Identification of new potential genetic risk factors for cholestasis and gallstone disease: report of three-generation family with cholestatic phenotype

Introduction: Gallstones are a frequent condition, typically asymptomatic but sometimes requiring invasive treatments. This study examines genetic testing in a family with a high incidence of symptomatic gallstones and cholestatic liver phenotypes.

Patients: We analyzed a three-generation family with a history of gallstones and elevated liver enzymes, including a 21-year-old male (patient 1), a 24-year-old female sibling (patient 2), their 70-year-old father (patient 3), 59-year-old mother (patient 4), and 64-year-old uncle (patient 5). The father showed mild liver fibrosis in a biopsy. The deceased paternal grandfather and his twin sister (not genotyped) also presented with gallstones. Genetic testing involved an in-house cholestasis panel for 15 cholestasis-related variants, followed by next-generation sequencing (NGS) of ABCB4, ABCB11, and ATP8B1 genes.

Results: Homozygosity was detected for the known ABCB4 variants c.504C>T and c.711A>T, and ABCB11 variants c.1331C>T and c.3084A>G. NGS revealed that all patients were homozygous for two intronic ABCB4 variants. Additionally, synonymous ATP8B1 base changes were found in patients 1-4, while patient 5 lacked the ATP8B1 variant rs319443. These variants may have functional implications despite being classified as synonymous. The major gallstone-predisposing variant ABCG8 p.D19H was homozygous in patients 1-3 and heterozygous in patients 4-5. Variants from recent GWAS (SPTLC3/LINC-01723, TMEM147, TNRC6B) were also identified in either heterozygous or homozygous state.

Discussion: The combined effect of these variants may explain the high prevalence of gallstone disease in this family, though functional studies are warranted. Expanding the use of NGS in clinical practice could help uncover new genetic risk factors for common diseases.

Publication History

Article published online:
20 January 2025