Targeted next-generation sequencing to diagnose disorders of HDL cholesterol

Journal of Lipid Research

Liam R. Brunham¹  Gordon A. Francis²  Jiri Frohlich³  Teddy Chan⁴  Jennifer A. Collins⁵  Lubomira Cermakova⁶  Sima Gerami⁶  Chiea Chuen Khor⁶  Herty Liany⁷  Jia Nee Foo⁷  Michael R. Hayden⁸  Singh N. Sadananda⁸  Meng Tiak Toh⁸  Laia Trigueros-Motos⁸  Roshni R. Singaraja⁸ 

[1] Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada;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;Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada;Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada;Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, Canada;Human Genetics, Genome Institute of Singapore,Agency for Science Technology and Research (A*STAR), Singapore;Translational Laboratory in Genetic Medicine,Agency for Science Technology and Research (A*STAR) and National University of Singapore, Singapore;

关键词: ATP binding cassette transporter A1;    diagnostic tools;    genetics;    genomics;    high density lipoprotein;    atherosclerosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown