The role of DLCN in the diagnosis of familial hypercholesterolemia: data from the MedPed Center in Bratislava

Overview

Familial hypercholesterolemia (FH) is a monogenic, autosomal dominant genetic disorder characterized by high levels of total and LDL cholesterol and a high risk of atherosclerosis-related cardiovascular disease (ARCAD). The Dutch Lipid Clinic Network (DLCN) score is most commonly used to establish a clinical diagnosis of FH; in Slovakia, this score is a prerequisite for analyzing DNA mutations in the genes that are the most common cause of FH. Our goal was to determine how the accuracy of the clinical diagnosis of FH based on the DLCN correlates with the results obtained from DNA analysis of the genes for the LDL receptor (LDLr), ApoB, and PCSK9. We focused on unrelated individuals—probands. Complete data from DNA analysis and clinical and biochemical testing were available for 182 probands. We compared patients with primary hypercholesterolemia who, based on their DLCN score, had definite FH (defFH) or probable/possible FH (pFH). The LDLr, ApoB, and PCSK9 genes were analyzed using Next Generation Sequencing (NGS). 102 probands were classified into the defFH group and 89 into the pFH group. Patients with defFH were younger, had a statistically significantly higher prevalence of xanthomatosis (46.1% vs 13.5%), and higher levels of total cholesterol and LDL cholesterol than patients in the pFH group (P < 0.001). We found no difference in the incidence of ASKVO in personal or family history. 72.5% of patients with a clinical diagnosis of defFH had a confirmed mutation in the LDLr or ApoB genes, compared with 25.8% in the pFH group (P < 0.001). This statistically significant difference was driven by a significantly higher prevalence of mutations in the LDLr gene (60.8% vs 14.6%, P < 0.001). The prevalence of mutations in the ApoB gene did not differ between the two groups (11.8% vs 10.1%). No pathogenic variant was detected in the PCSK9 gene in any patient. We demonstrated that in the MedPed project, DLCN represents an effective criterion for the genetic diagnosis of FH. It can be assumed that, in combination with universal screening for FH in children, the detection of monogenic FH could be significantly improved, thereby enhancing effective primary prevention of early cardiovascular events.

Keywords:

atherosclerosis-related cardiovascular disease (ARCAD) – Dutch Lipid Clinic Network (DLCN) – familial hypercholesterolemia (FH) – MedPed – monogenic familial hypercholesterolemia