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Interpretive Handbook

Test 83375 :
Familial Hypercholesterolemia/Autosomal Dominant Hypercholesterolemia Genetic Testing Reflex Panel

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Autosomal dominant hypercholesterolemia (ADH) is characterized by high levels of low-density lipoprotein (LDL) cholesterol, and associated with premature cardiovascular disease and myocardial infarction. Approximately 1 in 500 individuals worldwide are affected by ADH. Most ADH is caused by genetic variants leading to decreased intracellular uptake of cholesterol. The majority of these cases have familial hypercholesterolemia (FH), which is due to variants in the LDLR gene, which encodes for the LDL receptor. Approximately 15% of ADH cases have familial defective apolipoprotein B-100 (FDB) due to variants in the LDL receptor-binding domain of the APOB gene, which encodes for apolipoprotein B-100.


ADH can occur in either the heterozygous or homozygous state, with 1 or 2 mutant 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 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. Similar to FH, FDB homozygotes express more severe disease, although not nearly as severe as FH homozygotes. Approximately 40% of males and 20% of females with an APOB variant will develop coronary artery disease. In general, when compared to FH, individuals with FDB have less severe hypercholesterolemia, fewer occurrences of tendinous xanthoma, and a lower incidence of coronary artery disease. Plasma LDL cholesterol levels in patients with homozygous FDB are similar to levels found in patients with heterozygous (rather than homozygous) FH.


The LDLR gene maps to chromosome 19p13 and consists of 18 exons spanning 45 kb. Hundreds of variants 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. The majority of variants in the LDLR gene are missense, small insertion or deletion variants, and other point variants, most of which are detected by full gene sequencing. Approximately 10% to 15% of variants in the LDLR gene are large rearrangements, such as large exonic deletions and duplications.


The APOB gene maps to chromosome 2p. The vast majority of FDB cases are caused by a single APOB variant at residue 3500, resulting in a glutamine substitution for the arginine residue (R3500Q). This common FDB variant occurs at an estimated frequency of 1 in 500 individuals of European descent. A less frequently occurring variant at that same codon, which results in a tryptophan substitution (R3500W), is more prevalent in individuals of Chinese and Malay descent, and has been identified in the Scottish population as well. The R3500W variant 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, variants at residue 3500 lead to a reduced binding affinity of LDL for its receptor.


Identification of 1 or more variants in individuals suspected of having ADH helps to determine appropriate treatment of this disease. Treatment is aimed at lowering plasma LDL levels and increasing LDL receptor activity. FH heterozygotes and FDB homozygotes and 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 these individuals may consist of LDL apheresis, portacaval anastomosis, and liver transplantation. Screening of at-risk family members allows for effective primary prevention by instituting statin therapy and dietary modifications at an early stage.


This test provides a reflex approach to diagnosing the above disorders. The tests can also be separately ordered:

-LDLRS / Familial Hypercholesterolemia, LDLR Full Gene Sequencing

-LDLM / Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis

-APOB / Apolipoprotein B-100 Molecular Analysis, R3500Q and R3500W


See Familial/Autosomal Dominant Hypercholesterolemia Diagnostic Algorithm in Special Instructions.

Useful For Suggests clinical disorders or settings where the test may be helpful

Aiding in the diagnosis of familial hypercholesterolemia defective apoB-100 in individuals with elevated, untreated low-density lipoprotein cholesterol concentrations


Distinguishing the diagnosis of autosomal dominant hypercholesterolemia from other causes of hyperlipidemia, such as familial combined hyperlipidemia


Genetic evaluation of hypercholesterolemia utilizing a cost-effective, reflex-testing approach

Interpretation Provides information to assist in interpretation of the test results

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

Blood samples may contain donor DNA if obtained from patients who received heterologous blood transfusions or allogeneic blood or marrow transplantation. Results from samples obtained under these circumstances may not accurately reflect the recipient's genotype. For individuals who have received blood transfusions, the genotype usually reverts to that of the recipient within 6 weeks. For individuals who have received allogeneic blood or marrow transplantation, a pretransplant DNA specimen is recommended for testing.


Absence of a variant does not preclude the diagnosis of autosomal dominant hypercholesterolemia unless a specific variant has been previously identified in an affected family member.


The APOB genotyping component of this test only detects the R3500W and R3500Q variants; other APOB variants are not detected.


The LDLR sequencing method will not detect LDLR variants 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.


In addition to disease-related probes, the multiplex ligation-dependent probe amplification technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.

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 HH, Brown MS, Goldstein JL: Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Hum Mutat 1992;1:445-466

2. Goldstein JL, Hobbs HH, 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. Whitfield AJ, Barrett PH, van Bockxmeer FM, Burnett JR: Lipid disorders and mutations in the APOB gene. Clin Chem 2004;50:1725-1732

4. 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