Genetic spectrum of familial hypercholesterolemia and correlations with clinical expression: Implications for diagnosis improvement

Clin Genet. 2021 Nov;100(5):529-541. doi: 10.1111/cge.14036. Epub 2021 Aug 3.


Familial hypercholesterolemia (FH) is the most common genetic disease caused by variants in LDLR, APOB, PCSK9 genes; it is characterized by high levels of LDL-cholesterol and premature cardiovascular disease. We aim to perform a retrospective analysis of a genetically screened population (528 unrelated patients-342 adults and 186 children) to evaluate the biochemical and clinical correlations with the different genetic statuses. Genetic screening was performed by traditional sequencing and some patients were re-analyzed by next-generation-sequencing. Pathogenic variants, mainly missense in the LDLR gene, were identified in 402/528 patients (76.1%), including 4 homozygotes, 17 compound heterozygotes and 1 double heterozygotes. A gradual increase of LDL-cholesterol was observed from patients without pathogenic variants to patients with a defective variant, to patients with a null variant and to patients with two variants. Six variants accounted for 51% of patients; a large variability of LDL-cholesterol was observed among patients carrying the same variant. The frequency of pathogenic variants gradually increased from unlikely FH to definite FH, according to the Dutch Lipid Clinic Network criteria. Genetic diagnosis can help prognostic evaluation of FH patients, discriminating between the different genetic statuses or variant types. Clinical suspicion of FH should be considered even if few symptoms are present or if LDL-cholesterol is only mildly increased.

Keywords: genotype-phenotype correlation; homozygous familial hypercholesterolemia; null variant; pathogenic variant; pediatric FH; variant cluster.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Amino Acid Substitution
  • Biomarkers
  • Child
  • Exons
  • Female
  • Gene Frequency
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Genetic Testing / methods
  • Genetic Testing / standards
  • Genotype
  • Humans
  • Hyperlipoproteinemia Type II / diagnosis*
  • Hyperlipoproteinemia Type II / epidemiology
  • Hyperlipoproteinemia Type II / genetics*
  • Male
  • Mutation
  • Phenotype*
  • Quality Improvement
  • ROC Curve
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism


  • Biomarkers
  • Receptors, LDL

Grants and funding