Heterozygous CFTR variants associated with low-phospholipid-associated cholelithiasis phenotypes expand hepatobiliary disorders spectrum.

Abstract

Low-phospholipid-associated cholelithiasis (LPAC) syndrome is mainly associated with ABCB4 variants, although up to half of cases remain genetically unexplained. Given the role of CFTR in biliary homeostasis and its involvement in CFTR-related pancreatobiliary disorders, we investigated whether CFTR variants may contribute to LPAC phenotypes. We conducted a monocentric study including 34 patients fulfilling LPAC diagnostic criteria who underwent whole-exome sequencing with analysis restricted to an extended hepatobiliary gene panel including CFTR. Variants of interest were identified in 14/34 patients (41%), including 4 ABCB4 variant carriers (12%) and 10 CFTR variant carriers (29%). Patients carrying CFTR variants presented with classical LPAC features, including cholelithiasis, recurrent biliary symptoms, and cholangitis, while pancreatic involvement was observed in half of carriers. Compared with the CFTR carrier frequency estimated from the French newborn screening program (∼2.6%), CFTR variant carriers were significantly enriched in the cohort (11.5-fold enrichment, 95% CI 5.9-18.6, p < 0.001), suggesting a contributory role in a subset of LPAC phenotypes. These findings support consideration of CFTR in the genetic evaluation of selected patients with LPAC and reinforce the concept of hepatobiliary transporter disorders as a phenotypic continuum extending beyond ABCB4 deficiency.