Identification of novel APOB mutations by targeted next-generation sequencing for the molecular diagnosis of familial hypobetalipoproteinemia

Atherosclerosis. 2016 Jul;250:52-6. doi: 10.1016/j.atherosclerosis.2016.04.010. Epub 2016 Apr 11.


Background and aims: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by decreased plasma levels of LDL-cholesterol and apolipoprotein B (ApoB). Currently, genetic diagnosis in FHBL relies largely on Sanger sequencing to identify APOB and PCSK9 gene mutations and on western blotting to detect truncated ApoB species.

Methods: Here, we applied targeted enrichment and next-generation sequencing (NGS) on a panel of three FHBL genes and two abetalipoproteinemia genes (APOB, PCSK9, ANGPTL3, MTTP and SAR1B).

Results: In this study, we identified five likely pathogenic heterozygous rare variants. These include four novel nonsense mutations in APOB (p.Gln845*, p.Gln2571*, p.Cys2933* and p.Ser3718*) and a rare variant in PCSK9 (Minor Allele Frequency <0.1%). The affected family members tested were shown to be carriers, suggesting co-segregation with low LDL-C.

Conclusions: Our study further demonstrates that NGS is a reliable and practical approach for the molecular screening of FHBL-causative genes that may provide a mean for deciphering the genetic basis in FHBL.

Keywords: APOB; Familial hypobetalipoproteinemia; Molecular diagnosis; PCSK9; Target next generation sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abetalipoproteinemia / genetics
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Apolipoprotein B-100 / genetics*
  • Cholesterol, LDL / genetics
  • Codon, Nonsense
  • Gene Library
  • Genetic Variation
  • Heterozygote
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hypobetalipoproteinemias / diagnosis
  • Hypobetalipoproteinemias / genetics*
  • Middle Aged
  • Mutation*
  • Pedigree
  • Phenotype
  • Proprotein Convertase 9 / genetics
  • Reproducibility of Results
  • Sequence Analysis, DNA
  • Young Adult


  • APOB protein, human
  • Apolipoprotein B-100
  • Cholesterol, LDL
  • Codon, Nonsense
  • PCSK9 protein, human
  • Proprotein Convertase 9