Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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. Mutations in LDLR 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 (generally >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 in many different populations, with an approximate average incidence of 1 in 500 individuals, but as high as 1 in 67 to 1 in 100 individuals in some populations in South Africa and 1 in 270 in the French Canadian population. Homozygous FH occurs at a frequency of approximately 1 in 1,000,000.
Treatment for FH is aimed at lowering the plasma level of LDL 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, and treatment in this population 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). Although most FH-causing mutations are small (eg, point mutations), approximately 10% to15% of mutations in the LDLR gene are large rearrangements such as exonic deletions and duplications, which are not amenable to sequencing (eg, LDLRS/81013 Familial Hypercholesterolemia, LDLR Full Gene Sequencing) but can be detected by this MLPA assay.
Aiding in the diagnosis of familial hypercholesterolemia (FH) in individuals with elevated untreated low-density lipoprotein (LDL) cholesterol
Distinguishing the diagnosis of FH from other causes of hyperlipidemia, such as familial defective ApoB-100 and familial combined hyperlipidemia
Comprehensive LDL receptor genetic analysis for suspect FH individuals who test negative for an LDLR point mutation by sequencing (LDLRS/81013 Familial Hypercholesterolemia, LDLR Full Gene Sequencing)
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Absence of a mutation does not preclude the diagnosis of familial hypercholesterolemia (FH) unless a specific mutation has already been identified in an affected family member.
In the event of negative results by this technique, LDLR sequencing (LDLRS/81013 Familial Hypercholesterolemia, LDLR Full Gene Sequencing) should be considered to rule out point mutations and small deletions/duplications.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Hobbs H, Brown MS, Goldstein JL: Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992:1:445-466
2. Goldstein JL, Hobbs H, Brown MS: Familial hypercholesterolemia. In The Metabolic Basis of Inherited Disease. Edited by CR Scriver, AL Beaudet, D Valle, et al New York, McGraw-Hill Book Company, 2006 pp 2863-2913
3. Van Aalst-Cohen ES, Jansen AC, Tanck MW, et al: Diagnosing familial hypercholesterolemia: the relevance of genetic testing. Eur Heart J 2006;27:2240-2246
4. Soutar AK, Naoumova RP: Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2007;4(4):214-225
5. Schouten JP, McElgunn CJ, Waaijer R, et al: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res, 2002;30(12):e57