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Familial hypercholesterolemia (FH) is an autosomal dominant disorder that is characterized by high levels of low-density lipoprotein (LDL) cholesterol and associated with premature cardiovascular disease and myocardial infarction. FH is caused by mutations in the LDLR gene, which encodes for the LDL receptor. LDLR mutations impair the ability of the LDL receptor to remove LDL cholesterol from plasma via receptor-mediated endocytosis, leading to elevated levels of plasma LDL cholesterol and subsequent deposition in the skin and tendons (xanthomas) and arteries (atheromas).
FH can occur in either the heterozygous or homozygous state, with 1 or 2 mutant LDLR alleles, respectively. In general, FH heterozygotes have 2-fold elevations in plasma cholesterol and develop coronary atherosclerosis after the age of 30. Homozygous FH individuals have severe hypercholesterolemia (>650 mg/dL) with the presence of cutaneous xanthomas prior to 4 years of age, childhood coronary heart disease, and death from myocardial infarction prior to 20 years of age. Heterozygous FH is prevalent among many different populations, with an approximate average worldwide incidence of 1 in 500 individuals, but as high as 1 in 67 to 1 in 100 individuals in some South African populations and 1 in 270 in the French Canadian population. Homozygous FH occurs at a frequency of approximately 1 in 1,000,000.
Treatment is aimed at lowering plasma LDL levels and increasing LDL receptor activity. Identification of LDLR mutation(s) in individuals suspected of having FH helps to determine appropriate treatment. FH heterozygotes are often treated with 3-hydroxy-3-methylglutaryl CoA reductase inhibitors (ie, statins), either in monotherapy or in combination with other drugs such as nicotinic acid and inhibitors of intestinal cholesterol absorption. Such drugs are generally not effective in FH homozygotes; treatment in these individuals may consist of LDL apheresis, portacaval anastomosis, and liver transplantation.
The LDLR gene maps to chromosome 19p13 and consists of 18 exons spanning 45 kb. Hundreds of mutations have been identified in the LDLR gene, the majority of them occurring in the ligand binding and epidermal growth factor (EGF) precursor homology regions in the 5' region of the gene (type II and III mutations, respectively). The majority of LDLR mutations are missense, small insertion, deletion and other point mutations, most of which are detected by full-gene sequencing. Approximately 10% to 15% of LDLR mutations are large rearrangements, such as exonic deletions and duplications, which cannot be detected by full-gene sequencing.
Aiding in the diagnosis of familial hypercholesterolemia (FH)
Distinguishing the diagnosis of FH from other causes of hyperlipidemia, such as familial defective apoB-100 and familial combined hyperlipidemia
An interpretive report will be provided.
Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.
Absence of a mutation does not preclude the diagnosis of familial hypercholesterolemia (FH) unless a specific mutation has been previously identified in an affected family member.
This method will not detect large rearrangement-type mutations or mutations that occur in the introns (except in the splicing regions) and regulatory regions (except the sterol-regulated portion of the promoter) of the gene.
Sometimes a genetic alteration of unknown significance may be identified. In this case, testing of family members may be useful to determine pathogenicity of the alteration.
An interpretive report will be provided.
1. Hobbs H, Brown MS, Goldstein JL: Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992;1:445-446
2. Goldstein JL, Hobbs H, Brown MS: Familial hypercholesterolemia. In The Metabolic Basis of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, WS Sly. New York, McGraw-Hill Book Company, 2006, pp 2863-2913
3. van Aalst-Cohen ES, Jansen AC, Tanck MW, et al: Diagnosing familial hypercholesterolaemia: the relevance of genetic testing. Eur Heart J 2006;27:2440-2446