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Homozygous Familial Hypercholesterolemia

Information for
Healthcare Professionals

85–90% of HoFH patients have pathogenic variants in the LDLR gene1,2

Watch this 2-minute video on the HoFH mechanism of disease.

HoFH is associated with pathogenic variants of several genes affecting LDL receptor (LDLR) activity2,3

The majority of LDL is cleared from the plasma by LDLRs located on the cellular membranes of the liver cells3

These pathogenic variants affect different aspects of LDLR function and can be broadly categorized into six classes:3

  • Absent synthesis of LDLR or precursor protein
  • Defective LDLR transport from the endoplasmic reticulum
  • Impaired binding to LDL
  • No LDLR/LDL internalization because of defective clustering in clathrin-coated pits
  • No LDLR recycling
  • Failed LDLR transport to the surface of the cell membrane

Pathogenic variants in other genes impairing LDLR function have also been identified in patients with HoFH:3,4

  • APOB: Gene encoding apolipoprotein B
  • LDLR: Gene encoding the low-density lipoprotein receptor
  • LDLRAP1: Gene encoding low-density lipoprotein receptor adaptor protein 1
  • PCSK9: Gene encoding proprotein convertase subtilisin/kexin type 9 protein (PCSK9)

APOB = apolipoprotein B; LDLR = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9; LDLRAP1 = low-density lipoprotein receptor adapter protein 1; FH = familial hypercholesterolemia; ARH = autosomal recessive hypercholesterolemia

Pathogenic variants cause LDL pathway dysfunction and reduce removal of LDL-C from the blood, leading to premature atherosclerosis and cardiovascular complications1,3-5

This figure applies to FH in general.

Genetic Criteria

Genetic confirmation of bi-allelic pathogenic/likely pathogenic variants on different chromosomes at the LDLR, APOB, PCSK9, or LDLRAP1 genes or >2 such variants at different loci.6

LDLR-deficient pathogenic variants are associated with little or no LDL binding and uptake3

Compared with patients who are double LDLR-defective and LDLR-defective + LDLR-deficient, patients who are double LDLR-deficient (null/null) present with:3,6-8

  • Higher LDL-C
  • Higher incidence of CVD
  • Worse prognosis
  • Reduced response to drug therapy

The majority of LDL is cleared from the plasma by LDLR located on the cellular membranes of the liver2

CVD-free survival in HoFH patients in the SAFEHEART registry8*

*The SAFEHEART registry is a nationwide registry that includes FH patients living in Spain. Patients are enrolled and followed-up every year to record relevant changes in lipid-lowering treatment and development of cardiovascular events. The graph shows survival data from 34 HoFH patients enrolled from 2004 to 2015


1. France M et al. Atherosclerosis. 2016;255:128–139; 2. Cuchel M et al. Eur Heart J. 2014;35:2146–2157; 3. Gidding SS et al. Circulation. 2015;132:2167–2192; 4. Cuchel M et al. Eur Heart J,. 2023;00:1-15. 5. Nordestgaard BG et al. Eur Heart J 2013; 34:3478-3490; 6. Bruckert E. Atheroscler Suppl. 2014;15:26–32; 7. Alonso R et al. J Clin Lipidol. 2016;10:953–961; 8. Sjouke B et al. Eur Heart J. 2015;36:560–565.