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Hypercholesterolemia, autosomal dominant, 3(FHCL3)

MedGen UID:
Concept ID:
Disease or Syndrome
Synonyms: Familial hypercholesterolemia 3; Familial Hypercholesterolemia, Autosomal Dominant, 3; FHCL3; PCSK9-Related Familial Hypercholesterolemia, Autosomal Dominant
Gene (location): PCSK9 (1p32.3)
Monarch Initiative: MONDO:0011369
OMIM®: 603776

Disease characteristics

Excerpted from the GeneReview: Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) that leads to atherosclerotic plaque deposition in the coronary arteries and proximal aorta at an early age and increases the risk of premature cardiovascular events such as angina and myocardial infarction; stroke occurs more rarely. Xanthomas (cholesterol deposits in tendons) may be visible in the Achilles tendons or tendons of the hands and worsen with age as a result of extremely high cholesterol levels. Xanthelasmas (yellowish, waxy deposits) can occur around the eyelids. Individuals with FH may develop corneal arcus (white, gray, or blue opaque ring in the corneal margin as a result of cholesterol deposition) at a younger age than those without FH. Individuals with a more severe phenotype, often as a result of biallelic variants, can present with very significant elevations in LDL-C (>500 mg/dL), early-onset coronary artery disease (CAD; presenting as early as childhood in some), and calcific aortic valve disease. [from GeneReviews]
Hannah E Ison  |  Shoa L Clarke  |  Joshua W Knowles   view full author information

Additional descriptions

Familial hypercholesterolemia-3 (FHCL3) is an autosomal dominant disorder of lipid metabolism characterized by a selective increase of low density lipoprotein particles in plasma, giving rise to tendon and skin xanthomas, arcus corneae, and coronary artery disease (summary by Varret et al., 1999). For a general description and a discussion of genetic heterogeneity of hypercholesterolemia, see 143890. Varret et al. (1999) reported a large 3-generation French family (HC2) in which 7 individuals had hypercholesterolemia. All affected members had levels of total cholesterol above the 97th percentile when compared with age- and sex-matched French individuals. The proband was a 36-year-old woman, ascertained at age 17 years with 3.32 g/l total cholesterol, 2.36 g/l LDL-C, 0.48 g/l HDL-C, 0.61 g/l triglycerides, and arcus corneae. Her sister, aged 40 years, was ascertained at age 20 years with similar lipid levels, arcus corneae, tendon xanthomas, and xanthelasmas. Haddad et al. (1999) reported a large Utah kindred (K1173) segregating hypercholesterolemia. In this pedigree, the LDL levels (mean, 237 +/-70) were similar to those of familial hypercholesterolemia pedigrees with mutations in the LDL receptor gene (FHCL1; 606945), and penetrance was complete even at young ages. Triglyceride levels were significantly lower than in FHCL1 pedigrees, but mean age and body mass index were also lower. There were no differences in the frequency of tendon xanthomas or coronary artery disease.  http://www.omim.org/entry/603776
From MedlinePlus Genetics
Familial hypercholesterolemia can also cause health problems related to the buildup of excess cholesterol in tissues other than the heart and blood vessels. If cholesterol accumulates in the tissues that attach muscles to bones (tendons), it causes characteristic growths called tendon xanthomas. These growths most often affect the Achilles tendons, which attach the calf muscles to the heels, and tendons in the hands and fingers. Yellowish cholesterol deposits can develop under the skin of the eyelids and are known as xanthelasmata. Cholesterol can also accumulate at the edges of the clear, front surface of the eye (the cornea), leading to a gray-colored ring called an arcus cornealis.

People with familial hypercholesterolemia have a high risk of developing a form of heart disease called coronary artery disease at a young age. This condition occurs when excess cholesterol in the bloodstream is deposited on the inner walls of blood vessels, particularly the arteries that supply blood to the heart (coronary arteries). The abnormal buildup of cholesterol forms clumps (plaques) that narrow and harden artery walls. As the plaques get bigger, they can clog the arteries and restrict the flow of blood to the heart. The buildup of plaques in coronary arteries causes a form of chest pain called angina and greatly increases a person's risk of having a heart attack.

Familial hypercholesterolemia is an inherited condition characterized by very high levels of cholesterol in the blood. Cholesterol is a waxy, fat-like substance that is produced in the body and obtained from foods that come from animals (particularly egg yolks, meat, poultry, fish, and dairy products). The body needs this substance to build cell membranes, make certain hormones, and produce compounds that aid in fat digestion. In people with familial hypercholesterolemia, the body is unable to get rid of extra cholesterol, and it builds up in the blood. Too much cholesterol increases a person's risk of developing heart disease.  https://medlineplus.gov/genetics/condition/familial-hypercholesterolemia

Clinical features

From HPO
Tendon xanthomatosis
MedGen UID:
Concept ID:
Disease or Syndrome
The presence of xanthomas (intra-and extra-cellular accumulations of cholesterol) extensor tendons (typically over knuckles, Achilles tendon, knee, and elbows).
MedGen UID:
Concept ID:
Disease or Syndrome
An increased concentration of cholesterol in the blood.
Abnormal LDL cholesterol concentration
MedGen UID:
Concept ID:
Any deviation from the normal concentration of low-density lipoprotein cholesterol in the blood circulation.
MedGen UID:
Concept ID:
Disease or Syndrome
The presence of xanthomata in the skin of the eyelid.
Arcus senilis
MedGen UID:
Concept ID:
A hazy, grayish-white ring about 2 mm in width located close to but separated from the limbus (the corneoscleral junction). Corneal arcus generally occurs bilaterally, and is related to lipid deposition in the cornea. Corneal arcus can occur in elderly persons as a part of the aging process but may be associated with hypercholesterolemia in people under the age of 50 years.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  

Recent clinical studies


Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM
Circulation 2015 Oct 27;132(17):1648-66. doi: 10.1161/CIRCULATIONAHA.115.016080. PMID: 26503748


Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM
Circulation 2015 Oct 27;132(17):1648-66. doi: 10.1161/CIRCULATIONAHA.115.016080. PMID: 26503748


Bergeron N, Phan BA, Ding Y, Fong A, Krauss RM
Circulation 2015 Oct 27;132(17):1648-66. doi: 10.1161/CIRCULATIONAHA.115.016080. PMID: 26503748

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines


    • ACMG ACT, 2019
      American College of Medical Genetics and Genomics, Genomic Testing (Secondary Findings) ACT Sheet, APOB, LDLR, PCSK9 Pathogenic Variants (Familial Hypercholesterolemia), 2019
    • CSANZ, 2016
      The Cardiac Society of Australia and New Zealand, Diagnosis and Management of Familial Hypercholesterolaemia – Position Statement

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