Clinical Information

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. While LDLRAP1-associated hypercholesterolemia is rare, emerging evidence suggests heterozygous carriers of disease-causing LDLRAP1 variants may also present with hypercholesterolemia.(3,4,5,6)

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.(7)

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.(8) 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.(9,10)

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.(11)