Sanchez-Prieto_2025_J.Clin.Med_14_

Introduction and Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipid metabolism that is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and a high risk of atherosclerotic cardiovascular disease. Familial hypercholesterolemia is typically caused by mutations in the LDL receptor gene (LDLR), although other alterations may be found. The aim of this study was to perform a genetic study on a population identified through a new population-based diagnostic screen program for FH. Methods: Genetic variants in LDLR, apolipoprotein B (APOB), apolipoprotein E (APOE), proprotein convertase subtilisin/kexin type 9 (PCSK9), signal transducing Adaptor Family Member 1 (STAP1), low density lipoprotein receptor adaptor protein 1 (LDLRAP1) and lipase A, and lysosomal acid type lipase A (LIPA), as well as a genetic risk score, were evaluated in 84 individuals with a clinical diagnosis of FH based on the Dutch Lipid Clinics Network criteria (DLCN <= 6). These individuals were selected from a cohort of 752 patients with an abnormal lipid profile, obtained by screening existing centralized analytics. Results: A clinical diagnosis of FH was established in 17.9% of the patients evaluated, with mean LDL-C levels of 305.7 mg/dL (95% CI 250.4-360.9). Genetic variants were detected in 70.2% of these patients, with 50 different mutations identified, mainly in the LDLR. The most frequent pathogenic variants were c.1342C>T and c.313+1G>C. Null variants exhibited a more severe phenotype, and the risk score indicates that patients carrying genetic alterations have a 42% higher risk of developing cardiovascular disease. Conclusions: A high rate of genetic alterations was detected in patients with severe FH. In most cases, the phenotypic findings did not predict the genetic results, which provide important information regarding the cardiovascular risk of patients.