Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Abstract Autosomal‐dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low‐density lipoprotein cholesterol (LDL‐C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene ( LDLR ), the apolipoprotein B gene ( APOB ) and the proprotein convertase subtilisin/kexin 9 gene ( PCSK9 ). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR , APOB , and PCSK9 . We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients ( P < .05) and healthy controls ( P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL‐C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six‐SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients.