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Familial Hypercholesterolemia

Familial Hypercholesterolemia

Test Summary

Familial Hypercholesterolemia


Clinical Use

  • Diagnose familial hypercholesterolemia (FH)

Clinical Background

Familial hypercholesterolemia is a relatively common inherited disorder characterized by very high low-density lipoprotein-cholesterol (LDL-C) and a greater risk for premature coronary heart disease (CHD). Most cases of FH are autosomal dominant. Approximately 1 in 250 to 500 people in the United States have heterozygous FH, (ie, a single abnormal LDL-C–raising allele [ie, a pathogenic variant]).1,2 Homozygous forms of FH are rarer (roughly 1 in 160,000 to 1 million people); these patients have 2 pathogenic variants and more severe symptoms.2,3 However, despite the disorder having a negative impact on cardiovascular health, FH remains undiagnosed in over 90% of affected individuals in the United States.4 The risk of CHD for untreated individuals with FH rises to 50% in men by age 50 and 30% in women by age 60.5 Thus, early diagnosis of FH is crucial for disease management and, in some cases, to assess eligibility for treatment with certain newer lipid-lowering therapies.6

Although several organizations have developed diagnostic algorithms for FH, there currently is no international consensus on which algorithm is superior. Clinical diagnostic criteria used in these algorithms include a personal or family history of premature CHD and presence of tendon xanthomata (yellowish patches or lumps of cholesterol buildup in the tendons of the hands, feet, and heel) or corneal arcus (opaque ring in the corneal margin). For heterozygous FH diagnosis, the LDL-C threshold is ≥190 mg/dL for untreated adults (≥160 mg/dL with maximally-tolerated statin treatment)7 and ≥160 mg/dL for untreated children.6 For homozygous FH, the proposed threshold is ≥400 mg/dL.6 The American Heart Association (AHA) has proposed a clinical classification of FH, with the option of genetic testing to provide a definitive diagnosis.6 Some algorithms, such as the Dutch Lipid Clinic Network (DLCN) and Simon Broome Register criteria, indicate that a positive genetic test result is sufficient for FH diagnosis.8

A genetic diagnosis of FH requires detection of a pathogenic variant, most commonly occurring in 1 of 3 genes: LDLR, APOB, or PCSK9. These genes encode proteins responsible for LDL-C cycling in the liver. Defects in these proteins cause high circulating LDL-C levels by impairing reuptake of LDL-C from blood by its receptor (LDLR) or accelerating degradation of LDLR. For patients with known variant status, loss-of-function variants of LDLR are the most common (79% to 88% of FH cases), followed by loss-of-function variants of APOB (5% to 13%) and gain-of-function variants of PCSK9 (<1%).8-10 Each of these pathogenic variants conveys a lifetime of exposure to elevated LDL-C; thus, detection confers higher risk beyond that indicated by elevated LDL-C.9 Compared to individuals with lower LDL-C (<130 mg/dL), individuals with high LDL-C (≥190 mg/dL) and no pathogenic variants have a 6-fold higher risk of CHD—those with high LDL-C who are heterozygous FH have a 22-fold higher risk.9 Individuals with homozygous FH who have 2 identical pathogenic variants (or compound heterozygous individuals with 2 nonidentical pathogenic variants in the same gene or separate genes) are at higher risk for CHD at a younger age (mid-20s) than are heterozygous FH individuals.5

The International FH Guidelines recommend that genetic testing for FH should ideally be offered to all "index" cases with a phenotypic diagnosis of FH (eg, by DLCN criteria).11 Conversely, the guidelines recommend against genetic testing in an index case when a phenotypic diagnosis of FH is unlikely. Data support these recommendations, in that patients with a "definite" versus "possible" phenotypic FH diagnosis are more likely to have a pathogenic variant: genetic testing detects a pathogenic variant in 56% to 73% of patients with clinically diagnosed "definite FH," but only about 30% of those with "possible" FH.12,13

Cascade screening: a combination of lipid and DNA testing of first-, second-, and third-degree relatives of index cases is recommended following a phenotypic diagnosis of FH.11 If genetic testing is negative for pathogenic variants in LDLR, APOB, and PCSK9, cascade testing may be performed using LDL-C levels, and diagnosis be made based on an appropriate algorithm (eg, DLCN or Simon Broome Register criteria).11

For genetic diagnosis of FH, Quest Diagnostics offers DNA tests including the Familial Hypercholesterolemia Panel (Test Code 94877), which tests for variants in LDLR, APOB, and PCSK9. The Familial Hypercholesterolemia Single-Site test (Test Code 94878) is available for use when 1 or 2 familial pathogenic variants are known.

Individuals Suitable for Testing


  • Adults with untreated LDL-C levels ≥190 mg/dL (≥160 mg/dL with treatment)

  • Children with untreated LDL-C levels ≥160 mg/dL

  • Individuals with a personal or family history of premature CHD or other cardiovascular disease

  • Individuals with xanthomas or corneal arcus

Single Site or Panel

  • Close (first-, second-, and third-degree) relatives of patients with 1 or more known pathogenic LDLR, APOB, or PCSK9 variants


  • Next-generation sequencing of LDLR, APOB, and PCSK9

  • Computational, exon-level, copy number variant analysis

  • Copy number variants confirmed by microarray

Interpretive Information

A positive result indicates the presence of 1 or more pathogenic variants in LDLR, APOB, or PCSK9 genes and constitutes a definitive diagnosis of FH. Heterozygous FH-positive individuals are at higher risk for premature CHD than individuals without a pathogenic variant. Homozygous positive (or compound heterozygous) individuals have more severe symptoms and are at higher risk for premature CHD than heterozygous FH-positive individuals.5

A negative result indicates absence of a known pathogenic variant but does not exclude FH in a symptomatic patient; the disorder may be caused by variants in unexamined gene regions (eg, deep intronic) or other genes. Implications of this result depend on the patient's personal medical history and family history.

A "variant of unknown significance (VUS)" result means that the patient has a variant that has not been linked to FH. The phenotypic significance of the variant is not known.

Additional assistance in interpretation of results is available from our Genetic Counselors by calling 1.866.GENE.INFO (1.866.436.3463).


  1. de Ferranti SD, Rodday AM, Mendelson MM, et al. Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES). Circulation. 2016;133:1067-1072.

  2. Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. J Clin Lipidol. 2014;8:18-28.

  3. Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146-2157.

  4. Nordestgaard BG, Benn M. Genetic testing for familial hypercholesterolaemia is essential in individuals with high LDL cholesterol: who does it in the world? Eur Heart J. 2017;38:1580-1583.

  5. Youngblom E, Pariani M, Knowles JW. Familial Hypercholesterolemia. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews® [Internet]. Seattle, WA; University of Washington, Seattle; 1993-2017 https://www.ncbi.nlm.nih.gov/books/NBK174884/. Updated December 8, 2016, Accessed October, 11 2017.

  6. Gidding SS, Champagne MA, de Ferranti SD, et al. The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation. 2015;132:2167-2192.

  7. Ginsberg HN, Rader DJ, Raal FJ, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc Drugs Ther. 2016;30:473-483.

  8. Henderson R, O'Kane M, McGilligan V, et al. The genetics and screening of familial hypercholesterolaemia. J Biomed Sci. 2016;23:39. doi: 10.1186/s12929-12016-10256-12921.

  9. Khera AV, Won HH, Peloso GM, et al. Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia. J Am Coll Cardiol. 2016;67:2578-2589.

  10. Motazacker MM, Pirruccello J, Huijgen R, et al. Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia. Eur Heart J. 2012;33:1360-1366.

  11. Watts GF, Gidding S, Wierzbicki AS, et al. Integrated guidance on the care of familial hypercholesterolemia from the International FH Foundation. J Clin Lipidol. 2014;8:148-172.

  12. Futema M, Whittall RA, Kiley A, et al. Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis. 2013;229:161-168.

  13. Taylor A, Wang D, Patel K, et al. Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project. Clin Genet. 2010;77:572-580.

Content reviewed 10/2017


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