CREB3L3 associated severe hypertriglyceridemia: targeted NGS identification of a novel truncating variant and systematic review

Abstract Introduction Cyclic AMP Responsive Element Binding Protein 3 Like 3 (CREB3L3 ) plays a crucial role in hepatic triglyceride (TAG) metabolism. Variants in CREB3L3 have been reported in individuals with hypertriglyceridemia (HTG). In this article we present a family from Punjab, Pakistan, with a rare heterozygous CREB3L3 variant and systematically review the literature on CREB3L3 variants associated with HTG. After identification of an index case with HTG and a likely pathogenic heterozygous variant in CREB3L3 , five family members underwent cascade genetic screening using Next Generation Sequencing (NGS), followed by variant confirmation with Sanger sequencing. A systematic review according to the PRISMA guidelines was conducted to summarize the clinical and genetic characteristics of individuals with CREB3L3 -associated HTG. Results The 25-year-old male proband had fasting TAG of 1300 mg/dL (14.7 mmol/L). Genetic testing revealed a rare nonsense variant, CREB3L3 NM_032607.3:c.271G > T (p.Glu91Ter) in exon 3, absent from ClinVar. Treatment with fenofibrate and dietary modification reduced TAG levels by 33.5%. Two relatives carried the same variant: the father (in a mosaic state, 29% variant allele fraction), who had HTG, triple-vessel coronary disease, and prior bypass surgery and the sister, who was asymptomatic. The systematic review identified 24 reported cases with CREB3L3 variants and variable TAG levels (mild to severe HTG). Acute pancreatitis occurred in 3 (12.5%) cases. Conclusion This study reports the first association of the CREB3L3 c.271G > T (p.Glu91Ter) variant with severe HTG in a Pakistani family. The systematic review revealed diverse clinical presentations, including severe HTG and acute pancreatitis in some cases.