Identification of a new, likely pathogenic, heterozygous ABCB4 variant causing low phospholipid-associated...

Low phospholipid-associated cholelithiasis (LPAC) is a cholestatic genetic disorder caused by mutations in the ABCB4 gene, which encodes the multidrug resistance protein 3 (MDR3) that is crucial for bile phospholipid transport. We report a boy in late adolescence presenting with recurrent biliary symptoms post cholecystectomy, elevated cholestatic liver enzymes and a family history of hepatobiliary and pancreatic disease. Genetic testing revealed a novel heterozygous ABCB4 variant (c.833+5G>A). Functional studies demonstrated abnormal mRNA splicing, resulting in reduced MDR3 protein expression. The same variant was also identified in the patient's mother and sister, consistent with autosomal dominant inheritance. Following treatment with ursodeoxycholic acid, the patient achieved clinical and biochemical remission. This case highlights the importance of considering rarer genetic causes, including LPAC, in young patients with symptomatic cholelithiasis, particularly when there is a suggestive family history. Early recognition and targeted therapy can significantly improve clinical outcomes.