A novel homozygous CREB3L3 variant associated with severe hypertriglyceridaemia. A case report

Background Hypertriglyceridaemia (HTG) encompasses a spectrum from common multifactorial disorders to rare monogenic conditions. Variants in cyclic AMP-responsive element-binding protein 3-like protein 3 (CREB3L3), encoding the transcription factor cyclic AMP-responsive element-binding protein H (CREB-H), have emerged as important regulators of triglyceride metabolism. Case summary A 33-year-old woman presented with severe HTG (peak triglycerides 11.4 mmol/l) in the absence of secondary causes. She had marked obesity (body mass index (BMI) 39 kg/m2) and elevated fat mass (48.6%). Imaging revealed hepatosplenomegaly without hepatic steatosis or fibrosis. A post-heparin test suggested impaired triglyceride clearance. Genetic analysis identified a previously unreported homozygous nonsense variant in CREB3L3 (c.1069C>T; p.Arg357*). A heterozygous relative had also hypercholesterolemia. Discussion This case supports a causal role for biallelic CREB3L3 loss-of-function variants in severe HTG and expands the phenotype to include hepatosplenomegaly. The identification of a previously undescribed variant further broadens the genetic spectrum of CREB3L3-related disease. The clinical expression appears strongly modulated by metabolic factors such as obesity.