Familial Hypercholesterolemia
Familial Hypercholesterolemia
These tests are used to genetically diagnose familial hypercholesterolemia (FH) in individuals suitable for testing.
Test Summary
Familial Hypercholesterolemia
Clinical use
- Diagnose familial hypercholesterolemia (FH)
Clinical background
Familial hypercholesterolemia is a common inherited disorder characterized by very high levels of circulating low-density lipoprotein cholesterol (LDL-C). FH is caused by variants in genes involved in LDL-C cycling in the liver. Most cases of FH are inherited in an autosomal dominant pattern, and globally, approximately 1 in 220 people have heterozygous FH (ie, a single pathogenic variant in a gene associated with elevated LDL-C).1 Homozygous forms of FH are rarer (roughly 1 in 200,000 to 300,000 people); these patients have 2 pathogenic variants and more severe signs and symptoms.1
Due to lifelong exposure to high LDL-C levels, adults who have known FH gene variants and elevated LDL-C have a higher risk for incident atherosclerotic cardiovascular disease (ASCVD) and death. Some studies have estimated the magnitude of this risk without addressing relative LDL-C levels, which could amplify the risk conferred by FH variants. However, a recent large study addressed this by identifying individuals with and without FH variants among 20,000 US adults (≥20 years old) with elevated LDL-C.2 Those with FH variants had a 2- to 3-fold higher risk for incident ASCVD (a coronary heart disease event) than those without. These adults were further projected to have more deaths in the US population compared with those with comparable LDL-C but without gene variants (>12,000 more deaths in those with moderately elevated [130-189 mg/dL] and >15,000 more deaths in those with severely elevated LDL-C [≥190 mg/dL]).2
Early diagnosis of FH is crucial for disease management and reducing risk of premature ASCVD (ie, in men ≤55 years, women <65 years).1 One study found that patients treated with statins from childhood had a lower incidence of cardiovascular events (1% vs 26%) and death (0% vs 7%) than their parents at the same age (39 years) who received therapy much later in life.3 Despite the potential benefits of early diagnosis and treatment, FH remains undiagnosed in over 90% of affected individuals in the United States.4
According to International Atherosclerosis Society guidelines, clinical diagnostic criteria for FH include personal or family history of premature ASCVD, physical findings of tendon xanthomas (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), and elevated LDL-C5:
- For untreated heterozygous FH diagnosis, the LDL-C threshold is >190 mg/dL (>160 mg/dL for children and adolescents with a parental history of high LDL-C or premature ASCVD).
- For untreated homozygous FH, the LDL-C threshold is >400 mg/dL.
However, thresholds vary slightly depending on the professional guidelines1 and clinical FH diagnoses depend on age-, sex, and country-specific LDL-C concentrations; country-specific FH phenotypes; exclusion or correction of secondary causes of elevated LDL-C; and adjusting LDL-C levels for treatment.5
Alternatively, genetic testing alone can provide a definitive diagnosis.5 An international expert panel convened by the FH Foundation recommends testing for variants in the 3 genes most commonly associated with FH: LDLR, APOB, and PCSK9.1 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%).6-8 In addition to helping establish a definitive FH diagnosis, positive genetic test results may also facilitate ASCVD risk stratification, guide therapeutic decisions (eg, more intensive lipid lowering), and help increase adherence to therapy by increasing patient awareness of risk.1,5
When a pathogenic variant is identified, cascade genetic testing of the patient’s family for the variant is recommended.1,5 In this cascade-testing strategy, genetic testing is offered to first-degree relatives (or second-degree relatives, if first-degree relatives are unavailable or decline testing). If any are positive, the first-degree relatives of that relative are tested, which continues until all relatives with FH are found.1
For genetic diagnosis of FH, Quest Diagnostics offers DNA tests such as 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 targeted testing, when 1 or 2 familial pathogenic variants are known.
Individuals suitable for testing
Panel
- Individuals with clinically suspected FH, including1
- Adults with persistently high LDL-C levels (≥2 measurements), defined as one of the following
- ≥250 mg/dL
- ≥190 mg/dL with a 1st-degree relative with high cholesterol or premature ASCVD, or unavailable family history
- ≥160 mg/dL with family history of high cholesterol and personal or family history of premature ASCVD
- Adults with no LDL-C measurements before treatment but with personal and family history of premature ASCVD and family history of high cholesterol
- Children with persistently high LDL-C levels (≥2 measurements), defined as one of the following
- ≥190 mg/dL
- ≥160 mg/dL with a 1st-degree relative with high cholesterol or premature ASCVD, or unavailable family history
Single site or panel
- Close (first- and second-degree) relatives of patients with 1 or more known pathogenic LDLR, APOB, or PCSK9 variants1
Method
- 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 or likely pathogenic variants in LDLR, APOB, or PCSK9 genes and constitutes a genetic diagnosis of FH. Heterozygous FH-positive individuals are at higher risk for premature ASCVD than individuals without a pathogenic variant. Homozygous positive (or compound heterozygous) individuals have more severe symptoms and are at higher risk for premature ASCVD than heterozygous FH-positive individuals.9
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 (ie, 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 Genomic Science Specialists by calling Genomic Client Service at 1.866.GENE.INFO (1.866.436.3463).
References
- Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680. doi:10.1016/j.jacc.2018.05.044
- Zhang Y, Dron JS, Bellows BK, et al. Familial hypercholesterolemia variant and cardiovascular risk in individuals with elevated cholesterol. JAMA Cardiol. 2024;9(3):263-271. doi:10.1001/jamacardio.2023.5366
- Luirink IK, Wiegman A, Kusters DM, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019;381(16):1547-1556. doi:10.1056/NEJMoa1816454
- 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(20):1580-1583. doi:10.1093/eurheartj/ehx136
- Watts GF, Gidding SS, Hegele RA, et al. International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia. Nat Rev Cardiol. 2023;20(12):845-869. doi:10.1038/s41569-023-00892-0
- 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(22):2578-2589. doi:10.1016/j.jacc.2016.03.520
- 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(11):1360-1366. doi:10.1093/eurheartj/ehs010
- 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/s12929-016-0256-1
- 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(22):2167-2192. doi:10.1161/CIR.0000000000000297
Content reviewed 04/2024
These tests are used to genetically diagnose familial hypercholesterolemia (FH) in individuals suitable for testing.
Test Summary
Familial Hypercholesterolemia
Clinical use
- Diagnose familial hypercholesterolemia (FH)
Clinical background
Familial hypercholesterolemia is a common inherited disorder characterized by very high levels of circulating low-density lipoprotein cholesterol (LDL-C). FH is caused by variants in genes involved in LDL-C cycling in the liver. Most cases of FH are inherited in an autosomal dominant pattern, and globally, approximately 1 in 220 people have heterozygous FH (ie, a single pathogenic variant in a gene associated with elevated LDL-C).1 Homozygous forms of FH are rarer (roughly 1 in 200,000 to 300,000 people); these patients have 2 pathogenic variants and more severe signs and symptoms.1
Due to lifelong exposure to high LDL-C levels, adults who have known FH gene variants and elevated LDL-C have a higher risk for incident atherosclerotic cardiovascular disease (ASCVD) and death. Some studies have estimated the magnitude of this risk without addressing relative LDL-C levels, which could amplify the risk conferred by FH variants. However, a recent large study addressed this by identifying individuals with and without FH variants among 20,000 US adults (≥20 years old) with elevated LDL-C.2 Those with FH variants had a 2- to 3-fold higher risk for incident ASCVD (a coronary heart disease event) than those without. These adults were further projected to have more deaths in the US population compared with those with comparable LDL-C but without gene variants (>12,000 more deaths in those with moderately elevated [130-189 mg/dL] and >15,000 more deaths in those with severely elevated LDL-C [≥190 mg/dL]).2
Early diagnosis of FH is crucial for disease management and reducing risk of premature ASCVD (ie, in men ≤55 years, women <65 years).1 One study found that patients treated with statins from childhood had a lower incidence of cardiovascular events (1% vs 26%) and death (0% vs 7%) than their parents at the same age (39 years) who received therapy much later in life.3 Despite the potential benefits of early diagnosis and treatment, FH remains undiagnosed in over 90% of affected individuals in the United States.4
According to International Atherosclerosis Society guidelines, clinical diagnostic criteria for FH include personal or family history of premature ASCVD, physical findings of tendon xanthomas (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), and elevated LDL-C5:
- For untreated heterozygous FH diagnosis, the LDL-C threshold is >190 mg/dL (>160 mg/dL for children and adolescents with a parental history of high LDL-C or premature ASCVD).
- For untreated homozygous FH, the LDL-C threshold is >400 mg/dL.
However, thresholds vary slightly depending on the professional guidelines1 and clinical FH diagnoses depend on age-, sex, and country-specific LDL-C concentrations; country-specific FH phenotypes; exclusion or correction of secondary causes of elevated LDL-C; and adjusting LDL-C levels for treatment.5
Alternatively, genetic testing alone can provide a definitive diagnosis.5 An international expert panel convened by the FH Foundation recommends testing for variants in the 3 genes most commonly associated with FH: LDLR, APOB, and PCSK9.1 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%).6-8 In addition to helping establish a definitive FH diagnosis, positive genetic test results may also facilitate ASCVD risk stratification, guide therapeutic decisions (eg, more intensive lipid lowering), and help increase adherence to therapy by increasing patient awareness of risk.1,5
When a pathogenic variant is identified, cascade genetic testing of the patient’s family for the variant is recommended.1,5 In this cascade-testing strategy, genetic testing is offered to first-degree relatives (or second-degree relatives, if first-degree relatives are unavailable or decline testing). If any are positive, the first-degree relatives of that relative are tested, which continues until all relatives with FH are found.1
For genetic diagnosis of FH, Quest Diagnostics offers DNA tests such as 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 targeted testing, when 1 or 2 familial pathogenic variants are known.
Individuals suitable for testing
Panel
- Individuals with clinically suspected FH, including1
- Adults with persistently high LDL-C levels (≥2 measurements), defined as one of the following
- ≥250 mg/dL
- ≥190 mg/dL with a 1st-degree relative with high cholesterol or premature ASCVD, or unavailable family history
- ≥160 mg/dL with family history of high cholesterol and personal or family history of premature ASCVD
- Adults with no LDL-C measurements before treatment but with personal and family history of premature ASCVD and family history of high cholesterol
- Children with persistently high LDL-C levels (≥2 measurements), defined as one of the following
- ≥190 mg/dL
- ≥160 mg/dL with a 1st-degree relative with high cholesterol or premature ASCVD, or unavailable family history
Single site or panel
- Close (first- and second-degree) relatives of patients with 1 or more known pathogenic LDLR, APOB, or PCSK9 variants1
Method
- 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 or likely pathogenic variants in LDLR, APOB, or PCSK9 genes and constitutes a genetic diagnosis of FH. Heterozygous FH-positive individuals are at higher risk for premature ASCVD than individuals without a pathogenic variant. Homozygous positive (or compound heterozygous) individuals have more severe symptoms and are at higher risk for premature ASCVD than heterozygous FH-positive individuals.9
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 (ie, 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 Genomic Science Specialists by calling Genomic Client Service at 1.866.GENE.INFO (1.866.436.3463).
References
- Sturm AC, Knowles JW, Gidding SS, et al. Clinical genetic testing for familial hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018;72(6):662-680. doi:10.1016/j.jacc.2018.05.044
- Zhang Y, Dron JS, Bellows BK, et al. Familial hypercholesterolemia variant and cardiovascular risk in individuals with elevated cholesterol. JAMA Cardiol. 2024;9(3):263-271. doi:10.1001/jamacardio.2023.5366
- Luirink IK, Wiegman A, Kusters DM, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019;381(16):1547-1556. doi:10.1056/NEJMoa1816454
- 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(20):1580-1583. doi:10.1093/eurheartj/ehx136
- Watts GF, Gidding SS, Hegele RA, et al. International Atherosclerosis Society guidance for implementing best practice in the care of familial hypercholesterolaemia. Nat Rev Cardiol. 2023;20(12):845-869. doi:10.1038/s41569-023-00892-0
- 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(22):2578-2589. doi:10.1016/j.jacc.2016.03.520
- 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(11):1360-1366. doi:10.1093/eurheartj/ehs010
- 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/s12929-016-0256-1
- 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(22):2167-2192. doi:10.1161/CIR.0000000000000297
Content reviewed 04/2024