Diagnostic Yield of Whole Exome Sequencing in Adult-onset Cholestatic Liver Disease

Background & aims: Cholestatic liver diseases are a heterogeneous group of conditions that can remain unexplained despite a comprehensive diagnostic assessment. Genetic disorders may underlie many of these unexplained adult-onset cholestasis cases. However, genetic testing in adults has been focused on genes linked to progressive familial intrahepatic cholestasis (PFIC). This study evaluated the diagnostic utility of whole exome sequencing (WES) by targeting a broader set of genes beyond PFIC genes. Methods: Adults with unexplained cholestatic liver disease from one tertiary center underwent WES. Pathogenic and rare damaging variants in candidate cholestatic and liver disease genes were prioritized, and genotype-phenotype correlations were conducted. Results: Twenty-one patients with three distinct cholestatic phenotypes (recurrent lithiasis, intrahepatic cholestasis, and primary sclerosing cholangitis with unusual features) were included. WES yielded a genetic diagnosis of inherited cholestatic or liver disorder mimicking the cholestatic phenotype in 5 cases (23.8%). ABCB4 was the causative gene in 2 cases (40.0%), whereas genes outside the PFIC spectrum (ABCC2, PPOX, APOB) accounted for the other 3 (60.0%). Conclusion: This study highlights the value of WES in the diagnostic workup of adult-onset cholestatic liver disease and expands our understanding of its genetic landscape, paving the way for larger-scale studies.