Genetic testing for familial hypercholesterolemia—past, present, and future

In the early 1980s, the Nobel Prize winning cellular and molecular work of Mike Brown and Joe Goldstein led to the identification of the LDL receptor gene as the first gene where mutations cause the familial hypercholesterolemia (FH) phenotype. We now know that autosomal dominant monogenic FH can be caused by pathogenic variants of three additional genes (APOB/PCSK9/APOE) and that the plasma LDL-C concentration and risk of premature coronary heart disease differs according to the specific locus and associated molecular cause. It is now possible to use next-generation sequencing to sequence all exons of all four genes, processing 96 patient samples in one sequencing run, increasing the speed of test results, and reducing costs. This has resulted in the identification of not only many novel FH-causing variants but also some variants of unknown significance, which require further evidence to classify as pathogenic or benign. The identification of the FH-causing variant in an index case can be used as an unambiguous and rapid test for other family members. An FH-causing variant can be found in 20–40% of patients with the FH phenotype, and we now appreciate that in the majority of patients without a monogenic cause, a polygenic etiology for their phenotype is highly likely. Compared with those with a monogenic cause, these patients have significantly lower risk of future coronary heart disease. The use of these molecular genetic diagnostic methods in the characterization of FH is a prime example of the utility of precision or personalized medicine.