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J Lipid Res. 2015 Oct;56(10):1993-2001. doi: 10.1194/jlr.P058891. Epub 2015 Aug 8.

Targeted next-generation sequencing to diagnose disorders of HDL cholesterol.

Author information

1
Translational Laboratory in Genetic Medicine, Agency for Science Technology and Research (ASTAR) and National University of Singapore, Singapore.
2
Human Genetics, Genome Institute of Singapore, Agency for Science Technology and Research (ASTAR), Singapore.
3
Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, Canada.
4
Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
5
Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada.
6
Translational Laboratory in Genetic Medicine, Agency for Science Technology and Research (ASTAR) and National University of Singapore, Singapore Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
7
Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, Canada Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada Departments of Medicine University of British Columbia, Vancouver, Canada.
8
Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, Canada Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
9
Translational Laboratory in Genetic Medicine, Agency for Science Technology and Research (ASTAR) and National University of Singapore, Singapore Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, Canada Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore Departments of Medicine University of British Columbia, Vancouver, Canada.

Abstract

A low level of HDL cholesterol (HDL-C) is a common clinical scenario and an important marker for increased cardiovascular risk. Many patients with very low or very high HDL-C have a rare mutation in one of several genes, but identification of the molecular abnormality in patients with extreme HDL-C is rarely performed in clinical practice. We investigated the accuracy and diagnostic yield of a targeted next-generation sequencing (NGS) assay for extreme levels of HDL-C. We developed a targeted NGS panel to capture the exons, intron/exon boundaries, and untranslated regions of 26 genes with highly penetrant effects on plasma lipid levels. We sequenced 141 patients with extreme HDL-C levels and prioritized variants in accordance with medical genetics guidelines. We identified 35 pathogenic and probably pathogenic variants in HDL genes, including 21 novel variants, and performed functional validation on a subset of these. Overall, a molecular diagnosis was established in 35.9% of patients with low HDL-C and 5.2% with high HDL-C, and all prioritized variants identified by NGS were confirmed by Sanger sequencing. Our results suggest that a molecular diagnosis can be identified in a substantial proportion of patients with low HDL-C using targeted NGS.

KEYWORDS:

ATP binding cassette transporter A1; atherosclerosis; diagnostic tools; genetics; genomics; high density lipoprotein; molecular diagnosis

PMID:
26255038
PMCID:
PMC4583092
DOI:
10.1194/jlr.P058891
[Indexed for MEDLINE]
Free PMC Article

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