Ariza_2025_Genet.Med__101365

PURPOSE: Genetic testing is required to confirm a diagnosis of familial chylomicronemia syndrome (FCS). We assessed the pathogenicity of variants identified in the FCS canonical genes to diagnose FCS cases. METHODS: 245 patients with severe hypertriglyceridemia underwent next-generation sequencing. Preliminary variant pathogenicity criteria and classification, based on the American College of Medical Genetics and Genomics (ACMG) guidelines, were obtained online and verified. Phenotype evaluation was based on lipoprotein lipase activity deficiency, a clinical score, and/or type I hyperlipoproteinemia determined in 25 patients. RESULTS: Twenty-four biallelic variants were analysed. Evidence-based criteria allowed the reclassification of eight likely pathogenic (LP) variants in the LPL, APOA5, and LMF1 genes into pathogenic (P) and the change of two variants of uncertain significance (VUS) to LP. Conversely, two variations in LMF1 remained as VUS. Additionally, one variant in LPL and two in GPIHBP1 were likely benign (LB). Twenty FCS cases had biallelic P/LP variants and one patient, with an FCS phenotype, harboured biallelic VUS. FCS was excluded from four patients with P/LB combinations. CONCLUSION: The analysis of the clinical and biochemical features of patients with variants in the FCS canonical genes allowed a confident variant classification that helped in the diagnosis of novel FCS cases.