Clinical genetic testing provides improved diagnosis of FH
The Familial Hypercholesterolemia Foundation convened an international expert panel consisting of cardiologists, lipidologists, endocrinologists, genetic epidemiologists, molecular pathologists, patient representatives, nurses, genetic counselors and genetic testing experts, to compose a consensus statement on diagnosing familial hypercholesterolemia (FH) by using genetic testing.
In this document, they recommend that genetic testing should be the standard care for patients with definite or probable FH, as well as their at-risk relatives to reduce CV burden in families with FH. Testing should include the genes LDLR, APOB, PCSK9 and other genes based on patient phenotype. Furthermore, the panel elaborated on the steps leading to diagnosis of FH, pathogenic variants and higher CV risk asking for more aggressive lipid-lowering therapy, initiation and adherence to therapy and screening of at-risk relatives.
Recent research suggests that clinical genetic testing can contribute to better diagnosis of FH and detection of relatives at risk, leading to early initiation of lipid-lowering therapy and improved clinical outcomes.
Current diagnostic tools for FH rely on lipid levels, physical characteristics, premature CAD and family history with FH and/or CVD. However, the diagnostic efficacy of these tests is limited due to low sensitivity, resulting in underdiagnosis of FH and high CV burden.
FH is the most common genetic cause of CVD and it is therefore expected that genetic testing will facilitate the diagnosis of FH. The Dutch Lipid Clinic Network Diagnostic Criteria, the Simon Broome Register Diagnostic Criteria and the criteria presented in the 2015 American Heart Association scientific statement on FH all include genetic testing in establishing an FH diagnosis.
FH is often caused by pathogenic variants of LDLR, APOB and/or PCSK9, which have been associated with higher CVD risk. If these variants underlie FH, there is a need for aggressive LDL-lowering therapy. Identification of pathogenic variants in LDLR, APOB or PCSK9 points to a definite diagnosis of FH and has already been described as golden standard for FH diagnosis.
Genetic testing has been shown to have a positive effect on initiation and adherence to lipid-lowering therapy. Also, psychological adverse effects have not been observed in genetic testing.
More research is needed to investigate the value of genetic testing in specific subgroups of FH patients, including those in whom polygenic risk factors appear to play a role and those with disturbances in other metabolic pathways underlying their elevated LDL-c levels/CV risk.