A family with gallstone disease: defining inherited risk in the era of clinical genetic testing.

Gallstones are among the most frequent hepatobiliary conditions. Although in most cases, they remain asymptomatic, they can cause complications and, in such cases, invasive treatments like endoscopic retrograde cholangiography (ERC) or cholecystectomy are required. Here, we present the results of genetic testing of a single family with a high incidence of symptomatic gallstones and cholestatic liver phenotypes. Gallstone disease was detected among seven family members spanning three generations, and DNA samples were available from five of them. Genotyping was performed using TaqMan assays for known, selected genetic risk factors for gallstones and cholestasis, as well as next generation sequencing (NGS) of three genes involved in hepatobiliary transport. In all genotyped patients, we detected at least one copy of the gallstone-predisposing p.D19H variant in the hepatobiliary sterol transporter ABCG5/8, and in three cases, this variant was found in the rare homozygous state. In addition, the patients were all homozygous carriers of two intronic variants (c.2211+16C >T and c.3508-16T>C) and two common polymorphisms (c.504C>T and c.711A>T) in the ABCB4 gene, as well as the ATP8B1 gene variant c.696T>C. All genotyped patients also carried the predisposing variants c.1331C>T and c.3084A>G of the hepatobiliary bile salt export pump ABCB11 in either heterozygous or homozygous form. Hence, we propose that these variants taken together may have contributed to the high frequency of gallstone disease in this family, although functional studies for some variants are still lacking. In this report, we present these findings and discuss the challenges associated with interpreting sequencing data.