Thompson & Thompson Genetics in Medicine, 8th Edition

Case 16. Familial Hypercholesterolemia (Low-Density Lipoprotein Receptor [LDLR] Mutation, MIM 143890)

Autosomal Dominant


• Environmental modifiers

• Founder effects

• Gene dosage

• Genetic modifiers

Major Phenotypic Features

• Age at onset: Heterozygote—early to middle adulthood; homozygote—childhood

• Hypercholesterolemia

• Atherosclerosis

• Xanthomas

• Arcus corneae

History and Physical Findings

L.L., a previously healthy 45-year-old French Canadian poet, was admitted for a myocardial infarction. He had a small xanthoma on his right Achilles tendon. His brother also had coronary artery disease (CAD); his mother, maternal grandmother, and two maternal uncles had died of CAD. In addition to his family history and sex, his risk factors for CAD and atherosclerosis included an elevated level of low-density lipoprotein (LDL) cholesterol, mild obesity, physical inactivity, and cigarette smoking. On the basis of family history, L.L. was believed to have an autosomal dominant form of hypercholesterolemia. Molecular analysis revealed that he was heterozygous for a deletion of the 5′ end of the LDL receptor gene (LDLR), a mutation found in 59% of French Canadians with familial hypercholesterolemia. Screening of his children revealed that two of the three children had elevated LDL cholesterol levels. The cardiologist explained to L.L. that in addition to drug therapy, effective treatment of his CAD required dietary and lifestyle changes, such as a diet low in saturated fat and low in cholesterol, increased physical activity, weight loss, and smoking cessation. L.L. was not compliant with treatment and died a year later of a myocardial infarction.


Disease Etiology and Incidence

Familial hypercholesterolemia (FH, MIM 143890) is an autosomal dominant disorder of cholesterol and lipid metabolism caused by mutations in LDLR (see Chapter 12). FH occurs among all races and has a prevalence of 1 in 500 in most white populations. It accounts for somewhat less than 5% of patients with hypercholesterolemia.


The LDL receptor, a transmembrane glycoprotein predominantly expressed in the liver and adrenal cortex, plays a key role in cholesterol homeostasis. It binds apolipoprotein B-100, the sole protein of LDL, and apolipoprotein E, a protein found on very-low-density lipoproteins, intermediate-density lipoproteins, chylomicron remnants, and some high-density lipoproteins. Hepatic LDL receptors clear approximately 50% of intermediate-density lipoproteins and 66% to 80% of LDL from the circulation by endocytosis; poorly understood LDL receptor–independent pathways clear the remainder of the LDL.

Mutations associated with FH occur throughout LDLR; 2% to 10% are large insertions, deletions, or rearrangements mediated by recombination between Alu repeats within LDLR. Some mutations appear to be dominant negative. Most mutations are private mutations, although some populations—such as Lebanese, French Canadians, South African Indians, South African Ashkenazi Jews, and Afrikaners—have common mutations and a high prevalence of disease because of founder effects.

Homozygous or heterozygous mutations of LDLR decrease the efficiency of intermediate-density lipoprotein and LDL endocytosis and cause accumulation of plasma LDL by increasing production of LDL from intermediate-density lipoproteins and decreasing hepatic clearance of LDL. The elevated plasma LDL levels cause atherosclerosis by increasing the clearance of LDL through LDL receptor–independent pathways, such as endocytosis of oxidized LDL by macrophages and histiocytes. Monocytes, which infiltrate the arterial intima and endocytose oxidized LDL, form foam cells and release cytokines that cause proliferation of smooth muscle cells of the arterial media. Initially, the smooth muscle cells produce sufficient collagen and matrix proteins to form a fibrous cap over the foam cells; because foam cells continue to endocytose oxidized LDL, however, they eventually rupture through the fibrous cap into the arterial lumen and trigger the formation of thrombi, a common cause of strokes and myocardial infarction.

Environment, sex, and genetic background modify the effect of LDL receptor mutations on LDL plasma levels and thereby the occurrence of atherosclerosis. Diet is the major environmental modifier of LDL plasma levels; for example, most Tunisian FH heterozygotes have LDL levels in the normal North American range and rarely develop cardiovascular disease and xanthomas. Similarly, Chinese FH heterozygotes living in China rarely have xanthomas and cardiovascular disease, whereas Chinese FH heterozygotes living in Western societies have clinical manifestations similar to those of white FH heterozygotes. Dietary cholesterol suppresses the synthesis of LDL receptors, thereby raising plasma LDL levels; this effect of dietary cholesterol is potentiated by saturated fatty acids, such as palmitate from dairy products, and ameliorated by unsaturated fatty acids, such as oleate and linoleate. Because a similar diet does not elevate LDL levels equally among patients, other environmental and genetic factors must also influence LDL metabolism. A few families with FH segregate a different dominant locus that reduces plasma LDL, providing evidence for a genetic modifier. Other forms of FH include type B hypercholesterolemia (MIM 144010), caused by ligand-defective apolipoprotein B-100, and autosomal dominant hypercholesterolemia (MIM 603776), due to PCSK9 mutations. In subjects with the LDLR mutation IVS14+1G-A, the phenotype can be altered by a single nucleotide polymorphism (SNP) in APOA2, a SNP in EPHX2, or a SNP in GHR. A SNP in the promoter region of the G-substrate gene (GSBS) correlates with elevated plasma total cholesterol levels. A SNP in intron 17 of ITIH4 was associated with hypercholesterolemia susceptibility in a Japanese population.

Phenotype and Natural History

Hypercholesterolemia, the earliest finding in FH, usually manifests at birth and is the only clinical finding through the first decade in heterozygous patients; at all ages, the plasma cholesterol concentration is greater than the 95th percentile in more than 95% of patients. Arcus corneae and tendon xanthomas begin to appear by the end of the second decade and by death, 80% of FH heterozygotes have xanthomas (Fig. C-16). Nearly 40% of adult patients have recurrent nonprogressive polyarthritis and tenosynovitis. As tabulated, the development of CAD among FH heterozygotes depends on age and gender. In general, the untreated cholesterol level is greater than 300 mg/dL.


FIGURE C-16 An Achilles tendon xanthoma from a patient with familial hypercholesterolemia. See Sources & Acknowledgments.

Homozygous FH presents in the first decade with tendon xanthomas and arcus corneae. Without aggressive treatment, homozygous FH is usually lethal by the age of 30 years. The untreated cholesterol concentration is between 600 and 1000 mg/dL.


Elevated plasma LDL cholesterol and a family history of hypercholesterolemia, xanthomas, or premature CAD strongly suggest a diagnosis of FH. Confirmation of the diagnosis requires quantification of LDL receptor function in the patient's skin fibroblasts or identification of the LDLR mutation. In most populations, the plethora of LDLR mutations precludes direct DNA analysis unless a particular mutation is strongly suspected. The absence of DNA confirmation does not interfere with management of FH patients, however, because a definitive molecular diagnosis of FH does not provide prognostic or therapeutic information beyond that already derived from the family history and determination of plasma LDL cholesterol level.

Regardless of whether they have FH, all patients with elevated LDL cholesterol levels require aggressive normalization of the LDL cholesterol concentration to reduce their risk for CAD; rigorous normalization of the LDL cholesterol concentration can prevent and reverse atherosclerosis. In FH heterozygotes, rigorous adherence to a low-fat, high-carbohydrate diet usually produces a 10% to 20% reduction in LDL cholesterol, but most patients also require treatment with one or a combination of three classes of drugs: bile acid sequestrants, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, and nicotinic acid (see Chapter 13). Current recommendations are initiation of drug therapy at 10 years of age for patients with an LDL cholesterol level of more than 190 mg/dL and a negative family history for premature CAD, and at 10 years of age for patients with an LDL cholesterol level of more than 160 mg/dL and a positive family history for premature CAD. Among FH homozygotes, LDL apheresis can reduce plasma cholesterol levels by as much as 70%. The therapeutic effectiveness of apheresis is increased when it is combined with aggressive statin and nicotinic acid therapy. Liver transplantation has also been used on rare occasions.

Age- and Sex-Specific Rates (%) of CAD and Death in Familial Hypercholesterolemia Heterozygotes


CAD, Coronary artery disease.

From Rader DJ, Hobbs HH: Disorders of lipoprotein metabolism. In Kasper DL, Braunwald E, Fauci AS, et al, editors: Harrison's principles of internal medicine, ed 16, New York, 2004, McGraw-Hill.

Inheritance Risk

Because FH is an autosomal dominant disorder, each child of an affected parent has a 50% chance of inheriting the mutant LDLR allele. Untreated FH heterozygotes have a 100% risk for development of CAD by the age of 70 years if male and a 75% risk if female (see Table). Current medical therapy markedly reduces this risk by normalizing plasma cholesterol concentration.

Questions for Small Group Discussion

1. What insights does FH provide into the more common polygenic causes of atherosclerosis and CAD?

2. Familial defective apolipoprotein B-100 is a genocopy of FH. Why?

3. Vegetable oils are hydrogenated to make some margarines. What effect would eating margarine have on LDL receptor expression compared with vegetable oil consumption?

4. Discuss genetic susceptibility to infection and potential heterozygote advantage in the context of the role of the LDL receptor in hepatitis C infection.


Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. Longo D, Fauci AS, Kasper DL, et al. Harrison's principles of internal medicine. ed 18. McGraw-Hill: New York; 2012.

Sniderman AD, Tsimikas S, Fazio S. The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies. J Am Coll Cardiol. 2014;63:1935–1947.

Varghese MJ. Familial hypercholesterolemia: a review. Ann Pediatr Cardiol. 2014;7:107–117.

Youngblom E, Knowles JW. Familial hypercholesterolemia. [Available from]