Phenotype vs. genotype in severe familial hypercholesterolemia: what matters most for the clinician?

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Purpose of review

Familial hypercholesterolemia is associated with a high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). However, this risk is variable. This review evaluates recent evidence related to ASCVD risk stratification in familial hypercholesterolemia considering aspects of phenotype and genotype.

Recent findings

The heterogeneity in clinical, laboratory characteristics, and in ASCVD risk in both homozygous and heterozygous familial hypercholesterolemia individuals in part can be attributed to the type of molecular defect. In most individuals with LDL cholesterol more than 190 mg/dl, a familial hypercholesterolemia-causing variant is not encountered, however, when present, a variant implicates an even higher ASCVD risk for such individuals. Previous ASCVD events, elevated blood lipoprotein(a), cutaneous markers of cholesterol deposit are among other factors that indicate a higher ASCVD risk in familial hypercholesterolemia individuals underlying a more severe form of the phenotype.


Both clinical and genetic parameters help identify higher ASCVD risk among severe familial hypercholesterolemia individuals.

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