Assessment of Pediatric Hypertriglyceridemia Etiology: Insights from Next-Generation Sequencing Panels and Identification of Novel Variants

Hypertriglyceridemia is mostly associated with secondary conditions in children but can also result from monogenic disorders. The most prevalent genes identified as the underlying reason for impaired clearance of triglycerides from plasma by genome-wide association studies are the LPL, APOC2, APOA5, LMF1, APOE and GPIHBP1 genes. In this study, 26 pediatric patients with primary hypertriglyceridemia, 12 of whom were severe, were screened for monogenic causes via a next-generation sequencing panel that included 25 genes, namely, ABCA1, ABCG5, ABCG8, ANGPTL3, APOA1, APOA5, APOB, APOC2, APOC3, APOE, CETP, GPD1, GPIHBP1, LCAT, LDLR, LDLRAP1, LIPA, LIPC, LMF1, LPL, MTTP, NPC1L1, OSBPL5, PCSK9 and SAR1B. Additional findings, such as positive family history, hepatomegaly, splenomegaly, history of acute pancreatitis, hepatosteatosis, and atherosclerotic cardiovascular disease, were recorded. Twenty different variants, 16 of which were novel, were detected. Among these, six of the eight clinically significant mutations detected in the LPL, GPD1, GPIHBP1, APOC2, and LIPC genes were novel mutations. At least one variant was identified in 17 of 26 patients (65.4%), whereas no variants were detected in 9 patients (34.6%). Clinically significant variants that could explain the clinical findings were detected in 7 (58.3%) of the 12 patients with severe hypertriglyceridemia. In 4 out of the 6 patients with a familial history of hypertriglyceridemia, we identified pathogenic variants in the GPD1, LIPC, LPL and APOC2 genes, which are associated with hypertriglyceridemia. Targeting gene panels for suspected monogenic hypertriglyceridemia is a promising way to identify the underlying etiology, which enables genetic counseling and family screening to identify new patients and provides a personalized treatment approach.