Complex genetic architecture in severe hypobetalipoproteinemia

Lipids Health Dis. 2018 Mar 14;17(1):48. doi: 10.1186/s12944-018-0680-1.


Background: Abetalipoproteinemia and homozygous hypobetalipoproteinemia are classical Mendelian autosomal recessive and co-dominant conditions, respectively, which are phenotypically similar and are usually caused by bi-allelic mutations in MTTP and APOB genes, respectively. Instances of more complex patterns of genomic variants resulting in this distinct phenotype have not been reported.

Methods: A 43 year-old male had a longstanding severe deficiency of apolipoprotein (apo) B-containing lipoproteins and circulating fat soluble vitamins consistent with either abetalipoproteinemia or homozygous familial hypobetalipoproteinemia (FHBL). He also had acanthocytosis, a long term history of fat malabsorption, and mild retinopathy, but was free from coagulopathy, myopathy and neuropathy. He had taken high dose oral fat soluble vitamins since childhood.

Results: Targeted next generation DNA sequencing revealed several rare heterozygous missense variants in both MTTP and APOB genes known or predicted to be deleterious, in addition to a novel heterozygous missense variant in SAR1B, which encodes the gene causing chylomicron retention disease. Evaluation of first degree relatives with mild FHBL clarified the segregation of variants.

Conclusions: The proband's characteristic phenotype likely resulted from an oligogenic interaction involving multiple rare variants in MTTP and APOB, and related genes, each of which individually was associated with a milder or minimal clinical and biochemical phenotype.

Keywords: Abetalipoproteinemia; Acanthocytosis; Complex trait; DNA mutations; DNA sequencing; Hypobetalipoproteinemia; Oligogenic trait.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Apolipoprotein B-100 / genetics*
  • Carrier Proteins / genetics*
  • Genetic Predisposition to Disease
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Hypobetalipoproteinemias
  • Male
  • Monomeric GTP-Binding Proteins / genetics*
  • Mutation, Missense / genetics


  • APOB protein, human
  • Apolipoprotein B-100
  • Carrier Proteins
  • microsomal triglyceride transfer protein
  • SAR1B protein, human
  • Monomeric GTP-Binding Proteins