Timely diagnosis of sitosterolemia by next generation sequencing in two children with severe hypercholesterolemia

Atherosclerosis. 2017 Jul;262:71-77. doi: 10.1016/j.atherosclerosis.2017.05.002. Epub 2017 May 4.


Background and aims: Severe hypercholesterolemia associated or not with xanthomas in a child may suggest the diagnosis of homozygous autosomal dominant hypercholesterolemia (ADH), autosomal recessive hypercholesterolemia (ARH) or sitosterolemia, depending on the transmission of hypercholesterolemia in the patient's family. Sitosterolemia is a recessive disorder characterized by high plasma levels of cholesterol and plant sterols due to mutations in the ABCG5 or the ABCG8 gene, leading to a loss of function of the ATP-binding cassette (ABC) heterodimer transporter G5-G8.

Methods: We aimed to perform the molecular characterization of two children with severe primary hypercholesterolemia.

Results: Case #1 was a 2 year-old girl with high LDL-cholesterol (690 mg/dl) and tuberous and intertriginous xanthomas. Case #2 was a 7 year-old boy with elevated LDL-C (432 mg/dl) but no xanthomas. In both cases, at least one parent had elevated LDL-cholesterol levels. For the molecular diagnosis, we applied targeted next generation sequencing (NGS), which unexpectedly revealed that both patients were compound heterozygous for nonsense mutations: Case #1 in ABCG5 gene [p.(Gln251*)/p.(Arg446*)] and Case #2 in ABCG8 gene [p.(Ser107*)/p.(Trp361*)]. Both children had extremely high serum sitosterol and campesterol levels, thus confirming the diagnosis of sisterolemia. A low-fat/low-sterol diet was promptly adopted with and without the addition of ezetimibe for Case #1 and Case #2, respectively. In both patients, serum total and LDL-cholesterol decreased dramatically in two months and progressively normalized.

Conclusions: Targeted NGS allows the rapid diagnosis of sitosterolemia in children with severe hypercholesterolemia, even though their family history does not unequivocally suggest a recessive transmission of hypercholesterolemia. A timely diagnosis is crucial to avoid delays in treatment.

Keywords: ABCG5 gene; ABCG8 gene; Hypercholesterolemia; Next generation sequencing; Plasma phytosterols.

Publication types

  • Case Reports

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 5 / genetics*
  • ATP Binding Cassette Transporter, Subfamily G, Member 8 / genetics*
  • Anticholesteremic Agents / therapeutic use
  • Biomarkers / blood
  • Child
  • Child, Preschool
  • Cholesterol, LDL / blood*
  • Codon, Nonsense*
  • DNA Mutational Analysis / methods*
  • Diet, Fat-Restricted
  • Ezetimibe / therapeutic use
  • Female
  • Genetic Predisposition to Disease
  • Heterozygote
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Hypercholesterolemia / blood
  • Hypercholesterolemia / diagnosis
  • Hypercholesterolemia / genetics*
  • Hypercholesterolemia / therapy
  • Intestinal Diseases / blood
  • Intestinal Diseases / diagnosis
  • Intestinal Diseases / genetics*
  • Intestinal Diseases / therapy
  • Lipid Metabolism, Inborn Errors / blood
  • Lipid Metabolism, Inborn Errors / diagnosis
  • Lipid Metabolism, Inborn Errors / genetics*
  • Lipid Metabolism, Inborn Errors / therapy
  • Lipoproteins / genetics*
  • Male
  • Phenotype
  • Phytosterols / adverse effects*
  • Phytosterols / blood
  • Phytosterols / genetics
  • Predictive Value of Tests
  • Severity of Illness Index
  • Treatment Outcome
  • Up-Regulation


  • ABCG5 protein, human
  • ABCG8 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • Anticholesteremic Agents
  • Biomarkers
  • Cholesterol, LDL
  • Codon, Nonsense
  • Lipoproteins
  • Phytosterols
  • Ezetimibe

Supplementary concepts

  • Sitosterolemia