A novel missense variant in creb3l3 gene associated with severe hypertriglyceridemia

Background and Aims : Severe hypertriglyceridemia (HTG) is a rare disease consisting in increased plasma triglyceride (TG) levels (>10 mmol/L). Patients can show eruptive xanthomas, lipaemia retinalis, hepatosplenomegaly and pancreatitis. For long time five genes were considered causative of the disease with autosomal recessive inheritance: Lipoprotein lipase (LPL), Apolipoprotein A-V (APOA5), Apolipoprotein C-II (APOC2), Glycosyl-phosphatidyl-inositol-anchored HDL-binding protein (GPIHBP1) and Lipase maturation factor-1 (LMF1). The introduction of next-generation sequencing (NGS) highlighted the presences of rare variant in noncanonical gene associated to dominant familial hypertriglyceridemia, such as CREB-Binding Protein 3-Like 3 (CREB3L3) and Glucokinase Regulator (GCKR).Methods: We report the clinical, biochemical and molecular characterization of a 25 years old woman hospitalized urgently for acute pancreatitis with TG > 17 mmol/L. Patient was screened by NGS to detect variants in a large panel of 35 lipid related-genes.Results: No know pathogenic variants of HTG were found but NGS analysis revealed the presence at heterozygous state of rare missense variant c.742C>T (p.Arg248Cys) in the exon 6 of CREB3L3 gene. Variant was confirmed by Sanger sequencing. The variant was absent from databases of mutations (HGMD professional) and according to the ACMG guidelines can be classified as VUS. Bioinformatics predictions classified variant as damaging.Conclusions: Severe HTG is a complex disease that can benefit from NGS to identify variants in a large number lipid-related genes that can act as phenotype modifier. Our findings support the hypothesis that rare variants in a noncanonical gene for triglyceride metabolism as CREB3L3, can contribute to severe hypertriglyceridemia. Background and Aims : Severe hypertriglyceridemia (HTG) is a rare disease consisting in increased plasma triglyceride (TG) levels (>10 mmol/L). Patients can show eruptive xanthomas, lipaemia retinalis, hepatosplenomegaly and pancreatitis. For long time five genes were considered causative of the disease with autosomal recessive inheritance: Lipoprotein lipase (LPL), Apolipoprotein A-V (APOA5), Apolipoprotein C-II (APOC2), Glycosyl-phosphatidyl-inositol-anchored HDL-binding protein (GPIHBP1) and Lipase maturation factor-1 (LMF1). The introduction of next-generation sequencing (NGS) highlighted the presences of rare variant in noncanonical gene associated to dominant familial hypertriglyceridemia, such as CREB-Binding Protein 3-Like 3 (CREB3L3) and Glucokinase Regulator (GCKR). Methods: We report the clinical, biochemical and molecular characterization of a 25 years old woman hospitalized urgently for acute pancreatitis with TG > 17 mmol/L. Patient was screened by NGS to detect variants in a large panel of 35 lipid related-genes. Results: No know pathogenic variants of HTG were found but NGS analysis revealed the presence at heterozygous state of rare missense variant c.742C>T (p.Arg248Cys) in the exon 6 of CREB3L3 gene. Variant was confirmed by Sanger sequencing. The variant was absent from databases of mutations (HGMD professional) and according to the ACMG guidelines can be classified as VUS. Bioinformatics predictions classified variant as damaging. Conclusions: Severe HTG is a complex disease that can benefit from NGS to identify variants in a large number lipid-related genes that can act as phenotype modifier. Our findings support the hypothesis that rare variants in a noncanonical gene for triglyceride metabolism as CREB3L3, can contribute to severe hypertriglyceridemia.