Genetic Diagnostic Approaches in Familial Hypercholesterolemia Evaluation

Familial hypercholesterolemia (FH) manifested as atherosclerosis is a major cause of coronary heart disease. Different scoring systems based on clinical and paraclinical data are currently used, but the FH diagnosis should be made only in the presence of the causative genetic defect. In the present study, 12 symptomatic (previously diagnosed with atherosclerosis) and asymptomatic family members were investigated. Serum lipids were measured using commercial reagents. A genetic investigation was performed by Sanger sequencing using commercial reagents and custom primers, while copy number variations and a selected set of 40 point mutations were evaluated using in vitro diagnostic medical devices. For the investigated patients, serum lipids were within the reference range, due to the fact that the subjects were following lipid-lowering therapy, and smoking was the only identifiable additional risk factor. Four benign exon variants and three intron variants situated within the low-density lipoprotein cholesterol receptor gene were identified by Sanger sequencing. No copy number variations and none of the 40 investigated point mutations were determined. Although independently considered benign, the combined effect of the identified genetic conditions could be pathogenic under the influence of additional risk factors. Even in the presence of a diagnosis made using clinical scores, the molecular diagnosis is often challenging, attesting to the complexity of FH genetic etiology.