Familial Hypercholesterolemia via the PCSK9 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
870 PCSK9$940.00 81479 Add to Order
Targeted Testing

For ordering targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

Pathogenic gain-of-functions variants in the PCSK9 gene are found in < 5% of FH cases (Hopkins et al. 2011)

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 PCSK9$990.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

Few large deletions or duplications in the PCSK9 gene have been reported in cases of FH and they are a rare cause of FH.

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Clinical Features

Familial Hypercholesterolemia is associated with heterozygous or homozygous mutations in one of three known genes: LDLR, APOB, and PCSK9. In general, heterozygous mutations in any one of these genes can result in a 2-3 fold increase in plasma LDL and a dramatically increased risk of heart disease compared to unaffected individuals. Homozygous or compound heterozygous patients are rare and generally have a much more severe phenotype with an early onset. The prevalence of heterozygous FH is around 1:500 in the U.S. Caucasian population and is similar for most European populations (Goldstein et al. 1973; Vuorio et al. 1997; Slack, J.  1979; Kalina et al. 2001; Austin et al. 2004). FH is particularly common among populations of African ancestry which have a reported prevalence as high as 1/67 (Austin et al. 2004). Most cases of FH are attributed to loss-of-function mutations in LDLR (van Aalst-Cohen et al. 2006) which encodes the LDL receptor. A small fraction of FH cases, <5%, are attributed to gain-of-function mutations in the PCSK9 gene (Abifadel et al. 2003; Hopkins et al. 2011). PCSK9 encodes the NARC-1 (neural apoptosis regulated convertase) protein which contributes to cholesterol homeostasis through degradation of LDLR (Abifadel et al. 2003). Gain-of-function variants in PCSK9 result in increased degradation of LDLR which increases serum LDL levels. Pathogenic variants have been reported throughout the PCSK9 gene and comprise primarily missense variants.


Familial Hypercholesterolemia (FH) is characterized by elevated serum levels of total cholesterol. It is primarily recognized clinically by severely elevated levels of low density lipoprotein (LDL) cholesterol. Typically, high LDL is considered anything above 160 mg/dL in persons under 20 years of age, and anything above 190 mg/dL in adults over 20 years of age (Hopkins et al. 2011). Accumulation of LDL can cause early onset atherosclerosis and increases the risk of coronary heart disease (CHD) by approximately 20% (Hopkins et al. 2011; Austin et al. 2004). By age 50, approximately 45% of male and 20% of female FH patients suffer from coronary artery disease (Goldstein et al. 2001). Other symptoms of FH include fatty skin deposits called xanthomas, cholesterol deposits in the eyelids, and chest pains associated with coronary artery disease. FH is present from birth and is phenotypically heterogeneous. Patients with FH often respond well to drug treatment, i.e. statins, and to lifestyle changes, including increased exercise and diets low in saturated fats, making early risk assessment and diagnosis very beneficial.

Testing Strategy

Our DNA sequencing involves bidirectional Sanger sequencing of all 12 coding exons of the PCSK9 gene plus ~10 bp of flanking non-coding DNA on either side of each exon. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Patients with the one or more of the following: very high levels of LDL cholesterol, low levels of LDLR, strong family history of cardiovascular disease, xanthomas, or fatty liver.


Official Gene Symbol OMIM ID
PCSK9 607786
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hypercholesterolemia, Autosomal Dominant, 3 603776


Genetic Counselors
  • Abifadel M, Varret M, Rabès J-P, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, et al. 2003. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34: 154–156. PubMed ID: 12730697
  • Austin MA, Hutter CM, Zimmern RL, Humphries SE. 2004. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am. J. Epidemiol. 160: 407–420. PubMed ID: 15321837
  • Goldstein et al. 2001. In: The Metabolic and Molecular Basis of Inherited Disease - 8th edition (edited by C.R. Scriver et al.) New York: McGraw-Hill. 
  • Hopkins PN, Toth PP, Ballantyne CM, Rader DJ, National Lipid Association Expert Panel on Familial Hypercholesterolemia. 2011. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 5: S9–17. PubMed ID: 21600530
  • Kalina A, Császár A, Czeizel AE, Romics L, Szabóki F, Szalai C, Reiber I, Németh A, Stephenson S, Williams RR. 2001. Frequency of the R3500Q mutation of the apolipoprotein B-100 gene in a sample screened clinically for familial hypercholesterolemia in Hungary. Atherosclerosis 154: 247–251. PubMed ID: 11137107
  • Slack, J. 1979. Inheritance of familial hypercholesterolemia. Atheroscler Rev 5:35-66.
  • van Aalst-Cohen, Jansen AC, Tanck MW, Defesche JC, Trip MD, Lansberg PJ, Stalenhoef AF, Kastelein JJ.. 2006. Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. European Heart Journal 27: 2240–2246. PubMed ID: 16825289
  • Vuorio AF, Turtola H, Piilahti KM, Repo P, Kanninen T, Kontula K. 1997. Familial hypercholesterolemia in the Finnish north Karelia. A molecular, clinical, and genealogical study. Arterioscler. Thromb. Vasc. Biol. 17: 3127–3138. PubMed ID: 9409302
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants, due for example to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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