Familial hypercholesterolemia: A complex genetic disease with variable phenotypes.

Area of Science:

• Genetics
• Cardiovascular Disease
• Biochemistry

Background:

• Familial hypercholesterolemia (FH) is the most common genetic disease, characterized by elevated LDL-cholesterol leading to premature atherosclerosis.
• Key genes involved include LDLR, APOB, and PCSK9, with rarer contributions from APOE and STAP1 variants.

Purpose of the Study:

• To review the complex genetic basis of Familial hypercholesterolemia (FH).
• To highlight the challenges posed by genetic heterogeneity, variant clusters, and phenotypic variability in FH.
• To emphasize the importance of accurate variant pathogenicity evaluation for diagnosis and management.

Main Methods:

• Literature review of genetic factors contributing to Familial hypercholesterolemia.
• Analysis of genetic heterogeneity and phenotypic variability in FH patients.
• Discussion of variant types (null vs. defective) and their impact on LDL-cholesterol levels and cardiovascular risk.

Main Results:

• FH genetics are complex due to high heterogeneity, variant clusters, and significant phenotypic variability.
• Overlapping LDL-cholesterol levels exist between heterozygous (HeFH) and homozygous FH patients, with some HeFH patients showing normal lipid profiles.
• Null variants in the LDLR gene are associated with higher LDL-cholesterol and increased coronary artery disease risk compared to defective variants.

Conclusions:

• Accurate pathogenicity evaluation is crucial for defining genetic status and identifying causative FH variants.
• Phenotypic differences observed in HeFH patients depend on variant type and affected gene.
• Other lipid-related gene variants can modify FH phenotype or require differential diagnosis.