Targeted next-generation sequencing to diagnose disorders of HDL cholesterol

TitleTargeted next-generation sequencing to diagnose disorders of HDL cholesterol
Publication TypeJournal Article
Year of Publication2015
AuthorsSadananda, SN, Foo, JN, Toh, MT, Cermakova, L, Trigueros-Motos, L, Chan, T, Liany, H, Collins, JA, Gerami, S, Singaraja, RR, Hayden, MR, Francis, GA, Frohlich, J, Khor, CC, Brunham, LR
JournalJournal of Lipid Research
Date Published10/2015
ISSNPrint: 0022-2275; Online: 1539-7262

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.