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

Area of Science:

• Cardiology
• Genetics
• Metabolic Diseases

Background:

• Familial hypercholesterolemia (FH) significantly elevates lifetime risk of atherosclerotic cardiovascular disease (ASCVD).
• The ASCVD risk associated with FH is highly variable among affected individuals.
• Understanding risk stratification is crucial for managing FH patients.

Purpose of the Study:

• To review recent evidence on atherosclerotic cardiovascular disease (ASCVD) risk stratification in familial hypercholesterolemia (FH).
• To consider both phenotypic and genotypic aspects in assessing ASCVD risk within FH populations.
• To identify factors contributing to variable ASCVD risk in FH.

Main Methods:

• Literature review of recent studies on familial hypercholesterolemia (FH) and atherosclerotic cardiovascular disease (ASCVD).
• Analysis of clinical, laboratory, and genetic data related to ASCVD risk in FH.
• Evaluation of phenotype and genotype in risk stratification.

Main Results:

• Heterogeneity in clinical and laboratory characteristics, and ASCVD risk in FH is partly due to molecular defect type.
• While most individuals with LDL cholesterol >190 mg/dL lack FH variants, their presence indicates higher ASCVD risk.
• Prior ASCVD events, elevated lipoprotein(a), and cutaneous cholesterol deposits signify increased risk in severe FH phenotypes.

Conclusions:

• Both clinical and genetic parameters are essential for identifying higher ASCVD risk in severe familial hypercholesterolemia (FH) cases.
• Accurate risk stratification aids in targeted management strategies for FH patients.
• Further research into genotype-phenotype correlations can refine ASCVD risk prediction in FH.