Test Catalog

Test ID: FHRGP    
Familial Hypercholesterolemia and Related Disorders Multi-Gene Panel

Useful For Suggests clinical disorders or settings where the test may be helpful

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

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test includes next-generation sequencing (NGS) and supplemental Sanger sequencing to evaluate for variants in the ABCG5, ABCG8, APOB, LDLR, LDLRAP1, and PCSK9 genes. Additionally, NGS is used to test for the presence of large deletions and duplications in a subset of genes.

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

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 Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

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.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Clinical Correlations:

Some individuals who have involvement of 1 or more of the genes on the panel may have a variation that is not identified by the methods performed (eg, promoter variants, deep intronic variants). The absence of a variant, therefore, does not eliminate the possibility of familial hypercholesterolemia (FH) or a related disorder.

 

Test results should be interpreted in context of clinical findings, family history, and other laboratory data. Misinterpretation of results may occur if the information provided is inaccurate or incomplete.

 

If testing was performed because of a family history of FH or a related disorder, it is often useful to first test an affected family member. Identification of a pathogenic variant in an affected individual would allow for more informative testing of at risk individuals.

 

Technical Limitations:

Next-generation sequencing may not detect all types of genetic variants. Additionally, rare polymorphisms may be present that could lead to false-negative or false-positive results. If the patient has had an allogeneic blood or marrow transplant or a recent (ie, <6 weeks from time of sample collection) heterologous blood transfusion, these results may be inaccurate due to the presence of donor DNA.

 

Reclassification of Variants Policy:

At this time, it is not standard practice for the laboratory to systematically review likely pathogenic variants or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.

 

Contact the laboratory if additional information is required regarding the transcript or human genome assembly used for the analysis of this patientís results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

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

Special Instructions Library of PDFs including pertinent information and forms related to the test