Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Hypercholesterolemia, familial (FH)

Dr. rer. biol. hum. Katrin Goldmann, Dr. rer. nat. Christoph Marschall

Scientific Background

With a frequency of 1:200 to 1:500, familial hypercholesterolemia (FH, according to Fredrickson classification type 2A) is one of the most common monogenic diseases. The classic form of FH follows an autosomal dominant pattern of inheritance (ADH) and is characterized by an increase in LDL cholesterol (LDL-C) in the serum (LDL-C in heterozygous state 190-450 mg/dl, in homozygous state > 400 mg/dl). Pathogenic mutations in three genes that affect the function of the LDL receptor have been described as causal for ADH. The most common (74% of cases) is pathogenic mutations in the LDLR gene; however, genetic defects in Apolipoprotein B-100 (APOB gene 2-7%) or protease PCSK9 (< 3%) can also be causal.

The LDL-C concentration in the blood is regulated by the interaction of LDL and the LDL receptor (Apo B/E or LDLR). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in the degradation of the LDL receptors and thus also influences the LDL-C concentration. The phenotype of FH includes skin and tendon xanthomas as well as arcus lipoides which in homozygous carriers of the autosomal dominant form may appear in childhood. Untreated, homozygous FH results in death from myocardial infarction before the age of 30; in heterozygous patients, symptomatic coronary vascular disease before the age of 50 is likely. The detection of mutations in the causative genes may justify intensive therapeutic measures (e.g., lipid apheresis) if drug therapy is insufficient.

If a gain of function mutation in the PCSK9 gene is detected in a patient, treatment with alirocumab and evolocumab (approved in Europe in 2015) can be considered. Treatment is a monoclonal antibody that by reducing the number of pcsk9 molecules causes increased availability of LDL receptors on the hepatocyte cell surface and a significant reduction in LDL cholesterol in the plasma.

In rare cases, FH is inherited in an autosomal recessive manner. Pathogenic LDLRAP1 gene variants (LDL adaptor protein) have been identified that are associated with the autosomal recessive form (ARH). The treatment of homozygous carriers of LDLRAP1 mutations is the same as in LDLR mutations. Mutations in the APOB gene (FLDB) may also cause clinical FH.

lipid metabolism in familial hypercholesterolemia

Simplified representation of the extracellular lipid metabolism: Pathogenic variants in the LDL receptor gene or its most important ligand ApoB lead to an accumulation of ApoB-containing lipoproteins (especially LDL) in the circulation due to insufficient clearance. Since supply of sufficient cholesterol to the cell is not guaranteed, endogenous cholesterol biosynthesis (controlled by the pacemaker enzyme HMG-CoA reductase) is maximally stimulated and leads to a further increase in extracellular LDL-C. Prolonged retention of the LDL particles in the circulation results in the lipids being oxidized/modified followed by a macrophage immune response. The result is the subendothelial formation of foam cells and plaques in the blood vessels (atherosclerosis).


Lee et al. 2019, Lipids in Health and Disease 18:95 / Ramasamy I. 2016, Clin Chim Acta. 454:143 / Schulze-Bahr et al. 2015, Dtsch. Med. Wochenschr. 140:1538 / Hopkins et al. 2015, Circ. Cardiovasc. Genetic. / Gabcova-Balaziova et al. 2015, Endocr Regul. 49:164 / Goldstein et al. in Scriver et al. 2001 (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th Ed, Chapter 120