Clinical whole exome sequencing in severe hypertriglyceridemia

Background: Little data exist regarding the clinical application of whole exome sequencing (WES) for the molecular diagnosis of severe hypertriglyceridemia (HTG). Methods: WES was performed for 28 probands exhibiting severe HTG (≥1000 mg/dl) without any transient causes. We evaluated recessive and dominant inheritance models in known monogenic HTG genes, followed by disease-network gene prioritization and copy number variation (CNV) analyses to identify causative variants and a novel genetic mechanism for severe HTG. Results: We identified possible causative variants for severe HTG, including three novel variants, in nine probands (32%). In the recessive inheritance model, we identified two homozygous subjects with lipoprotein lipase (LPL) deficiency and one subject harboring compound heterozygous variants in both LPL and APOA5 genes (hyperchylomicronemia). In the dominant inheritance model, we identified probands harboring deleterious heterozygous variants in LPL, glucokinase regulatory protein, and solute carrier family 25 member 40 genes, possibly associated with this extreme HTG phenotype. However, gene prioritization and CNV analyses did not validate the novel genes associated with severe HTG. Conclusions: In 28 probands with severe HTG, we identified potential causative variants within nine genes associated with rare Mendelian dyslipidemias. Clinical WES may be feasible for such extreme cases, potentially leading to appropriate therapies.