Diagnosis of familial hypercholesterolemia in a large cohort of Italian genotyped hypercholesterolemic patients

Background and aims: Familial hypercholesterolemia (FH) is the most relevant genetic cause of early cardiovascular disease (CVD). FH is suspected when low density lipoprotein cholesterol (LDL-C) levels exceed the 95th percentile of the population distribution. Different diagnostic scoring systems have been developed, as the Dutch Lipid Clinic Network (DLCN) score, used worldwide. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic, and evaluate the DLCN score performance applied retrospectively to the case study. Methods: 836 hypercholesterolemic patients with LDL-C > 4.88 mmol/L were genotyped for FH causative gene variants in the LDLR, PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening. Results: Gene variant carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) non-carriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects showed that variant carriers had an odds ratio of 3.66 (1.43-10.24) for atherosclerotic plaques in comparison with non-carriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C. = 0.737) resulted to be more performing than the DLCN score (A.U.C. = 0.662), even including carotid US data (A.U.C. = 0.641) in a modified DLCN score version. Conclusions: the DLCN score failed to demonstrate a clear superiority in predicting FH gene variants in comparison with the measure of LDL-C levels in a retrospective case study.