Ito Shogo, Togawa Takao, Imagawa Kazuo, Ito Koichi, Endo Takeshi, Sugiura Tokio, Saitoh Shinji
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.
JPGN Rep. 2022 Mar 31;3(2):e196. doi: 10.1097/PG9.0000000000000196. eCollection 2022 May.
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.
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.
In the retrospective reanalysis group, we found mutations in , , , , , or 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 , , , , , , , , , or . 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.
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.
本研究旨在构建一个先进的基因检测组合，以确定新生儿/婴儿肝内胆汁淤积症（NIIC）患者的遗传病因，并在临床环境中对NIIC患者进行检测。
在2013年5月至2017年9月期间，我们用旧的18基因检测组合对NIIC患者进行了检测，但未能做出明确诊断。在本研究的回顾性重新分析组中，我们纳入了191例此类患者。此外，我们在2017年10月至2019年10月期间招募了124例NIIC患者进入前瞻性分析组。胆汁淤积定义为血清直接胆红素水平>1.0mg/dL。我们构建了一个61基因检测组合，用于对患者进行靶向二代测序。
在回顾性重新分析组中，我们在191例患者中的10例（5.2%）中发现了、、、、或的突变。在前瞻性分析组中，124例患者中的33例（26.6%）在、、、、、、、、或中有致病突变。前3种遗传诊断为阿拉吉尔综合征、新生儿杜宾-约翰逊综合征和由柠檬酸转运蛋白缺乏引起的新生儿肝内胆汁淤积症，它们共同构成了日本胆汁淤积症遗传病因的78.8%。我们还在回顾性重新分析组中鉴定出3种与2型克里格勒-纳贾尔综合征相关的基因型。
先进的NIIC基因检测组合不仅在重新分析组中，而且在前瞻性队列中都成功地发现了NIIC的分子遗传病因。2型克里格勒-纳贾尔综合征患者可能与NIIC患者一起被纳入。
