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Autosomal dominant familial hypercholesterolemia, Autosomal recessive familial, hypercholesterolemia, Familial hypercholesterolemia, FH, HeFH, HoFH, Hypercholesterolemia, LDLR, NextGen Sequencing Test, Sitosterolemia
This test utilizes next-generation sequencing to detect single nucleotide and copy number variants in 12 genes associated with familial hypercholesterolemia (FH), sitosterolemia, and other monogenic forms of inherited hypercholesterolemia: ABCG5, ABCG8, APOB, APOE, CETP, CYP27A1, LDLR, LDLRAP1, LIPA, LPL, LRP6, and PCSK9. See Targeted Genes and Methodology Details for Hypercholesterolemia Gene Panel and Method Description for additional details.
Identification of a disease-causing variant may assist with diagnosis, prognosis, clinical management, recurrence risk assessment, familial screening, and genetic counseling for FH, sitosterolemia, and other monogenic forms of inherited hypercholesterolemia.
This test also reports homozygous status for the APOE E2 allele, a risk allele for type III hyperlipoproteinemia.
Providing a genetic evaluation for patients with a personal or family history suggestive of familial hypercholesterolemia (FH), sitosterolemia, or other monogenic forms of inherited hypercholesterolemia
Establishing a diagnosis of FH, sitosterolemia, or other monogenic forms of inherited hypercholesterolemia
Specimen preferred to arrive within 96 hours of collection.
Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.
1. Invert several times to mix blood.
2. Send whole blood specimen in original tube. Do not aliquot.
All specimens will be evaluated at Mayo Clinic Laboratories for test suitability.
Test results should be interpreted in the 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 clinically significant family history, it is often useful to first test an affected family member. Detection of a reportable variant in an affected family member would allow for more informative testing of at-risk individuals.
To discuss the availability of additional testing options or for assistance in the interpretation of these results, contact the Mayo Clinic Laboratories genetic counselors at 800-533-1710.
Technical Limitations: Next-generation sequencing may not detect all types of genomic variants. In rare cases, false-negative or false-positive results may occur. The depth of coverage may be variable for some target regions; assay performance below the minimum acceptable criteria or for failed regions will be noted. Given these limitations, negative results do not rule out the diagnosis of a genetic disorder. If a specific clinical disorder is suspected, evaluation by alternative methods can be considered.
There may be regions of genes that cannot be effectively evaluated by sequencing or deletion and duplication analysis as a result of technical limitations of the assay, including regions of homology, high guanine-cytosine (GC) content, and repetitive sequences. Confirmation of select reportable variants will be performed by alternate methodologies based on internal laboratory criteria.
This test is validated to detect 95% of deletions up to 75 base pairs (bp) and insertions up to 47 bp. Deletions-insertions (delins) of 40 or more bp, including mobile element insertions, may be less reliably detected than smaller delins.
This analysis targets single and multi-exon deletions/duplications; however, in some instances single exon resolution cannot be achieved due to isolated reduction in sequence coverage or inherent genomic complexity. Balanced structural rearrangements (such as translocations and inversions) may not be detected.
This test is not designed to detect low levels of mosaicism or to differentiate between somatic and germline variants. If there is a possibility that any detected variant is somatic, additional testing may be necessary to clarify the significance of results.
Genes may be added or removed based on updated clinical relevance. Refer to the Targeted Genes and Methodology Details for Hypercholesterolemia Gene Panel for the most up to date list of genes included in this test. For detailed information regarding gene specific performance and technical limitations, see Method Description or contact a laboratory genetic counselor.
If the patient has had an allogeneic hematopoietic stem cell transplant or a recent blood transfusion, results may be inaccurate due to the presence of donor DNA. Call Mayo Clinic Laboratories for instructions for testing patients who have received a bone marrow transplant.
Reclassification of Variants:
At this time, it is not standard practice for the laboratory to systematically review previously classified variants on a regular basis. The laboratory encourages healthcare providers to contact the laboratory at any time to learn how the classification of a particular variant may have changed over time.
Evaluation and categorization of variants are performed using published American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations as a guideline.(8) Other gene-specific guidelines may also be considered. Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. Variants classified as benign or likely benign are not reported.
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 periodic updates to these tools may cause predictions to change over time. Results from in silico evaluation tools should be interpreted with caution and professional clinical judgment.
Rarely, incidental or secondary findings may implicate another predisposition or presence of active disease. Incidental findings may include, but are not limited to, results related to the sex chromosomes. These findings will be carefully reviewed to determine whether they will be reported.
Hypercholesterolemia, characterized by elevated cholesterol levels in the blood, can be an inherited (genetic) condition or can be acquired due to either lifestyle factors such as diet or exercise or an underlying medical condition. The genetic influence on cholesterol levels can be complex, with monogenic (single gene) or polygenic (many genes) etiologies. This gene panel assesses for monogenic causes of hypercholesterolemia only.
Autosomal dominant familial hypercholesterolemia (FH) is the most common inherited hypercholesterolemia condition and is characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C), leading to increased risk of premature cardiovascular disease and myocardial infarction. Affected individuals may also exhibit xanthomas that worsen with age. The majority of cases of FH are due to loss-of-function variants in the LDLR gene, but FH can also be caused by loss-of-function variants in the APOB gene or gain-of-function in the PCSK9 gene.(1,2) The most common form of FH is autosomal dominant heterozygous familial hypercholesterolemia (heFH) caused by single, heterozygous variants in LDLR, APOB, or PCSK9, but a more severe form of FH, homozygous FH (hoFH), results when an individual inherits two variants in one of the three associated genes, either in the homozygous or compound heterozygous state.(1,2) Recent studies suggest that the prevalence of heFH is as high as 1:200 to 1:250, and the prevalence of hoFH is between 1:160,000 to 1:250,000.(1,2)
Autosomal recessive FH, due to biallelic (homozygous or compound heterozygous) variants in the LDLRAP1 gene is a rare form of inherited hypercholesterolemia and is typically characterized by LDL-C levels above 400 mg/dL as well as cutaneous and tendon xanthomas. Individuals with heterozygous LDLRAP1 variants are expected to have normal LDL-C in the absence of other environmental or lifestyle factors.(1,2)
Sitosterolemia is a rare, autosomal recessive inherited lipid metabolism disease caused by biallelic variants in the ABCG5 or ABCG8 genes. The condition is characterized by increased intestinal absorption of plant sterols and has similar clinical manifestations to familial hypercholesterolemia including elevated LDL-C, xanthomas, increased risk of premature cardiovascular disease, and increased risk of myocardial infarction. The prevalence of sitosterolemia has not been well-established.(3)
Other, more rare genetic conditions that may present with elevated cholesterol levels include autosomal recessive lysosomal acid lipase deficiency due to variants in the LIPA gene, autosomal dominant hyperalphalipoproteinemia due to variants in the CETP gene, autosomal recessive lipoprotein lipase deficiency due to variants in the LPL gene, and atypical autosomal dominant hypercholesterolemia due to variants in the APOE gene (4). In addition, emerging evidence suggests that the LRP6 gene may be associated with autosomal dominant coronary artery disease, a condition in which hypercholesterolemia is a feature.(5,6)
Cerebrotendinous xanthomatosis is a rare, autosomal dominant condition caused by disease-causing variants in the CYP27A1 gene. Individuals with cerebrotendinous xanthomatosis do not typically have elevated plasma cholesterol levels but do have clinical manifestations that overlap with hypercholesterolemia conditions including xanthomas and increased risk for premature cardiovascular disease and myocardial infarction.(7)
An interpretive report will be provided.
All detected variants are evaluated according to American College of Medical Genetics and Genomics recommendations.(8) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.