Genetic causes of lipid profile variability in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is one of the most common monogenic diseases in Russia, most often related to causal variants in the LDLR, APOB, and PCSK9 genes. FH is characterized by severe hypercholesterolemia from birth and the early development of coronary atherosclerosis and coronary artery disease. However, in recent years, there is evidence indicating that the phenotype of genetically confirmed FH patients can vary from those with coronary artery disease to those without atherosclerosis. The wide profile of phenotypic manifestations is due to incomplete penetrance and/or variable expressivity of variants in the causal genes. This review demonstrates the main genetic causes of FH and additional genetic factors influencing lipid variability (additional rare and common variants in genes associated with lipid metabolism disorders). Understanding lipid profile variability in FH will help practicing physicians more effectively use genetic diagnostic methods, assess the risk of complications, and personalize treatment.

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