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ADHP
83375
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
Familial Hypercholesterolemia/Autosomal Dominant
Hypercholesterolemia Genetic Testing Reflex Panel
Clinical Information: 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 1:500 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 mutations in the LDLR gene, which
encodes for the LDL receptor. Approximately 15% of ADH cases have familial defective apolipoprotein
B-100 (FDB) due to mutations 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 1:500 individuals, but as high as 1:67 to 1:100 individuals in some South African populations
and 1:270 in the French Canadian population. Homozygous FH occurs at a frequency of approximately
1:1,000,000. 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 mutation 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 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. The majority of mutations in the LDLR gene are missense,
small insertion or deletion mutations, and other point mutations, most of which are detected by full gene
sequencing. Approximately 10% to 15% of mutations 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 mutation at residue 3500, resulting in a glutamine substitution
for the arginine residue (R3500Q). This common FDB mutation occurs at an estimated frequency of 1:500
individuals of European descent. A less frequently occurring mutation 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 mutation 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,
mutations at residue 3500 lead to a reduced binding affinity of LDL for its receptor. Identification of 1 or
more mutations 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 (i.e., 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
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