Familial Hypercholesterolemia (LDLR)
Familial hypercholesterolemia is an autosomal recessive disease caused by pathogenic variants in the LDLR gene. Although it has been diagnosed in individuals worldwide, the disease is more prevalent in individuals of Ashkenazi Jewish, Finnish, or French Canadian descent, as well as South African Afrikaners. For patients who inherit two mutant alleles, age of onset is in childhood or adolescence. The disease is characterized by high levels of cholesterol in the bloodstream and cholesterol deposits on the tendons (xanthomas). Due to the high levels of cholesterol, hardening of the arteries can occur at a young age and most patients have severe coronary heart disease by their mid-20s. Many patients have either coronary bypass surgery, or a fatal heart attack, in adolescence. Individuals who carry one mutant allele also have hypercholesterolemia, although not to the same extent. These individuals have a 20-fold increased risk of coronary heart disease compared to the general public. Without treatment, men have a 50% chance of having a heart attack by age 50, and women have a 30% chance by age 60. All patients with two mutant alleles are likely to have severe disease. Heterozygous carriers with a null variant are more likely to have severe disease compared to carriers of a missense variant, although it may not always be possible to predict the severity of disease based on the genotype.
For information about carrier frequency and residual risk, please see the residual risk table.