Heritable Mutations associated with Familial Hypercholesterolaemia

Sharon Kessels, Skye Newton, Arlene Vogan, Ruchi Mittal, Camille Schubert, Drew Carter, Benjamin Ellery, Tracy Merlin
Record ID 32018000219
Original Title: Clinical Utility Card Application 1534
Authors' objectives: 1. To determine the safety, effectiveness and cost-effectiveness of testing for heritable mutations in the LDLR, PCSK9 and APOB genes in individuals strongly suspected of or clinically diagnosed with familial hypercholesterolaemia (FH), compared with the usual standard of care without genetic testing.2. To determine the safety, effectiveness and cost-effectiveness of cascade testing for a known familial FH mutation in first, second and/or third[1] degree family members of an index case with an identified pathogenic FH mutation in the LDLR, PCSK9 or APOB gene, compared with no genetic cascade testing. [1] The base case includes first and second degree relatives, however evidence on third degree relatives was also considered (if available).
Authors' results and conclusions: Comparative Safety - Very few studies reported on the impact of genetic testing of affected individuals for familial hypercholesterolaemia (FH). One qualitative study reported that genetic testing provided very little new insight or personal benefit to affected individuals, but the authors believed there may be a benefit for family members. No studies were identified on the safety and/or physical harms from genetic testing for FH. Comparative Effectiveness - The genetic tests currently used to identify FH are sensitive and specific in the populations in which they were tested, and detected almost all mutations they were designed to detect. No studies were identified that assessed the analytical sensitivity and specificity of cascade testing, however the accuracy would be close to 100%, as methods used for testing for a known mutation are able to be tailored to ensure the mutation is found (if it exists). The risk of premature cardiovascular disease (CVD) and/or CVD events was higher in patients with an identified mutation, compared with the risk in patients without an identified mutation. Some studies reported higher odds ratios when patients were diagnosed with a specific mutation (e.g. D374Y in the PCSK9 gene), relative to other mutations. A single before and after case series in affected individuals reported that patients who received a genetic diagnosis of FH were more likely to take lipid lowering treatment (LLT) after diagnosis. In family members, a large volume of evidence of before and after case series was consistent that having a FH mutation will 1) result in most patients seeing a physician regarding their FH. 2) increase the intensity or rate of LLT (i.e. increase the proportion of patients receiving LLT and, for 30% of those already on LLT, it will increase the dose), and 3) marginally reduce the smoking rate and lead to a change in diet in around a third of patients. Further evidence support the effectiveness of LLT for reducing low density lipoprotein (LDL) cholesterol. Lower LDL cholesterol results in fewer coronary or vascular events, and reduced mortality. These results indicate that if FH mutations testing is performed then there will be changes in patient management and potential benefits in terms of the prevention of cardiovascular events. However, what is not clear is whether these changes occur anyway as a consequence of standard clinical practice where patients (and their family members) with hypercholesterolaemia are identified on the basis of clinical criteria. The critical clinical utility uncertainty for FH genetic testing in Australia is the added value of genetic testing over the standard practice management of patients with FH.
Project Status: Completed
Year Published: 2019
English language abstract: An English language summary is available
Publication Type: Not Assigned
Country: Australia
MeSH Terms
  • Hypercholesterolemia
  • Genetic Testing
  • Cholesterol
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Biomarkers
  • Genetic Predisposition to Disease
  • Hyperlipoproteinemia Type II
  • Predictive Value of Tests
  • Mutation
Organisation Name: Adelaide Health Technology Assessment
Contact Address: School of Public Health, Mail Drop 545, University of Adelaide, Adelaide SA 5005, AUSTRALIA, Tel: +61 8 8313 4617
Contact Name: ahta@adelaide.edu.au
Contact Email: ahta@adelaide.edu.au
Copyright: Adelaide Health Technology Assessment (AHTA)
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