The inheritance of familial hypercholesterolemia

Several forms of familial hypercholesterolemia are now recognized. The most common is characterized by elevated serum cholesterol levels with normal or only modestly elevated serum triglyceride levels, currently classified as type II hyperlipoproteinemia. It is the current consensus that this form of familial hypercholesterolemia is transmitted by a single dominant gene, although polygenic inheritance has been proposed by McKusick as an alternate hypothesis. Decision as to the most probable mode of inheritance of familial hypercholesterolemia must be based upon family studies which enumerate a recognizable characteristic of hypercholesterolemia and compare the observed incidence with models for Mendelian inheritance. Several characteristics have been used over the years. Serum total cholesterol level is now most widely accepted, although attempts at use of the beta lipoprotein level are now in progress, and in the future use of other attributes can be anticipated. When the serum total cholesterol level is used the available evidence indicates that polygenic inheritance is more probable than transmission by a single dominant gene. The practical implications of this conclusion are (1) In family studies of hypercholesterolemia, the serum cholesterol level of both parents must be tested. (2) Genetic counseling should take into account the probability that children will have serum cholesterol levels more nearly resembling a midparent than either normal parent or hypercholesterolemic parent. (3) It is not possible to select any single cholesterol level as a valid characteristic for familial hypercholesterolemia. (4) Children who have borderline cholesterol values cannot be classified as having or not having the hypercholesterolemic trait. (5) The effect of any single medication or therapeutic procedure predictably will vary in different families.