genetics of FH (Familial Hypercholesterolaemia)

Last edited 11/2018 and last reviewed 09/2021

Genetics of FH

• FH is an autosomal dominant disorder with a gene dosage effect:
  
  
  • raised cholesterol concentration that characterises heterozygous FH leads to a greater than 50% risk of coronary heart disease in men by the age of 50 years and at least 30% in women by the age of 60 years (1)
    • patients who are homozygotes (or compound heterozygotes) have much higher LDL-C levels and earlier coronary artery disease onset than heterozygous patients (1)
      
      
  • underlying defect in FH was initially thought to be due to increased synthesis of cholesterol, but we now know that the fractional catabolic rate of LDL is decreased in heterozygous FH individuals compared to normal subjects (2)
    
    
  • most common form of FH is a monogenic, autosomal dominant disorder, which causes defects in the gene that encodes the LDL receptor (LDLR)(1,2)
    • over 900 mutations of this gene have been identified (3), most pathogenic, leading to the LDL receptor having decreased capacity to clear LDL from the circulation
      
      
  • are also defects in the LDL receptor binding region of apolipoprotein B (APOB) (3) and rare gain of function proprotein convertase subtilisin/kexin type 9 (PCSK9) gene mutations (4)
    
    
  • a rare autosomal recessive form of FH , has also been described (2):
    • caused by loss-of-function mutations in the LDL receptor adaptor protein 1 (LDLRAP1), which encodes a protein required for clathrin-mediated internalization of the LDL receptor

Reference:

• Public Health England (August 2018).Familial Hypercholesterolaemia Implementing a systems approach to detection and management.
• Cuchel M, Bruckert E, Ginsberg H. Homozygous Familial Hypercholesterolaemia: New Insights and Guidance for Clinicians to Improve Detection and Clinical Management. Eur Heart J. 2014;35(32):2146-2157
• Hopkins P, Toth P. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5(3 Suppl):S9-17.
• Abifadel M, Elbitar S, El Khoury P, et al. Living the PCSK9 Adventure: from the Identification of a New Gene in Familial Hypercholesterolemia Towards a Potential New Class of Anticholesterol Drugs. Curr Atheroscler Rep. 2014 Sep;16(9):43.