Article ID: 66426
Aims: Familial chylomicronemia syndrome (FCS) and multifactorial chylomicronemia syndrome (MCS) are clinically overlapping causes of severe hypertriglyceridemia (HTG). This study aimed to delineate the genetic characterization of FCS and MCS in Taiwanese patients with severe HTG.
Methods: After exclusion of identifiable secondary causes, patients with severe HTG, defined as fasting plasma triglyceride (TG) concentrations ≥ 500 mg/dL, were enrolled. Whole-exome sequencing (WES) was performed with focused analysis of canonical FCS-related genes, including LPL, APOC2, APOA5, LMF1, and GPIHBP1. Cascade screening was performed when appropriate.
Results: Among the 20 patients with severe HTG (mean age, 47.2±10.8 years; 60% male), five patients were classified as having FCS and 15 as having MCS. The mean highest untreated plasma TG concentration was 2163.0±1382.9 mg/dL in the FCS group and 3196.8±2095.5 mg/dL in the MCS group; the corresponding mean TG/TC ratios were 7.9±3.5 and 7.1±3.4, respectively. Among patients with FCS, four carried homozygous APOA5 G185C and one carried compound heterozygous LPL variants consisting of R270H and linked L279R/S474X. MCS showed genetic heterogeneity, including heterozygous disease-causing variants in FCS-related genes, the APOE ε2/ε2 genotype, and candidate TG-raising variants. Several variants in APOA5, LMF1, APOC3, CREB3L3, GCKR, MLXIPL, and NCAN were considered as candidate TG-raising variants. Cascade screening supported the autosomal recessive inheritance in LPL- or APOA5-associated FCS.
Conclusion: WES-based genetic testing helps define the genetic architecture of FCS and MCS. This study highlights the heterogeneous genetic background of severe HTG in Taiwan and provides a foundation for future population-specific studies of disease-causing and candidate TG-raising variants.
