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Familial Hypercholesterolemia: A Reportable ACMG Secondary Finding


  • Familial Hypercholesterolemia (FH) is a disorder characterized by very high levels of LDL cholesterol (LDL-C) and is the most common inherited cardiovascular disease, with a prevalence of 1:200 to 1:250
    • May account for up to 3% of heart attacks in those < 60 years of age
    • Prevalence varies among population with high carrier rates in Old Order Amish (1:10) and South Africans of Ashkenazi Jewish (1:67) and Afrikaner descent (1:72-1:100)
  • Pathogenic variants in 3 genes – LDLR, APOB and PCSK9 – account for 70 to 95% of FH
  • FH has an autosomal dominant pattern of inheritance with incomplete penetrance
    • FH usually refers to the more common ‘heterozygous’ form where only one gene copy has a deleterious mutation
    • There is a rare, more severe ‘homozygous’ form of FH where someone inherits two mutated copies of the LDLR gene, one from each parent

NOTE: Because medical interventions can prevent severe morbidity and mortality, Familial Hypercholesterolemia is on the ACMG list of secondary findings. In summary, the ACMG document on reporting such findings makes the following recommendations:

  • In the course of genetic testing for research or clinical care, the laboratory may identify variants in genes unrelated to the initial indication for testing, but nevertheless may have important health implications
  • Results of such secondary findings should be communicated to the individuals who may benefit from this knowledge
  • An individual can ‘opt out’ of receiving secondary findings


  • Findings may appear in childhood or adulthood
  • There are formalized diagnostic criteria using clinical and laboratory findings
    • Finding a pathogenic mutation in one of the related genes is considered the ‘gold standard’
  • Appropriate surveillance and treatment can result in good outcomes
  • Left untreated, there is a 50% chance of a coronary artery event by age 50 in men and 30% risk by age 60 in women
  • Treatment is multidisciplinary and includes, but is not limited to, specialists in cardiology, lipid management and genetics
    • Assess patient and correct for CVD risk factors such as diet, BP, smoking, obesity
    • Specialized pharmacotherapy including statins and other lipid reducing medication
    • In severe cases, LDL apheresis and liver transplant, although rare, may be required


Excessive cholesterol results in the following findings on clinical and radiologic exam

  • Atherosclerotic plaques in coronary arteries and proximal aorta
  • Corneal arcus – grey/white ring around the periphery of the cornea, a result of lipid deposit when seen in individuals < 45 years of age (common finding in older people)
  • Soft tissues
    • Tendon xanthomas (Achilles, hands, fingers, knees,elbows)
    • Xanthelasma (eyelids)
Xanthelasma Example
Credit: Klaus D. Peter, Gummersbach, Germany


What gene/protein is affected and what does it do?

  • LDLR – Low Density Lipoprotein Receptor:  (Most commonly associated with FH)  LDLR is the receptor that binds low density lipoproteins (LDLs), the primary cholesterol carrying proteins in the bloodstream
    • Reduction or damage to LDL receptors can lead to elevated LDL-C levels
  • APOB – Apolipoprotein B:  APOB is the main apolipoprotein on chylomicrons and LDLs and is important in the functioning of the low-density lipoprotein receptor
  • PCSK9 – Proprotein Convertase Subtilisin / Kexin type 9: The PCSK9 protein reduces the number of LDL Receptors
    • Pathogenic variants result in a ‘gain-of-function’ reducing the number of LDL receptors more than usual, leading to higher LDL-C levels


  • FH is an autosomal dominant disorder
  • It appears that almost all affected individuals will have a parent who is a carrier of a pathogenic variant, meaning the new mutation rate is low

Risks to family members and future offspring:

  • If a parent of an affected individual carries a mutation, the brothers and sisters of that affected individual have a 50% chance of carrying the mutation
  • Offspring of affected individuals have a 50% chance of inheriting the mutation and therefore having FH
    • Preimplantation genetics and prenatal testing is available

Learn More – Primary Sources:

ACMG Recommendations for Reporting Incidental Findings in Clinical Exome and Genome Sequencing

GeneReviews: Familial Hypercholesterolemia

The Knowns and Unknowns of Contemporary Statin Therapy for Familial Hypercholesterolemia

Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities

OMIM: Familial Hypercholesterolemia




Locate a genetic counselor or genetics services:

Genetic Services Locator-ACMG

Genetic Services Locator-NSGC

Genetic Services Locator-CAGC