Genetic Variant Analysis in Low Phospholipid-Associated Cholelithiasis Patients through Whole Exome Sequencing

Low phospholipid-associated cholelithiasis (LPAC) syndrome is a specific gallstone disease affecting around 1% of hospitalized symptomatic gallstone patients in adults. Half of the LPAC patients carry a potentially relevant variant in the ABCB4 gene, encoding the MDR3 protein, responsible for phospholipid secretion into bile. This promotes cholesterol crystallization and recurrent gallstone formation, often persisting after cholecystectomy (CCE). Genetic variants in other genes may contribute to gallstone formation, including ABCB11/BSEP, involved in bile salt export, and ATP8B1/FIC1, which help maintain bile composition. ABCG8:p.D19H variant is also known to be associated with increased risk for gallstone formation.

The HiChol registry data on 20 LPAC patients reveals that 19 (95%) of them underwent CCE at a median age of 32 years, which suits the LPAC criteria. The gender distribution showed a slight predominance of females (11 patients, 55%) over males (9 patients, 45%). The results from whole exome sequencing (WES) analysis revealed pathogenic variants in ABCB4/MDR3 in 6 patients (30%), reinforcing the established genetic basis of the disorder. These findings emphasize the significant link between LPAC and CCE, underscoring the need for targeted diagnostic and therapeutic approaches. In around two-thirds of this cohort, no relevant ABCB4/MDR3 was detectable. In these cases, we identified variants affecting ATP8B1, ABCB11, MYO5B, NR1H4, ABCC12, and ABCC4 involved in bile metabolism and transport.

Ongoing analysis of WES data is being carried out to identify further potential genetic contributors to the LPAC phenotype. Moreover, clinical and quality of life data is documented for a genotype-phenotype correlation.

Publication History

Article published online:
20 January 2025