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Gene test interpretation: Familial hypercholesterolemia genes (LDLR, APOB, PCSK9)

Gene test interpretation: Familial hypercholesterolemia genes (LDLR, APOB, PCSK9)
Literature review current through: Jan 2024.
This topic last updated: Nov 30, 2023.

INTRODUCTION — This monograph discusses interpretation of results and possible changes in care following genetic testing for three genes associated with familial hypercholesterolemia (FH): LDLR, APOB, and PCSK9.

It does not discuss the indications for testing and is not intended to replace clinical judgment in decisions to test or in care of the tested individual. These subjects are discussed separately [1]. (See 'UpToDate topics' below.)

HOW TO READ THE REPORT — Genetic testing may complement a clinical evaluation for atherosclerotic disease risk that includes family history, personal history, physical examination, and laboratory testing.

Testing involves two steps: determining the genotype (presence or absence of variants in one or more genes) and interpreting the pathogenicity of the variant(s).

Genotyping may include complete gene sequencing or evaluation for a subset of known variants. The likelihood of finding a pathogenic or likely pathogenic variant in an FH gene correlates with family history and clinical findings including premature cardiovascular disease, physical features (tendon xanthomas), and lipid profile. Any testing performed for research or through a direct-to-consumer service that would affect management (positive testing, negative testing in an individual with a suspected genetic disorder) should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified or other nationally certified laboratory with verified patient identification. (See "Genetic testing", section on 'Basic principles'.)

The testing laboratory uses information from clinical and basic science research to classify variants into one of five categories of pathogenicity (table 1) [2]. The classification may be revised over time, especially for a variant of uncertain significance (VUS). The uncertainty reflects the available research, not the accuracy of sequencing or the likelihood of disease. A VUS should be reevaluated periodically to determine if additional information about its pathogenicity has become available, especially for individuals for whom the information would impact their management or counseling and testing of their at-risk relatives. (See "Secondary findings from genetic testing", section on 'Definitions and classification of variants'.)

The tables review caveats and considerations for reviewing test results (table 2) and terms used in genetic test reports (table 3).

OVERVIEW OF CLINICAL IMPLICATIONS

Pathogenesis — Low-density lipoproteins (LDLs) are cholesterol-rich particles that are essential for normal physiology (production of steroid hormones and bile acids, integrity of cell membranes). Elevated levels of LDL-cholesterol (LDL-C) are associated with increased risk of atherosclerotic cardiovascular, cerebrovascular, and peripheral arterial disease.

FH is a hereditary condition in which LDL catabolism is impaired and LDL-C is increased [3,4]. FH gene variants represent rare causes of hyperlipidemia in which a single variant in one gene has a large impact on phenotype; this contrasts with polygenic hypercholesterolemia, a complex trait in which many common variants each have a small impact on phenotype [5].

Pathogenic variants in three genes account for the vast majority of FH (table 4):

LDLR – Encodes the LDL receptor (previously called the apoB/E receptor), which takes up LDL particles and removes them from the circulation. Pathogenic variants in LDLR comprise over 90 percent of genetically-identified FH cases [6].

APOB – Encodes apolipoprotein B (previously called apoB100), the major protein component of LDL. It is responsible for LDL binding to (and uptake by) the LDL receptor. The full length protein is called apoB100; truncated forms are referred to by their percentage of the full-length molecule (apoB48 is 48 percent of apoB100). Comprises approximately 5 to 10 percent of genetically-identified FH cases.

PCSK9 – Encodes proprotein convertase subtilisin kexin 9, a secreted protein that binds the LDL receptor and causes its lysosomal proteolysis, preventing it from recycling back to the cell (hepatocyte) surface. Loss-of-function variants in PCSK9 lower the LDL-C and do not cause FH. Gain-of-function variants are uncommon and can cause a severe FH phenotype that comprises <1 percent of genetically-identified FH cases.

In all individuals with FH, cardiovascular disease risk increases with age, which correlates with increasing lifetime exposure to high LDL-C. Risk also depends on how the variant affects protein function (receptor defective versus receptor null), other genetic factors, other comorbidities such as diabetes and obesity, and environmental contributors such as tobacco and diet [4,6]. At any given LDL-C, cardiovascular risk appears greater for those with FH than those without, possibly because elevated LDL-C has been present from birth [7].

Negative genetic testing does not exclude the diagnosis of FH if the individual meets clinical criteria (see "Familial hypercholesterolemia in adults: Overview", section on 'Definition'). These individuals may have a variant that was not included in the genetic testing panel, a variant in another gene such as APOE (encodes apolipoprotein E) or LDLRAP1, a variant in an as-yet undiscovered gene, or another form of hypercholesterolemia such as polygenic hypercholesterolemia [6]. Other hereditary lipid disorders are summarized in the table (table 5). Referral for additional testing may be indicated.

Inheritance — FH is autosomal dominant. Inheritance of a pathogenic variant in an FH gene from one parent is sufficient to increase disease risk. Some experts use the term autosomal codominant because disease risk is intermediate in heterozygotes and more severe in homozygotes and compound heterozygotes.

This contrasts with polygenic hypercholesterolemia, a complex trait that does not follow typical Mendelian inheritance patterns. (See "Principles of complex trait genetics".)

Diagnosis — FH is diagnosed using a combination of clinical criteria (family history, personal history of premature cardiovascular or other atherosclerotic disease, physical examination findings such as tendon xanthomas, xanthelasmas, or corneal arcus, and LDL-C) and/or by genetic testing [6]. Experts believe that a large proportion of people with FH remain undiagnosed.

Clinical findings may be scored using a system such as that from the Dutch Lipid Clinic Network (table 6), the Simon Broome Familial Hypercholesterolemia Register (table 7), or the American Heart Association. These systems help to assign a diagnosis of definite, probable, or possible FH. (See "Familial hypercholesterolemia in adults: Overview", section on 'Definition'.)

FH is further classified according to clinical severity, which correlates with whether one or both alleles of the implicated gene are involved:

Homozygous FH is caused by biallelic pathogenic variants in FH genes (homozygosity or compound heterozygosity, typically in LDLR). It is associated with elevated LDL-C at birth and risk of atherosclerotic cardiovascular disease onset in childhood (life-threatening if untreated). The untreated LDL-C is generally >500 mg/dL (>13 mmol/L). (See "Familial hypercholesterolemia in children".)

Heterozygous FH is caused by a pathogenic variant at one allele of an FH gene. It is associated with elevated LDL-C in childhood (generally ≥160 mg/dL) and with an increased risk for premature atherosclerotic cardiovascular disease in early middle age. (See "Familial hypercholesterolemia in adults: Overview".)

Clinical findings overlap in heterozygous and homozygous FH because other factors may influence LDL-C and atherosclerotic disease risk. Genetic testing provides additional precision in distinguishing between them.

MANAGEMENT

Children — Children generally undergo genetic testing if they have a positive family history or personal history of premature atherosclerotic cardiovascular disease (or other atherosclerotic disease), tendon xanthomas, increased low-density lipoprotein cholesterol (LDL-C), or other associated findings (algorithm 1).

Children with FH based on clinical and/or genetic findings should generally be evaluated and managed by (or in collaboration with) a hyperlipidemia expert regardless of genetic test results. The table lists this and other management implications (table 8).

Aggressive lipid-lowering treatment is indicated to reduce the risk of early mortality from premature atherosclerotic disease. Statin therapy is initiated as early as infancy in homozygous FH and as early as 8 to 10 years with heterozygous FH. (See "Familial hypercholesterolemia in children", section on 'Management'.)

Those with homozygous FH almost invariably require additional lipid-lowering approaches. These children should also be evaluated by a pediatric cardiologist who can perform additional evaluations and provide additional treatments as appropriate. Specific medications are discussed separately. (See "Familial hypercholesterolemia in children", section on 'Management of HoFH'.)

Negative genetic testing results do not eliminate the need for treatment in appropriate settings. Reasons for negative results should be reviewed. (See 'How to read the report' above.)

Reference ranges for lipids in children are discussed separately. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis", section on 'Normative values'.)

Resources for locating appropriate specialists are listed below. (See 'Locating a specialist' below.)

Adults — Most adults will already have information about their LDL-C values from routine screening. If this information is not available, it should be obtained before making decisions about management.

Reference ranges for lipids in adults and use of fasting versus nonfasting samples are discussed separately. (See "Laboratory test reference ranges in adults", section on 'Cholesterol, serum' and "Screening for lipid disorders in adults".)

Adults with high LDL-C — Adults with high LDL-C are at risk for atherosclerotic cardiovascular disease, and a pathogenic or likely pathogenic variant in LDLR, APOB, or PCSK9 (or other FH gene) further increases risk [6].

Shared decision-making should take into account family history, other cardiovascular risk factors, and LDL-C. Positive results from genetic testing may improve management as follows (table 8):

Help guide choice of, and improve adherence to, lipid-lowering therapies [6]. In the United States, genetic information may facilitate access to some therapies.

Individuals with heterozygous FH generally require a high-intensity statin. The goal LDL-C depends on other risk factors and whether there is preexisting cardiovascular, cerebrovascular, or peripheral arterial disease. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Individuals with homozygous FH may benefit from LDL apheresis or targeted agents such as lomitapide or a PCSK9 inhibitor. (See "Treatment of drug-resistant hypercholesterolemia" and "PCSK9 inhibitors: Pharmacology, adverse effects, and use".)

Those with extreme elevations of LDL-C (>500 mg/dL [>13mmol/L]) should be referred to a hyperlipidemia expert. (See 'Locating a specialist' below.)

Promote additional risk reduction, including smoking cessation, diet and weight management, and diabetes and hypertension screening and treatment.

Facilitate testing and counseling of at-risk relatives. (See 'At-risk relatives' below.).

Negative genetic testing results do not eliminate the need for treatment in appropriate settings. Reasons for negative results should be reviewed. (See 'How to read the report' above.)

If FH or another lipid disorder is suspected and initial testing is negative, it may be prudent to consult a genetic counselor, clinical geneticist, or hyperlipidemia expert. (See 'Locating a specialist' below.)

Adults with normal LDL-C — Adults with normal LDL-C are unlikely to test positive for a pathogenic variant in LDLR, APOB, or PCSK9, although some heterozygotes may not manifest hyperlipidemia until later in adulthood or may have an LDL-C below 190 mg/dL.

Those with positive genetic testing should generally have more intensive monitoring (eg, annual lipid panel; acknowledging lack of evidence-based recommendations) and more intensive screening and interventions for other cardiovascular risk factors (smoking, hypertension, diabetes), with details individualized according to their personal risk assessment.

Those with a positive family history who test negative for the familial variant can be managed similarly to the general population based on a comprehensive cardiovascular risk assessment. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Overview of primary prevention of cardiovascular disease".)

At-risk relatives — At-risk relatives of an individual with FH (homozygous or heterozygous) should be offered counseling to determine their risk and to assist with testing for the familial variant(s) as appropriate, with pre- and post-testing counseling [6].

At-risk generally refers to first-degree relatives (children, siblings, parents), with cascade testing recommended for their first-degree relatives. In cases in which a first-degree relative is unavailable for testing, a second-degree relative (aunt, uncle, grandparent, grandchild) may also be included. The best initial test may be a lipid panel.

Testing of children should involve shared decision-making with the parent(s). The algorithm summarizes an approach to the timing of testing in at-risk children (algorithm 1). Other considerations related to testing children and genetic discrimination are discussed separately. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)

RESOURCES

UpToDate topics

Children

FH – (See "Familial hypercholesterolemia in children".)

Other dyslipidemias – (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis".)

Adults

FH diagnosis – (See "Familial hypercholesterolemia in adults: Overview".)

FH management – (See "Familial hypercholesterolemia in adults: Treatment".)

Other dyslipidemias – (See "Inherited disorders of LDL-cholesterol metabolism other than familial hypercholesterolemia".)

Locating a specialist

Lipid disorders

The FH Foundation (theFHfoundation.org)

The National Lipid Association (lipid.org)

Genetics:

Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

Genetic counselors – National Society of Genetic Counselors (NSGC)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Amy Curry Sturm, MS, CGC, LGC, who contributed to earlier versions of this topic review.

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