Diagnostic algorithm for neonatal intrahepatic cholestasis integrating single‐gene testing and next‐generation sequencing in East Asia

Abstract Background and Aim Advances in molecular genetics have uncovered causative genes responsible for neonatal cholestasis. Panel‐based next‐generation sequencing has been used clinically in infants with neonatal cholestasis. We aimed to evaluate the clinical application of single‐gene testing and next‐generation sequencing and to develop a diagnostic algorithm for neonatal intrahepatic cholestasis. Methods From January 2010 to July 2021, patients suspected of having neonatal intrahepatic cholestasis were tested at the Seoul National University Hospital. If there was a clinically suspected disease, single‐gene testing was performed. Alternatively, if it was clinically difficult to differentiate, a neonatal cholestasis gene panel test containing 34 genes was performed. Results Of the total 148 patients examined, 49 (33.1%) were received a confirmed genetic diagnosis, including 14 with Alagille syndrome, 14 with neonatal intrahepatic cholestasis caused by citrin deficiency, 7 with Dubin–Johnson syndrome, 5 with arthrogryposis‐renal dysfunction‐cholestasis syndrome, 5 with progressive familial intrahepatic cholestasis type II, 1 with Rotor syndrome, 1 with Niemann‐Pick disease type C, 1 with Kabuki syndrome, and 1 with Phenylalanyl‐tRNA synthetase subunit alpha mutation. Sixteen novel pathogenic or likely pathogenic variants of neonatal cholestasis were observed in this study. Based on the clinical characteristics and laboratory findings, we developed a diagnostic algorithm for neonatal intrahepatic cholestasis by integrating single‐gene testing and next‐generation sequencing. Conclusions Alagille syndrome and neonatal intrahepatic cholestasis caused by citrin deficiency were the most common diseases associated with genetic neonatal cholestasis. Single‐gene testing and next‐generation sequencing are important and complementary tools for the diagnosis of genetic neonatal cholestasis.