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Unit Code 89073:
Familial Hypercholesterolemia, LDLR Large Deletion/Duplication, Molecular Analysis

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Useful For

Aiding in the diagnosis of familial hypercholesterolemia (FH)

in individuals with elevated untreated 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 (#81013 "Familial Hypercholesterolemia, LDLR Full

Gene Sequencing")

Clinical Information

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, #81013 "Familial Hypercholesterolemia, LDLR Full Gene Sequencing")

but can be detected by this MLPA assay.

Reference Values

An interpretive report will be provided.

Interpretation

An interpretive report will be provided.

Cautions

Absence of a mutation does not preclude the diagnosis of 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

(#81013 "Familial Hypercholesterolemia, LDLR Full Gene Sequencing")

should be considered to rule out point mutations and small deletions/

duplications

Special Instructions and Forms

• Informed Consent Form for DNA Testing 
• Familial/Autosomal Dominant Hypercholesterolemia Patient Information Sheet 

Clinical Reference

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

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