Table 1

Genetic Causes of Familial Hypercholesterolemia Phenotypes

I. Molecular Defects in the Low-Density Lipoprotein Receptor Pathway
  • Deletion, missense, nonsense, and insertion mutations in low-density lipoprotein receptor (LDLR) affecting receptor function (>1,600 mutations reported to date);

  • Mutations in apolipoprotein B (APOB) that affect the ability of the ligand to recognize LDLR (most commonly a single base change at position 3,500);

  • Gain-of-function mutations in PCSK9 causing a reduction in LDLR on the cell surface;

  • Mutations in LDLR accessory protein 1 (LDLRAP1) causing improper placement of LDLR on the hepatocyte membrane (a rare and recessively inherited form).

II. Polygenic Hypercholesterolemia
III. Other Monogenic, Epigenetic, and Nongenetic Forms (yet to be discovered)