Targeted next-generation sequencing to diagnose disorders of HDL cholesterol |
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Authors: | Singh N. Sadananda Jia Nee Foo Meng Tiak Toh Lubomira Cermakova Laia Trigueros-Motos Teddy Chan Herty Liany Jennifer A. Collins Sima Gerami Roshni R. Singaraja Michael R. Hayden Gordon A. Francis Jiri Frohlich Chiea Chuen Khor Liam R. Brunham |
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Affiliation: | 2. Human Genetics, Genome Institute of Singapore,Agency for Science Technology and Research (A*STAR), Singapore;4. Healthy Heart Program Prevention Clinic, St. Paul''s Hospital, Vancouver, Canada;11. Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada;112. Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada;8. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore |
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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. |
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Keywords: | ATP binding cassette transporter A1 diagnostic tools genetics genomics high density lipoprotein atherosclerosis molecular diagnosis |
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