A Rare Variant in a Familial Case of Intrahepatic Cholestasis of Pregnancy: A Potential Novel Genetic Contributor.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder with a multifactorial pathogenesis and a well-established genetic component. While pathogenic variants in genes such as and are implicated in a subset of cases, many remain genetically unexplained. This study aimed to investigate the genetic background of ICP in a multi-generational family with recurrent hepatobiliary disease. Whole-exome sequencing was performed on the proband and five female relatives. Variant filtering prioritized rare, exonic or splice-site variants predicted to undergo damage by tools and which were present in all affected family members. Identified variants were assessed using population databases and compared with a control group of 433 unrelated women with uncomplicated pregnancies. Variant confirmation was performed using Sanger sequencing and high-resolution melting analysis. No pathogenic variants were identified in known ICP-associated genes. However, a rare heterozygous missense variant in (c.1610G>A; p.Arg537His; rs779950110) was found in all affected individuals and two younger female relatives. This variant is exceedingly rare in population databases, absent in controls, and predicted to be pathogenic by multiple algorithms. , although not previously linked to ICP, is an ATP-binding cassette transporter expressed in various tissues, including liver compartments. This study reports a novel variant segregating with ICP and early-onset hepatobiliary disease in a family. These findings suggest as a potential new susceptibility gene in ICP, warranting further functional investigation.