Real-life Progression of the Use of a Genetic Panel in to Diagnose Neonatal Cholestasis

The study aimed to construct an advanced gene panel to ascertain the genetic etiology of patients with neonatal/infantile intrahepatic cholestasis (NIIC), and test patients with NIIC in a clinical setting. METHODS: From the group of NIIC patients, whom we had previously tested with our old 18-gene panel from May 2013 to September 2017 but could not establish a definitive diagnosis, we included 191 in the retrospective reanalysis group for this study. Additionally, we recruited 124 patients with NIIC into a prospective analysis group from October 2017 to October 2019. Cholestasis was defined as a serum direct bilirubin level >1.0 mg/dL. We constructed a 61-gene panel for targeted next-generation sequencing of the patients. RESULTS: In the retrospective reanalysis group, we found mutations in ABCC2, MPV17, NPC1, CFTR, NR1H4, or CYP27A1 in 10 (5.2%) of the 191 patients. In the prospective analysis group, 33 (26.6%) of the 124 patients had a causative mutation in JAG1, NOTCH2, ABCC2, SLC25A13, ABCB11, POLG, NPC1, CFTR, ATP8B1, or ABCB4. The top 3 genetic diagnoses were of Alagille syndrome, neonatal Dubin-Johnson syndrome, and neonatal intrahepatic cholestasis caused by citrin deficiency, which together constitute 78.8% of the genetic causes of cholestasis in Japan. We also identified 3 genotypes associated with Crigler-Najjar syndrome type 2 in the retrospective reanalysis group. CONCLUSIONS: The advanced NIIC gene panel successfully uncovered molecular genetic etiologies of NIIC not only in the reanalysis group but also in the prospective cohort. Crigler-Najjar syndrome type 2 patients may be included along with NIIC patients.