Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

Lorenz Rieck, Frieda Bardey, Thomas Grenkowitz, Lars Bertram, Johannes Helmuth, Claudia Mischung, Joachim Spranger, Elisabeth Steinhagen-Thiessen, Thomas Bobbert, Ursula Kassner, Ilja Demuth*

*Corresponding author for this work
    10 Citations (Scopus)


    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.

    Original languageEnglish
    JournalClinical Genetics
    Issue number5
    Pages (from-to)457-467
    Number of pages11
    Publication statusPublished - 01.11.2020

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