Targeted next-generation sequencing to diagnose disorders of HDL cholesterol

• Main 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
• Format: Article
• Language: English
• Published: Elsevier 2015-10-01
• Series: Journal of Lipid Research
• Subjects: ATP binding cassette transporter A1; diagnostic tools; genetics; genomics; high density lipoprotein; atherosclerosis
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520309743

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.