Update on genetics of familial hypercholesterolemia

Area of Science:

• Genetics
• Cardiology
• Biochemistry

Background:

• Familial hypercholesterolemia (FH) is a monogenic disorder causing high LDL cholesterol and early cardiovascular disease.
• Caused by variants in genes like LDLR, APOB, and PCSK9, a significant percentage of cases lack identified causative variants.
• Understanding FH is crucial for preventing premature atherosclerosis.

Purpose of the Study:

• To review current understanding and diagnostic approaches for Familial hypercholesterolemia.
• To highlight challenges in genetic variant detection and interpretation in FH.
• To explore advanced methods for diagnosing FH and similar conditions.

Main Methods:

• Review of current literature on Familial hypercholesterolemia genetics and diagnostics.
• Analysis of updated terminology for FH phenotypes, including biallelic and digenic forms.
• Integration of polygenic risk scores (PRS) and lipoprotein(a) assessment in diagnostic strategies.

Main Results:

• FH is an autosomal semi-dominant disorder with gene-dosage effects.
• Refined terminology clarifies homozygous and digenic FH forms.
• Polygenic risk scores and lipoprotein(a) help explain FH-like phenotypes and identify severe hypercholesterolemia.
• Functional studies and data integration improve variant classification.

Conclusions:

• Comprehensive FH diagnosis combines monogenic variant detection, PRS, and lipoprotein(a) assessment.
• This integrated approach allows for tailored risk stratification.
• Personalized management strategies for Familial hypercholesterolemia can be developed.