Familial Hypercholesterolemia via the PCSK9 Gene

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.

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. White 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.

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

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

This test provides full coverage of all coding exons of the PCSK9 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).