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Autosomal dominant hypercholesterolemia (ADH) is characterized by high levels of LDL cholesterol and associated with premature cardiovascular disease and myocardial infarction. The majority of ADH is caused by genetic variants that lead to decreased intracellular uptake of cholesterol. Approximately 1 in 500 individuals worldwide are affected by ADH and 15% of individuals with ADH have familial defective apolipoprotein B-100 (FDB) due to mutations in the LDL receptor-binding domain of the APOB gene, which maps to chromosome 2p and encodes for apolipoprotein B-100. FDB can occur in either the heterozygous or homozygous state, with the latter expressing more severe disease. Approximately 40% of males and 20% of females with an APOB mutation will develop coronary artery disease.
The vast majority of FDB cases are caused by a single APBO mutation at residue 3500, resulting in a glutamine substitution for the arginine residue (R3500Q). This common FDB mutation occurs at an estimated frequency of 1:500 individuals of European descent. Another, less frequently occurring mutation at that same codon results in a tryptophan substitution, R3500W, and is more prevalent in individuals of Chinese and Malay descent, but has been identified in the Scottish population as well. The R3500W mutation is estimated to occur in approximately 2% of ADH cases. Residue 3500 interacts with other apolipoprotein B-100 residues to induce conformational changes necessary for apolipoprotein B-100 binding to the LDL receptor. Thus, mutations at residue 3500 lead to a reduced binding affinity of LDL for its receptor.
There is a high degree of phenotypic overlap between FDB and familial hypercholesterolemia (FH), the latter due to mutations in LDLR, which encodes for the LDL receptor (LDLR). In general, individuals with FDB have less severe hypercholesterolemia, fewer occurrences of tendinous xanthomas, and a lower incidence of coronary artery disease, compared with FH. Plasma LDL cholesterol levels in patients with homozygous FDB are similar to levels found in patients with heterozygous (rather than homozygous) FH.
Identification of APOB mutations in individuals suspected of having ADH helps to obtain a definitive diagnosis of the disease as well as determine appropriate treatment. Therapy for FDB is aimed at lowering the plasma levels of LDL, and both heterozygotes and homozygotes generally respond well to statins. Screening of at-risk family members allows for effective primary prevention by instituting statin therapy and dietary modifications at an early stage.
Aiding in the diagnosis of familial defective apolipoprotein B-100 in individuals with elevated untreated LDL cholesterol concentrations
Distinguishing the diagnosis of familial defective apolipoprotein B-100 from other causes of hyperlipidemia, such as familial hypercholesterolemia and familial combined hyperlipidemia
Comprehensive genetic analysis for hypercholesterolemic individuals who test negative for a mutation in the LDLR gene by sequencing (LDLRS / Familial Hypercholesterolemia, LDLR Full Gene Sequencing) and/or gene dosage (LDLM / Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis)
An interpretive report will be provided.
This test does not detect APBO mutations other than R3500W and R3500Q.
Absence of a mutation does not preclude the diagnosis of familial defective apolipoprotein B-100 unless a specific mutation has already been identified in an affected family member.
If considering other causes of autosomal dominant hypercholesterolemia (eg, familial hypercholesterolemia), order LDLRS / Familial Hypercholesterolemia, LDLR Full Gene Sequencing, or LDLM / Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis.
This assay is a genetic test for the APOB gene and will not provide an apolipoprotein B measurement. If apolipoprotein B analysis is desired, see APLB / Apolipoprotein B, Plasma.
An interpretive report will be provided.
1. Whitfield AH, Barrett PHR, Van Bockxmeer FM, and Burnett JR: Lipid disorders and mutations in the APOB gene. Clin Chem 2004;50:1725-1732
2. Innerarity TL, Mahley RW, Weisgraber KH, et al: Familial defective apolipoprotein B100: a mutation of Apolipoprotein B that causes hypercholesterolemia. J Lipid Res 1990;31:1337-1349
3. Soria LF, Ludwig EH, Clarke HR, et al: Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. Proc Natl Acad Sci USA 1989;86:587-591