Exome Sequencing Enhances Screening for Familial Hypercholesterolemia Within a Multi-Site Healthcare System

Area of Science:

• Genetics
• Cardiovascular Disease
• Medical Diagnostics

Background:

• Familial hypercholesterolemia (FH) is an inherited disorder increasing premature coronary artery disease risk.
• Genetic sequencing offers definitive FH diagnosis, surpassing current clinical criteria like the Dutch Lipid Clinic Network.
• Early and accurate FH diagnosis enables timely intervention and risk management.

Purpose of the Study:

• To evaluate the efficiency of germline genetic screening via exome sequencing for identifying FH genotype-positive individuals.
• To compare genetic diagnosis rates with traditional clinical diagnostic criteria.

Main Methods:

• Exome+ sequencing was performed on participants from three diverse US sites.
• Genetic variants in FH-associated genes (APOB, LDLR, PCSK9) were analyzed.
• Demographic, clinical, and cardiovascular history data were collected via chart review.

Main Results:

• Exome sequencing identified pathogenic variants in 0.50% of 84,413 participants, revealing 419 FH cases.
• Nearly 90% of identified FH carriers were newly diagnosed.
• Only 30.8% of genetically confirmed FH cases met clinical diagnostic criteria.

Conclusions:

• Germline genetic sequencing is a highly effective tool for identifying FH carriers.
• Wider adoption of genetic sequencing can significantly enhance FH detection rates.
• Genetic screening identifies individuals missed by conventional diagnostic methods, enabling earlier treatment.