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Unit Code 81013:
Familial Hypercholesterolemia, LDLR Full Gene Sequencing

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Useful For

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

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. 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.

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 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.

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;1:445-446

 

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

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