Familial hypercholesterolemia: A complex genetic disease with variable phenotypes

Eur J Med Genet. 2020 Apr;63(4):103831. doi: 10.1016/j.ejmg.2019.103831. Epub 2019 Dec 25.


Familial hypercholesterolemia (FH) is the most frequent genetic disease and is characterized by elevation of LDL-cholesterol that accumulates in tissues leading to premature atherosclerosis and sometime tendon xanthomas. Main causes of FH are pathogenic variants in the genes encoding the LDL receptor (LDLR), its ligand - the apolipoprotein B (APOB) - or Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9). Rarer causes include variants in genes encoding apolipoprotein E (APOE) and the signal-transducing adaptor family member 1 (STAP1). Genetics of FH is extremely complicated by 1. high heterogeneity, 2. presence of variant clusters and 3. phenotypic variability. In fact, a great variability was observed among patients with the same genetic status: an overlap of LDL-cholesterol levels was observed between heterozygous patients (HeFH) and homozygous FH patients, as well as some HeFH showed a normal lipid profile. A correct pathogenicity evaluation is the first step to correctly define the genetic status helping to identify the variants which really cause the FH. Several phenotypic differences were observed among HeFH patients carrying different variant types (null or defective) or variants in different affected genes. Patients with a null variant in LDLR gene showed higher LDL-cholesterol levels and higher risk for coronary artery disease than patients with a defective variant. Pathogenic variants in several lipid-related genes causing different dyslipidemias were found among FH patients acting as both modifying factors (worsening the phenotype) and confounding factors (needing a differential diagnosis to be discriminated from FH). This review aims at depicting the complex genetic basis of FH.

Keywords: FH phenocopies; Familial hypercholesterolemia; Genetic heterogeneity; Lp(a); Modifier factors; Pathogenicity evaluation; Phenotypic variability.

Publication types

  • Review

MeSH terms

  • Cholesterol, LDL / blood
  • Humans
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / diagnosis
  • Hyperlipoproteinemia Type II / genetics*
  • Phenotype


  • Cholesterol, LDL