Abstract 11169: Whole Exome Sequencing in Subjects With Mendelian Form of Primary Severe Hypertriglyceridemia

Abstract

Background: Few data exist regarding clinical application of whole exome sequencing (WES) for the molecular diagnosis of the subjects with Mendelian form of primary severe hypertriglyceridemia (HTG). Methods: WES was performed on 28 individuals exhibiting severe HTG (≥ 1,000 mg/dl) without any transient causes (15 men, mean age 42 ± 20 yr, median triglyceride 1,756 mg/dl [interquartile range 1,288-2,443]) followed by recessive and dominant inheritance modeling in known monogenic HTG genes and disease-network candidate analysis gene ranking to identify a causative mutation(s), including novel underlying genetic mechanism for severe HTG. Results: Using our schema, we identified possible causative mutation(s) in 14 individuals (50%). Among them, we identified 2 individuals with lipoprotein lipase (LPL) deficiency with double mutations in LPL gene, and 2 individuals with a heterozygous mutation carrier in LPL gene. Moreover, we identified one individual harboring a double mutations in LPL gene and APOA5 gene. Also we identified one individual with a heterozygous mutation in lipase maturation factor 1 (LMF1) gene, which is rarer form of familial hyperchylomicronemia, and 2 individuals with type 3 hyperlipidemia harboring mutations in APOE gene, including novel ones. Interestingly, we also identified 6 other individuals harboring a deleterious mutation in cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3), MLX Interacting Protein-Like (MLXIPL), SLC25A40 genes, glucokinase regulatory protein (GCKR), possibly associated with this extreme phenotype. Conclusion: We identified potential causative mutations in 14 among 28 individuals (50%) with severe HTG within the coding region of the genes known to cause rare Mendelian dyslipidemias. Clinical WES is now feasible where molecular diagnoses could be made in such extreme cases, which could potentially provide appropriate therapies.