Familial hypercholesterolemia (FH) is characterized as a monogenic, autosomal dominant disorder, producing severe hypercholesterolemia within families due to causal variants within genes regulating the low-density lipoprotein receptor pathway. Demonstration of a causal variant is widely accepted as evidence of substantially higher cardiovascular risk. However, recent large-scale population studies challenge this characterization of FH, which appears to account for only a minor portion of those with severe hypercholesterolemia. Moreover, a substantial portion of FH variant positive patients do not have marked hypercholesterolemia. These discordances raise doubt as to how FH should be defined and how the concentration of low-density lipoprotein in plasma is regulated in individuals with and without FH. Moreover, review of the evidence suggests the impact of an FH causal variant on cardiovascular risk may be less than previously accepted and that all patients with severe hypercholesterolemia should be prioritized for therapy and family screening.
Keywords: LDL pathway; cascade screening; familial hypercholesterolemia; genetic variant.
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