Unexplained cholestasis in adults and adolescents: diagnostic benefit of genetic examination

Abstract

<p><b>Objectives:</b> A few adult and adolescent patients with even severe cholestatic liver disease remain unexplained after standard diagnostic work-up. We studied the value of genetic examination in such patients and developed a panel of eight genes with known cholestatic associations.</p> <p><b>Materials and methods:</b> Thirty-three patients with unexplained cholestasis despite a thorough clinical work-up were examined for sequence variations in the coding regions of the <i>ABCB4, ABCB11, ABCC2, ABCG5, ATP8B1, JAG1, NOTCH2,</i> and <i>UGT1A1</i> genes and the promoter region of <i>UGT1A1</i> by massive parallel sequencing of DNA extracted from whole blood. Hepatologists and clinical geneticists evaluated the causal potential of genetic variants.</p> <p><b>Results:</b> In 9/33 patients (27%), we identified genetic variants as a certain causal factor and in further 9/33 (27%) variants as a possible contributing factor. In most cases, a detailed family history was necessary to establish the importance of genetic variants. Genetic causes were identified in 6/13 women (46%) with intrahepatic cholestasis during pregnancy and persisting abnormal biochemistry after delivery.</p> <p><b>Conclusions:</b> Our study suggests that a small number of well-known genetic variants are involved in at least 27–54% of patients with unexplained cholestasis. An expanded panel will likely explain more cases. This motivates genetic testing of these patients. Genetic testing, however, cannot stand alone but should be combined with a clinical genetic work-up in collaboration between hepatologists and clinical geneticists.</p