Familial Hypercholesterolemia and Hypobetalipoproteinemia via the APOB Gene

Hypercholesterolemia is characterized by elevated serum levels of total cholesterol, in particular, elevated levels of low density lipoprotein (LDL) cholesterol (LDL-C) (>160 mg/dL in persons under 20 years of age, and >190 mg/dL in adults over 20 years of age, Hopkins et al. 2011. PubMed ID: 21600530). Accumulation of LDL-C can cause early onset atherosclerosis and Coronary Heart Disease (CHD). Familial Hypercholesterolemia (FH) refers to high cholesterol that runs in a family. FH often leads to premature CHD and is one of the most common diseases of lipid metabolism. By age 50, approximately 45% of male and 20% of female FH patients suffer from coronary artery disease, a primary causative factor for CHD (Goldstein et al. 2001).

The prevalence of heterozygous FH (autosomal dominant FH) is between 1:300 and 1:500 in most countries and is much higher within certain populations, for example, 1:67 in Ashkenazi Jews (Goldstein et al. 1973. PubMed ID: 4718953; Vuorio et al. 1997. PubMed ID: 9409302; Slack. 1979; Kalina et al. 2001. PubMed ID: 11137107; Austin et al. 2004. PubMed ID: 15321837). There are as many as 34 million people with FH worldwide, yet FH remains severely underdiagnosed with some studies suggesting <1% of possible FH patients have been identified in many countries (Sjouke et al. 2015. PubMed ID: 24585268; Nordestgaard et al. 2013. PubMed ID: 23956253).

Other symptoms of FH include fatty skin deposits called xanthomas, cholesterol deposits in the eyelids or in the peripheral corneal stroma (i.e. corneal arcus), and chest pains associated with coronary artery disease. FH is present from birth and confers a lifelong risk of atherosclerosis and CHD. Overall, patients with FH respond well to drug treatment making early, accurate diagnosis key factors for reducing risk of atherosclerosis and CHD.

Variants in one of the FH genes, APOB, are also associated with another disorder known as Familial Hypobetalipoproteinemia (FHBL). FHBL is characterized by very low serum levels of apolipoprotein B along with low LDL, and total cholesterol levels <150 mg/dL (Schonfeld et al. 2003. PubMed ID: 12562873). The incidence of FHBL and Abetalipoproteinemia is less than 1 in 1 million (Lee and Hegele. 2004. PubMed ID: 24288038). In contrast to FH, individuals with FHBL are less likely to develop cardiovascular disease (Tarugi et al. 2007. PubMed ID: 17570373). In severe cases, FHBL patients may display clinical symptoms that include fat and vitamin malabsorption, non-alcoholic fatty liver disease, retinitis pigmentosa, neurologic disorders, and red cell acanthocytosis (Tarugi et al. 2001. PubMed ID: 11590210; Hegele. 2009. PubMed ID: 19139765).

Several genes are reported to be associated with FH, however, over 86% of patients with FH are found to harbor pathogenic variants in either LDLR, APOB, PCSK9, which are associated with autosomal dominant FH, or in LDLRAP1 which is associated with autosomal recessive FH. Patients with biallelic variants in LDLR, APOB, or PCSK9, known as homozygous FH (HoFH), are rare and generally have a severe phenotype with a very high risk of early onset CHD. Variants in the APOB gene account for up to 7% of FH cases (Varret et al. 2008. PubMed ID: 18028451).

APOB encodes apolipoprotein B (apo B-48 and apo B-100), the major protein component of LDL particles and ligand for LDL receptor binding (Hegele. 2009. PubMed ID: 19139765). Causative variants associated with FH are located throughout the APOB gene and are comprised primarily by missense variants resulting in defective APOB protein. One variant, defined as p.Arg3500Gln (aka R3500Q), is a recurring pathogenic variant found in up to 1:500 people in White populations in North America and Europe (Rauh et al. 1992. PubMed ID: 1600334; Boren et al. 2001. PubMed ID: 11115503). APOB gene variants associated with FHBL are comprised primarily by nonsense and other protein truncating variants resulting in low levels of full-length APOB protein (Young et al. 1986. PubMed ID: 2419898; Fouchier. 2005. PubMed ID: 15805152).

Pathogenic variants in LDLR are the most common cause of heterozygous Familial Hypercholesterolemia (FH) followed by variants in APOB, PCSK9, and LDLRAP1. The exact proportion of pathogenic variants within these genes varies among populations, but data from several studies indicate the contribution of LDLR, APOB, and PCSK9 pathogenic variants to FH cases ranges from 37-82%, 0-7%, and 0-3%, respectively (Varret et al. 2008. PubMed ID: 18028451). The frequency of LDLRAP1/ARH variants in recessive FH is unclear, but the carrier frequency has been reported to be as high as 1:143 in the Sardinian population (Filigheddu et al. 2009. PubMed ID: 19477448).

Over 15% of pathogenic variants reported for the LDLR and LDLRAP1 genes are either large deletions or insertions (Human Gene Mutation Database). Few large deletions or insertions in the APOB and PCSK9 genes have been reported.

The incidence of Familial Hypobetalipoproteinemia (FHBL) and Abetalipoproteinemia (ABL) is less than 1 in 1 million (Lee and Hegele. 2004. PubMed ID: 24288038). Variants in the APOB, MTTP, and ANGPTL3 genes have been reported to cause FHBL or ABL, but the fraction of cases attributed to variants in each gene is unclear (Schonfeld et al. 2003. PubMed ID: 12562873; Benayoun et al. 2007. PubMed ID: 17275380; Wang et al. 2015. PubMed ID: 25733326).

This test provides full coverage of all coding exons of the APOB 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).