Intrafamilial variability in the clinical expression of familial hypercholesterolemia: importance of risk factor determination for genetic counselling.

A specific mutation in the low-density lipoprotein receptor (LDLR) gene causes familial hypercholesterolemia (FH) in about 60% of Afrikaner FH heterozygotes. Molecular diagnosis of this so-called FH Afrikaner-1 mutation was performed in a family with the disease. One individual did not develop coronary heart disease (CHD) by age 84, despite having the FH Afrikaner-1 mutation, while his son who inherited the same gene, developed CHD before age 50 and had to undergo bypass surgery. All the sibs in the third generation inherited the defective LDLR gene allele. This variation in clinical presentation creates a counselling dilemma. It also raises questions about the effect of diet and life style, and the possibility of other genes either contributing to the severity of the disease, or protecting against high lipid levels in plasma. An investigation of the influence of selected factors on the clinical expression of the FH Afrikaner-1 mutation in this family indicated that it was especially the elevated apolipoprotein (a) levels, in addition to low levels of high density lipoprotein cholesterol and raised triglyceride and apolipoprotein B levels, that were associated with a greater risk of developing CHD. These findings are thus in accordance with the view that the severity of CHD in FH patients is not only determined by nature of the gene defect, but is also influenced by other risk factors.