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Test ID: FHRGP Familial Hypercholesterolemia and Related Disorders Multi-Gene Panel, Next-Generation Sequencing, Varies


Advisory Information


Targeted testing for familial variants (also called site-specific or known mutation testing) is available for the genes on this panel. See:

-KVAR1 / Known Variant Analysis-1 Variant, Varies

-KVAR2 / Known Variant Analysis-2 Variants, Varies

-KVAR3 / Known Variant Analysis-3+ Variants, Varies

 

Call 800-533-1710 to confirm the appropriate test for targeted testing.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Necessary Information


1. Familial/Autosomal Dominant Hypercholesterolemia Patient Information is required, see Special Instructions. Testing may proceed without the patient information however it aids in providing a more thorough interpretation. Ordering providers are strongly encouraged to complete the form and send it with the specimen.

2. Include physician name and phone number with specimen.



Specimen Required


Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube: Lavender top (EDTA)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Specimen Type: DNA

Container/Tube: 2 mL screw top tube

Specimen Volume: 100 mcL (microliters)

Collection Instructions:

1. The preferred volume is 100 mcL at a concentration of 250 ng/mcL.

2. Include concentration and volume on tube.

Specimen Stability Information: Frozen (preferred)/Ambient/Refrigerated


Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. If not ordering electronically, complete, print, and send a Cardiovascular Test Request (T724) with the specimen.

Useful For

Confirming a clinical diagnosis of familial hypercholesterolemia or sitosterolemia

 

Cascade screening of at-risk family members and early diagnosis, treatment, and dietary modifications

 

Ascertaining carrier status of family members of individuals diagnosed with familial hypercholesterolemia for genetic counseling purposes

Method Name

Custom Sequence Capture and Targeted Next-Generation Sequencing Followed by Polymerase Chain Reaction (PCR) and Supplemental Sanger Sequencing or qPCR

Reporting Name

Hypercholesterolemia Gene Panel

Specimen Type

Varies

Specimen Minimum Volume

Whole blood: 1 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Clinical Information

Familial hypercholesterolemia (FH) is an inherited condition that results in elevated levels of low-density lipoprotein cholesterol (LDL-C). FH is associated with premature cardiovascular disease and myocardial infarction. Early diagnosis and treatment help to mitigate these risks.

 

The most common form of FH is autosomal dominant heterozygous familial hypercholesterolemia (heFH) caused by loss-of-function variants found in the LDLR gene. Recent studies suggest that the prevalence of heFH is as high as 1 in 200 to 250, and may be even higher in some founder populations such as those of French Canadian, Ashkenazi Jewish, Lebanese, and South African descent. In general, FH heterozygotes have 2-fold elevations in plasma cholesterol and develop coronary atherosclerosis after the age of 30. Hundreds of variants have been identified in the LDLR gene. The majority of variants in the LDLR gene are small point variants (missense, nonsense) or small insertions or deletions. Most of these variants are detectable by sequencing of the LDLR gene. An additional 10% of variants in the LDLR gene are large intragenic rearrangements, such as large exon deletions and duplications. Absent or decreased LDL-receptor results in a reduced capacity to clear LDL from circulation.

 

A more severe form of familial hypercholesterolemia can also be caused by homozygous or compound heterozygous (biallelic) variants in the LDLR gene. This condition is referred to as homozygous familial hypercholesterolemia (hoFH). Recent studies suggest the prevalence of hoFH is as high as 1 in 250,000. Individuals with homozygous FH typically have severe hypercholesterolemia (generally >650 mg/dL) with the presence of cutaneous xanthomas prior to 4 years of age, childhood coronary heart disease, and oftentimes, death from myocardial infarction prior to 20 years of age.

 

Another form of autosomal dominant hypercholesterolemia is called familial defective apolipoprotein B-100 (FDB). FDB is caused by loss-of-function variants in the APOB gene that reduce the binding affinity between the protein encoded by APOB (apolipoprotein B-100) and the protein encoded by LDLR (low-density lipoprotein receptor). Individuals with heterozygous APOB variants have elevated LDL-C, although the elevation is typically less than that observed in individuals with heterozygous LDLR variants; increased rates of coronary artery calcifications; and premature myocardial infarction. Approximately 1 in 1667 Northern European Caucasians carry the R3500Q (HGVS: c.10580G>A, p.Arg3527Gln) variant in the APOB gene, and approximately 1 in 800 East Asians carry the R3500W (HGVS: c.10579C>T, p.Arg3527Trp) variant in the APOB gene. Although other variants resulting in autosomal dominant hypercholesterolemia have been described in APOB; most appear within a hotspot (or frequently affected) region surrounding the p.Arg3527 residue. Homozygosity and compound heterozygosity for APOB variants can also occur; these individuals typically have LDL-C levels above 300 mg/dL. Individuals with homozygous FDB are sometimes misdiagnosed with heFH.

 

Autosomal dominant hypercholesterolemia can also be caused by gain-of-function variants in the PCSK9 gene. Variants in this gene are rare, but when present, they result in increased PCSK9 protein levels, leading to increased degradation of low-density lipoprotein receptors. Recently, drugs targeting PCSK9 (called PCSK9 inhibitors) have been developed. These drugs inhibit the binding of PCSK9 to LDL-receptors, thus reducing degradation of LDL-receptors and increasing the amount of LDL-C cleared in certain individuals.

 

Loss-of-function variants in the LDLRAP1 gene cause a rare form of familial hypercholesterolemia called autosomal recessive familial hypercholesterolemia. Once LDL-C binds to the LDL-receptor the LDLRAP1 protein binds to the complex and internalization of the complex, which results in degradation of either the LDL particle or the entire complex occurs. Unlike autosomal dominant hypercholesterolemia caused by heterozygous variants in LDLR, APOB, and PCSK9, biallelic variants in LDLRAP1 are required for elevated LDL-C levels. Individuals with homozygous or compound heterozygous LDLRAP1 variants typically have LDL-C levels above 400 mg/dL, cutaneous and tendon xanthomas, and coronary artery disease. Heterozygosity for LDLRAP1 variants does not result in elevated cholesterol levels, so the parents of children with biallelic LDLRAP1 variants are typically normocholesterolemic.

 

Sitosterolemia, a rare autosomal recessive inherited lipid metabolism disease, is caused by biallelic variants in the ABCG5 or ABCG8 genes and has similar clinical manifestations to familial hypercholesterolemia. Sitosterolemia is characterized by increased intestinal absorption of plant sterols (15% to 60% compared to <5% in unaffected individuals). These individuals also typically have elevated total cholesterol and LDL cholesterol levels, although individuals with normal LDL-C levels have also been reported. Untreated individuals with sitosterolemia exhibit tendon and tuberous xanthomas in childhood, premature atherosclerosis, myocardial infarction, and coronary heart disease. At least one report of an individual with sitosterolemia being misdiagnosed with homozygous FH has been reported. The authors noted that the Dutch Lipid Clinic Network diagnostic (DLCN) criteria could not distinguish between homozygous FH and sitosterolemia in this individual.

 

Identification of the genetic cause of an individual's clinical features helps to determine the appropriate treatment for their clinical features. Treatment is aimed at lowering plasma LDL levels and plasma sterol levels. Common treatments included statins, LDL apheresis, dietary modifications, and more recently PCSK9 inhibitors. Screening of at-risk family members allows for effective primary prevention by instituting appropriate therapy and dietary modifications at an early stage.

 

Table 1. Genes included in the Familial Hypercholesterolemia and Related Disorders Multigene Panel

Gene Symbol (alias)

Protein

OMIM

Inheritance

Phenotype Disorder

ABCG5

ATP-binding cassette, subfamily G, member 5

605459

AR

Sitosterolemia

ABCG8

ATP- binding cassette, subfamily G, member 8

605460

AR

Sitosterolemia

 

APOB

Apolipoprotein B

107730

AD

 

 

AR

Hypercholesterolemia, due to ligand-defective apo B

 

Hypobetalipoproteinemia

LDLR

Low density lipoprotein receptor

606945

AD

Hypercholesterolemia, familial

 

LDLRAP1

Low density lipoprotein receptor adaptor protein 1

605747

AR

Hypercholesterolemia, familial, autosomal recessive

PCSK9

Proprotein convertase, subtilisin/kexin-type, 9

607786

AD

Hypercholesterolemia, familial, 3

AD: autosomal dominant

AR: autosomal recessive

Reference Values

An interpretive report will be provided.

Interpretation

Evaluation and categorization of variants is performed using the most recent published American College of Medical Genetics and Genomics (ACMG) recommendations as a guideline. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

 

Multiple in silico evaluation tools may be used to assist in the interpretation of these results. The accuracy of predictions made by in silico evaluation tools is highly dependent upon the data available for a given gene, and predictions made by these tools may change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.

Clinical Reference

1. Youngblom E, Pariani M, Knowles JW: Familial hypercholesterolemia. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger, et al. University of Washington, Seattle. Accessed 2/16/18. Available at www.ncbi.nlm.nih.gov/books/NBK174884/

2. Singh S, Bittner V: Familial hypercholesterolemia-epidemiology, diagnosis, and screening. Curr Atheroscler Rep 2015;17(2):482

3. Nordestgaard BG, Chapman MJ, Humphries SE, et al: Familial hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J 2013;34:3478-3490

4. Vandrovcova J, Thomas ER, Atanur SS, et al: The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. Genet Med 2013;15:12:948-957

5. Bouhaire VE,Goldberg AC: Familial hypercholesterolemia. Cardiol Clin 2015;33(2):169-179

6. Andersen LH, Miserez AR, Ahmad Z, Andersen RL: Familial defective apolipoprotein B-100: A review. J Clin Lipidol 2016;10(6):1297-1302

7. Priest JR, Knowles JW: Standards of Evidence and Mechanistic Inference in Autosomal Recessive Hypercholesterolemia. Arterioscler Thromb Vasc Biol 2016;36(8):1465-1466

8. Fellin R, Arca M, Zuliani G, et al: The history of Autosomal Recessive Hypercholesterolemia (ARH). From clinical observations to gene identification. Gene 2015;555(1):23-32

9. Brinton EA, Hopkins PN, Hegele RA, et al: The association between hypercholesterolemia and sitosterolemia, and report of a sitosterolemia kindred. J Clin Lipidol 2018 Jan-Feb;12(1):152-161

10. Wang W, Jiang L, Chen PP, et al: A case of sitosterolemia misdiagnosed as familial hypercholesterolemia: A 4-year follow-up. J Clin Lipidol 2018 Jan-Feb;12(1):236-239

Day(s) and Time(s) Performed

Wednesday; Varies

Analytic Time

2 weeks

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

CPT Code Information

81479

81406 x 2

81407

LOINC Code Information

Test ID Test Order Name Order LOINC Value
FHRGP Hypercholesterolemia Gene Panel In Process

 

Result ID Test Result Name Result LOINC Value
601697 Gene(s) Evaluated 36908-2
601708 Result Summary 50397-9
601709 Result Details 82939-0
601710 Interpretation 69047-9
601711 Additional Information 48767-8
601712 Method 49549-9
601713 Disclaimer 62364-5
601714 Reviewed By 18771-6
Mayo Clinic Laboratories | Cardiology Catalog Additional Information:

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