Molecular and functional characterization of familial chylomicronemia syndrome

Atherosclerosis. 2018 Feb:269:272-278. doi: 10.1016/j.atherosclerosis.2017.11.006. Epub 2017 Nov 14.


Background and aims: Familial chylomicronemia syndrome is a rare autosomal recessive disorder leading to severe hypertriglyceridemia (HTG) due to mutations in lipoprotein lipase (LPL)-associated genes. Few data exist on the clinical features of the disorder or on comprehensive genetic approaches to uncover the causative genes and mutations.

Methods: Eight patients diagnosed with familial hyperchylomicronemia with recessive inheritance were included in this study (two males and six females; median age of onset 23.0 years; mean triglyceride level 3446 mg/dl). We evaluated their clinical features, including coronary artery disease using coronary computed tomography, and performed targeted next-generation sequencing on a panel comprising 4813 genes associated with known clinical phenotypes. After standard filtering for allele frequency <1% and in silico annotation prediction, we used three types of variant filtering to identify causative mutations: homozygous mutations in known familial hyperchylomicronemia-associated genes, homozygous mutations with high damaging scores in novel genes, and deleterious mutations within 37 genes known to be associated with HTG.

Results: A total of 1810 variants out of the 73,389 identified with 94.3% mean coverage (×20) were rare and nonsynonymous. Among these, our schema detected four pathogenic or likely pathogenic mutations in the LPL gene (p.Ala248LeufsTer4, p.Arg270Cys, p.Ala361Thr, and p.Val227Gly), including one novel mutation and a variant of uncertain significance. Patients harboring LPL gene mutations showed no severe atherosclerotic changes in the coronary arteries, but recurrent pancreatitis with long-term exposure to HTG was observed.

Conclusions: These results demonstrate that LPL gene plays a major role in extreme HTG associated with hyperchylomicronemia, although the condition may not cause severe atherosclerosis.

Keywords: Familial chylomicronemia syndrome; Lipoprotein; Lipoprotein lipase deficiency; Triglyceride.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Child
  • Child, Preschool
  • Computed Tomography Angiography
  • Coronary Angiography / methods
  • Coronary Artery Disease / diagnostic imaging
  • Coronary Artery Disease / genetics
  • DNA Mutational Analysis / methods
  • Disease Progression
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease
  • Heredity
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Hyperlipoproteinemia Type I / blood*
  • Hyperlipoproteinemia Type I / complications
  • Hyperlipoproteinemia Type I / diagnosis
  • Hyperlipoproteinemia Type I / genetics*
  • Hypertriglyceridemia / blood*
  • Hypertriglyceridemia / diagnosis
  • Hypertriglyceridemia / genetics*
  • Infant
  • Lipoprotein Lipase / genetics*
  • Male
  • Mutation*
  • Pancreatitis / diagnosis
  • Pancreatitis / genetics
  • Phenotype
  • Recurrence
  • Risk Factors
  • Time Factors
  • Triglycerides / blood*
  • Up-Regulation
  • Young Adult


  • Triglycerides
  • LPL protein, human
  • Lipoprotein Lipase