Clinical Information

Familial hypercholesterolemia (FH) is an inherited condition that results in elevated levels of low-density lipoprotein cholesterol (LDL-C). FH is associated with premature cardiovascular disease and myocardial infarction. Early diagnosis and treatment help to mitigate these risks.

The most common form of FH is autosomal dominant heterozygous familial hypercholesterolemia (heFH) caused by loss-of-function variants found in the LDLR gene. Recent studies suggest that the prevalence of heFH is as high as 1 in 200 to 250 and may be even higher in some founder populations such as those of French Canadian, Ashkenazi Jewish, Lebanese, and South African descent. In general, FH heterozygotic individuals have 2-fold elevations in plasma cholesterol and develop coronary atherosclerosis after the age of 30. Hundreds of variants have been identified in the LDLR gene. The majority of variants in the LDLR gene are small point variants (missense, nonsense) or small insertions or deletions. Most of these variants are detectable by sequencing of the LDLR gene. An additional 10% of variants in the LDLR gene are large intragenic rearrangements, such as large exon deletions and duplications. Absent or decreased LDL-receptor results in a reduced capacity to clear LDL from circulation.

A more severe form of familial hypercholesterolemia can also be caused by homozygous or compound heterozygous (biallelic) variants in the LDLR gene. This condition is referred to as homozygous familial hypercholesterolemia (hoFH). Recent studies suggest the prevalence of hoFH is as high as 1 in 250,000. Individuals with homozygous FH typically have severe hypercholesterolemia (generally >650 mg/dL) with the presence of cutaneous xanthomas prior to 4 years of age, childhood coronary heart disease, and oftentimes, death from myocardial infarction prior to 20 years of age.

Another form of autosomal dominant hypercholesterolemia is called familial defective apolipoprotein B-100 (FDB). FDB is caused by loss-of-function variants in the APOB gene that reduce the binding affinity between the protein encoded by APOB (apolipoprotein B-100) and the protein encoded by LDLR (low-density lipoprotein receptor). Individuals with heterozygous APOB variants have elevated LDL-C, although the elevation is typically less than that observed in individuals with heterozygous LDLR variants; increased rates of coronary artery calcifications; and premature myocardial infarction. Approximately 1 in 1667 Northern European Caucasians carry the R3500Q (HGVS: c.10580G>A, p.Arg3527Gln) variant in the APOB gene, and approximately 1 in 800 East Asians carry the R3500W (HGVS: c.10579C>T, p.Arg3527Trp) variant in the APOB gene. Although other variants resulting in autosomal dominant hypercholesterolemia have been described in APOB; most appear within a hotspot (or frequently affected) region surrounding the p.Arg3527 residue. Homozygosity and compound heterozygosity for APOB variants can also occur; these individuals typically have LDL-C levels above 300 mg/dL. Individuals with homozygous FDB are sometimes misdiagnosed with heFH.

Autosomal dominant hypercholesterolemia can also be caused by gain-of-function variants in the PCSK9 gene. Variants in this gene are rare, but when present, they result in increased PCSK9 protein levels, leading to increased degradation of low-density lipoprotein receptors. Recently, drugs targeting PCSK9 (called PCSK9 inhibitors) have been developed. These drugs inhibit the binding of PCSK9 to LDL-receptors, thus reducing degradation of LDL-receptors and increasing the amount of LDL-C cleared in certain individuals.

Loss-of-function variants in the LDLRAP1 gene cause a rare form of familial hypercholesterolemia called autosomal recessive familial hypercholesterolemia. Once LDL-C binds to the LDL-receptor the LDLRAP1 protein binds to the complex and internalization of the complex, which results in degradation of either the LDL particle or the entire complex occurs. Unlike autosomal dominant hypercholesterolemia caused by heterozygous variants in LDLR, APOB, and PCSK9, biallelic variants in LDLRAP1 are required for elevated LDL-C levels. Individuals with homozygous or compound heterozygous LDLRAP1 variants typically have LDL-C levels above 400 mg/dL, cutaneous and tendon xanthomas, and coronary artery disease. Heterozygosity for LDLRAP1 variants does not result in elevated cholesterol levels, so the parents of children with biallelic LDLRAP1 variants are typically normocholesterolemic.

Sitosterolemia, a rare autosomal recessive inherited lipid metabolism disease, is caused by biallelic variants in the ABCG5 or ABCG8 genes and has similar clinical manifestations to familial hypercholesterolemia. Sitosterolemia is characterized by increased intestinal absorption of plant sterols (15% to 60% compared to <5% in unaffected individuals). These individuals also typically have elevated total cholesterol and LDL cholesterol levels, although individuals with normal LDL-C levels have also been reported. Untreated individuals with sitosterolemia exhibit tendon and tuberous xanthomas in childhood, premature atherosclerosis, myocardial infarction, and coronary heart disease. At least one report of an individual with sitosterolemia being misdiagnosed with homozygous FH has been reported. The authors noted that the Dutch Lipid Clinic Network diagnostic (DLCN) criteria could not distinguish between homozygous FH and sitosterolemia in this individual.

Identification of the genetic cause of an individual's clinical features helps to determine the appropriate treatment for their clinical features. Treatment is aimed at lowering plasma LDL levels and plasma sterol levels. Common treatments included statins, LDL apheresis, dietary modifications, and more recently PCSK9 inhibitors. Screening of at-risk family members allows for effective primary prevention by instituting appropriate therapy and dietary modifications at an early stage.

Table 1. Genes included in this panel

AD: autosomal dominant

AR: autosomal recessive