Genetic testing for familial hypercholesterolemia-past, present, and future.

Area of Science:

• Genetics
• Cardiovascular Disease
• Molecular Biology

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL-C levels.
• Mutations in the LDL receptor gene were the first identified cause of FH.
• Autosomal dominant monogenic FH can also result from variants in APOB, PCSK9, and APOE genes.

Purpose of the Study:

• To evaluate the utility of next-generation sequencing for FH diagnosis.
• To identify novel FH-causing variants and variants of unknown significance.
• To highlight the role of genetic testing in personalized medicine for FH.

Main Methods:

• Next-generation sequencing (NGS) to analyze all exons of four key FH genes (LDL receptor, APOB, PCSK9, APOE).
• High-throughput processing of 96 patient samples per sequencing run.
• Utilizing identified FH variants for rapid family member testing.

Main Results:

• NGS enables faster and more cost-effective FH genetic testing.
• Numerous novel FH-causing variants and variants of unknown significance were identified.
• FH-causing variants are found in 20-40% of FH phenotype patients; polygenic causes are common in others.
• Patients with polygenic FH have a lower risk of coronary heart disease compared to monogenic FH.

Conclusions:

• Molecular genetic diagnostics represent a significant advancement in FH characterization.
• NGS facilitates precision medicine for FH, enabling tailored patient management.
• Understanding genetic etiology is crucial for assessing cardiovascular disease risk in FH patients.