SEARCHCOHORTpediatrics, gastroenterology

cohort·pediatrics, gastroenterology, clinical trial, observational study, research methods·PMC10158323

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

JPGN reports · 7 authors, 3 centres

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TL;DR

This study evaluated a new 61-gene panel for diagnosing neonatal intrahepatic cholestasis (NIIC) in two Japanese patient cohorts.

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This study investigated the diagnostic efficacy of an advanced 61-gene panel for neonatal intrahepatic cholestasis (NIIC). Two cohorts were analyzed: a retrospective group of 191 patients previously undiagnosed with an 18-gene panel, and a prospective group of 124 patients tested for the first time. In the retrospective group, 10 of 191 patients (5.2%) received a new molecular diagnosis. In the prospective group, 33 of 124 patients (26.6%) received a definitive diagnosis. The top three genetic causes identified in the prospective cohort were Alagille syndrome, neonatal Dubin-Johnson syndrome, and citrin deficiency, accounting for 78.8% of the genetic diagnoses. The study concludes that the expanded panel successfully identifies etiologies in both cohorts and suggests that clinicians should consider Crigler-Najjar syndrome type 2 in NIIC patients. A limitation is the potential for selection bias between cohorts.

STUDY TYPE

cohort

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pediatrics

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ORIGINAL PAPER

PMC10158323

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

JPGN reports

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ABSTRACT

Objectives: 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: neonatal intrahepatic cholestasis, next-generation sequencing, molecular genetic diagnosis, genetic liver diseases, Crigler-Najjar syndrome

CITATION EXPORT

Shogo Ito, Takao Togawa, Kazuo Imagawa et al.. Real-life Progression of the Use of a Genetic Panel in to Diagnose Neonatal Cholestasis. JPGN reports. (2022). https://doi.org/10.1097/PG9.0000000000000196

AUTHORS

7 · 3 CENTRES

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

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