Genetics of familial hypercholesterolemia

Curr Atheroscler Rep. 2015 Apr;17(4):491. doi: 10.1007/s11883-015-0491-z.


Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics.

Publication types

  • Review

MeSH terms

  • Apolipoprotein B-100 / genetics
  • Cholesterol Ester Storage Disease / diagnosis
  • Diagnosis, Differential
  • Genetic Counseling
  • Genetic Predisposition to Disease
  • Genetic Testing
  • Humans
  • Hypercholesterolemia / diagnosis
  • Hyperlipoproteinemia Type II / diagnosis
  • Hyperlipoproteinemia Type II / genetics*
  • Intestinal Diseases / diagnosis
  • Lipid Metabolism, Inborn Errors / diagnosis
  • Phytosterols / adverse effects
  • Proprotein Convertase 9
  • Proprotein Convertases / genetics
  • Receptors, LDL / genetics
  • Serine Endopeptidases / genetics
  • Xanthomatosis, Cerebrotendinous / diagnosis


  • APOB protein, human
  • Apolipoprotein B-100
  • LDLR protein, human
  • Phytosterols
  • Receptors, LDL
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases

Supplementary concepts

  • Sitosterolemia