Genetic testing for familial hypercholesterolaemia

Abstract

Familial hypercholesterolaemia (FH) is a codominant genetic disorder causing premature atherosclerotic cardiovascular disease (ASCVD). It is common, affecting 1 in 250 individuals worldwide and of the ∼100,000 Australians estimated to have FH, most are undiagnosed and treatment is often suboptimal. Several scoring algorithms based on low-density lipoprotein-cholesterol (LDL-C) levels, physical findings, and elements of personal and family history, help clinicians diagnose FH at varying levels of confidence ranging from possible to definite. Targeted DNA sequencing to identify the underlying pathogenic variant in any of the three FH genes (LDLR, APOB, and PCSK9) has become more accessible, but it is not essential for diagnosis of FH, and is currently not widely used. However, identification of a pathogenic variant is considered the ‘gold standard’ for FH diagnosis. Expanded FH panels can identify pathogenic variants in other hypercholesterolaemia genes, such as APOE, LIPA, and ABCG5/8. FH cascade screening is recommended to identify affected family members, and the benefits of early intervention to lower LDL-C and reduce the associated ASCVD burden are clear. National registries can also play a key role in identifying patients with FH. FH genetic testing should be incorporated as standard of care for patients and their relatives with suspected FH.