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

Shogo Ito; Takao Togawa; Kazuo Imagawa; Koichi Ito; Takeshi Endo; Tokio Sugiura; Shinji Saitoh

doi:10.1097/PG9.0000000000000196

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

JPGN Rep. 2022 Mar 31;3(2):e196. doi: 10.1097/PG9.0000000000000196. eCollection 2022 May.

Authors

Shogo Ito¹, Takao Togawa¹, Kazuo Imagawa², Koichi Ito¹, Takeshi Endo³, Tokio Sugiura¹, Shinji Saitoh¹

Affiliations

¹ From the Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
² Department of Child Health, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
³ Department of Pediatrics, Nagoya City University East Medical Center, Nagoya, Japan.

Abstract

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.

Keywords: Crigler-Najjar syndrome; genetic liver diseases; molecular genetic diagnosis; neonatal intrahepatic cholestasis; next-generation sequencing.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.