This test provides a comprehensive analysis of the genes associated with familial hypercholesterolemia (FH).
Individuals with unexplained elevated cholesterol or early cardiovascular disease may benefit from the confirmation of an FH diagnosis through genetic testing to initiate appropriate medical therapy and enable more targeted therapy. Early and appropriate medical intervention can reduce the risk of cardiovascular events. At-risk relatives could be identified and preventive therapy could be initiated. The Centers for Disease Control (CDC) Office of Public Health Genomics has categorized genetic testing for FH as a “Tier 1” classification, which indicates that there is evidence to support the use of this genetic test in medical practice.
APOB LDLR LDLRAP1 PCSK9
APOB LDLR LDLRAP1 PCSK9
Familial hypercholesterolemia (FH) is characterized by an increase of low-density lipoprotein cholesterol (LDL-C) that can cause plaque to build up in the arteries (atherosclerotic plaque deposits) at an early age. This build-up of plaque can lead to the development of premature coronary artery disease (CAD). CAD leads to an increased risk for heart attack and stroke.
Some individuals with FH may have no symptoms and are only found to have elevated LDL-C levels through routine lipid testing. Individuals with FH may come to medical attention due to symptoms that are related to the development of cardiovascular disease. These symptoms can include chest pain, heart attack, stroke, and/or peripheral vascular disease. Some individuals with FH are found to have xanthomas (fatty skin growths) and/or corneal arci (cholesterol deposits in the eye).
Approximately 60%-80% of individuals with FH are expected to have a pathogenic variant identified in one of the genes on this panel. A negative genetic test result does not rule out the possibility that an individual may have FH.
|Gene||% of FH cases attributed|
|PCSK9||Up to 3%|
FH is inherited in both autosomal dominant and autosomal recessive patterns.
FH exhibits reduced penetrance, meaning not everyone who inherits a predisposition to develop FH will go on to manifest the disorder. However, the penetrance is high—estimated at 90% for individuals with pathogenic variants in LDLR and PCSK9.
Individuals with untreated FH and one pathogenic variant are 20 times more likely to develop coronary heart disease. Men have a 50% risk by age 50 years and women have a 30% risk by age 65 years. Individuals with untreated FH and two pathogenic variants are at risk of developing overt atherosclerosis before 20 years of age. Early or preventive intervention—medications to lower lipid levels and diet and lifestyle changes—can substantially reduce the risk of developing coronary heart disease in individuals with FH, bringing their risk for coronary heart disease closer to the general population’s.
The prevalence of autosomal dominant familial hypercholesterolemia is 1 in 200-500. It is higher in French Canadian, Christian Lebanese, and Ashkenazi Jewish populations. The prevalence of autosomal recessive familial hypercholesterolemia ranges from 1 in 160,000 to 1 in 1,000,000.
This test may be considered for individuals with:
For links to published management guidelines, please refer to our Management guidelines page.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|