Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically

Area of Science:

• Genetics
• Cardiovascular Disease
• Molecular Biology

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder causing high LDL cholesterol.
• Next-generation sequencing (NGS) is advancing FH research, enabling better prevalence estimates and understanding of polygenic influences.
• Severe hypercholesterolemia patients often have complex genetic underpinnings.

Purpose of the Study:

• To investigate the contributions of monogenic and polygenic factors in severe hypercholesterolemia.
• To assess the diagnostic yield of comprehensive genetic screening in a clinical FH cohort.

Main Methods:

• Targeted NGS with custom annotation was applied to 313 individuals with severe hypercholesterolemia (LDL-C >5.0 mmol/L).
• Copy number variations (CNVs) and polygenic risk scores (PRS) for elevated LDL-C were evaluated.
• Genetic findings were correlated with LDL-C levels.

Main Results:

• Monogenic FH-causing mutations were identified in 47.3% of patients via NGS.
• Inclusion of CNVs increased detection to 53.7%; inclusion of extreme PRS raised this to 67.1%.
• The proportion of patients with an identified genetic component rose from 57.0% to 92.0% as LDL-C levels increased from >5.0 to >8.0 mmol/L.

Conclusions:

• A significant majority of patients with severe hypercholesterolemia have a detectable genetic basis.
• Comprehensive genetic screening, combining NGS, CNV analysis, and PRS, is effective in identifying genetic contributors.
• These findings support a thorough genetic evaluation for individuals with severe hypercholesterolemia.