format) and emailed to
chemicalpathologist@adhb.govt.nz . Subject of the email should be
‘FH Gene Test ” and also include the
patient’s NHI.If the completed approval form does not accompany the sample, a notification will be sent requesting its completion.
As the sample storage integrity is limited, the sample will only be kept for ten days. If the approval form is not received before then, even if the approval criteria are fulfilled the sample will be discarded and a recollect will need to be arranged.