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Genetic aspects of familial hypercholesterolemia and its diagnosis.

Heterozygote familial hypercholesterolemia (FH) is a frequent genetic trait (one in 500) that predisposes to coronary atherosclerosis. Male heterozygotes often develop clinical manifestations of coronary heart disease in their fourth or fifth decade, females, about 10 years later. Other risk factors for ischemic heart disease like smoking interact with the gene for FH. Homozygotes and compound heterozygotes (i.e., those who carry two different FH genes) are very rare (one in 1,000,000) have severe hypercholesterolemia with xanthomas, and develop coronary heart disease early in life. FH is caused by one of many different mutations (deletions, insertions, missense, or nonsense mutations) affecting the well-defined low density lipoprotein (LDL) receptor gene on chromosome 19. Some populations that started with a small founder group like the Afrikaners in South Africa and the French Canadians carry only a few FH mutations. The diagnosis of heterozygote FH is often difficult, since physical findings (xanthomas) are frequently absent, and overlap of laboratory test values between affected and nonaffected subjects occurs. The a priori probability of heterozygosity of FH varies from one in 500 in population studies to one in two in family studies and must be considered when assessing borderline quantitative test results based on cholesterol, LDL cholesterol, or LDL-receptor assays. The mutational heterogeneity of FH makes it very difficult to use DNA methodology for population detection. However, direct molecular diagnosis by appropriate DNA probes is possible if the specific LDL receptor defect is known. Indirect molecular diagnosis based on genetic linkage of a common DNA variant of the LDL receptor to the basic defect is often feasible but requires family studies.