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

Molecular and functional characterization of familial chylomicronemia syndrome.

Author information

1
Department of Cardiovascular and Internal Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan.
2
Department of Cardiovascular and Internal Medicine, Kanazawa University, Graduate School of Medicine, Kanazawa, Japan. Electronic address: ht240z@sa3.so-net.ne.jp.
3
Department of Laboratory Science, Molecular Biochemistry and Molecular Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

Abstract

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

[Indexed for MEDLINE]

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