Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2021; 27(44): 7705-7715
Published online Nov 28, 2021. doi: 10.3748/wjg.v27.i44.7705
Autosomal recessive 333 base pair interleukin 10 receptor alpha subunit deletion in very early-onset inflammatory bowel disease
Jia-Jia Lv, Wen Su, Xiao-Yan Chen, Yi Yu, Xu Xu, Chun-Di Xu, Xing Deng, Jie-Bin Huang, Xin-Qiong Wang, Yuan Xiao
Jia-Jia Lv, Wen Su, Yi Yu, Xu Xu, Chun-Di Xu, Xing Deng, Jie-Bin Huang, Xin-Qiong Wang, Yuan Xiao, Department of Pediatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
Xiao-Yan Chen, Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, Shanghai Province, China
Author contributions: Lv JJ and Su W contributed equally to this work; Lv JJ and Su W performed the experiments, data acquisition, analysis and interpretation, and drafting of the article; Chen XY, Yu Y, Xu X, Xu CD, Deng X, and Huang JB analyzed the data and critically revised the article; Wang XQ and Xiao Y designed the project and critically revised the article for important intellectual content; and all authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81741103.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Ruijin Hospital (Shanghai).
Informed consent statement: All study participants or their legal guardians provided informed consent prior to study enrollment.
Conflict-of-interest statement: There are no conflicts of interest to declare.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Yuan Xiao, MD, PhD, Associate Chief Physician, Deputy Director, Lecturer, Department of Pediatrics, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Ruijin 2nd Road, Shanghai 200025, Shanghai Province, China. xy11438@rjh.com.cn
Received: May 31, 2021
Peer-review started: May 31, 2021
First decision: July 1, 2021
Revised: July 9, 2021
Accepted: November 9, 2021
Article in press: November 9, 2021
Published online: November 28, 2021

Interleukin 10 receptor alpha subunit (IL10RA) dysfunction is the main cause of very early-onset inflammatory bowel disease (VEO-IBD) in East Asians.


To identify disease-causing gene mutations in four patients with VEO-IBD and verify functional changes related to the disease-causing mutations.


From May 2016 to September 2020, four young patients with clinically diagnosed VEO-IBD were recruited. Before hospitalization, using targeted gene panel sequencing and trio-whole-exome sequencing (WES), three patients were found to harbor a IL10RA mutation (c.301C>T, p.R101W in one patient; c.537G>A, p.T179T in two patients), but WES results of the fourth patient were not conclusive. We performed whole-genome sequencing (WGS) on patients A and B and reanalyzed the data from patients C and D. Peripheral blood mononuclear cells (PBMCs) from patient D were isolated and stimulated with lipopolysaccharide (LPS), interleukin 10 (IL-10), and LPS + IL-10. Serum IL-10 levels in four patients and tumor necrosis factor-α (TNF-α) in the cell supernatant were determined by enzyme-linked immunosorbent assay. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr705 and Ser727 in PBMCs was determined by western blot analysis.


The four children in our study consisted of two males and two females. The age at disease onset ranged from 18 d to 9 mo. After hospitalization, a novel 333-bp deletion encompassing exon 1 of IL10RA was found in patients A and B using WGS and was found in patients C and D after reanalysis of their WES data. Patient D was homozygous for the 333 bp deletion. All four patients had elevated serum IL-10 levels. In vitro, IL-10-stimulated PBMCs from patient D failed to induce STAT3 phosphorylation at Tyr705 and only minimally suppressed TNF-α production induced by LPS. Phosphorylation at Ser727 in PBMCs was not affected by LPS or LPS + IL-10 in both healthy subjects and in patient D.


WGS revealed a novel 333-bp deletion of IL10RA in four patients with VEO-IBD, whereas the WES results were inconclusive.

Keywords: Interleukin 10 receptor alpha subunit mutation, Very early-onset inflammatory bowel disease, Whole-genome sequencing, Immunodeficiency, Crohn’s disease, Whole-exon sequencing

Core Tip: Children less than 6 years old with very early-onset inflammatory bowel disease (VEO-IBD) exhibit severe and refractory disease phenotypes, which indicate a monogenic type disease. Here, we report four cases clinically diagnosed with VEO Crohn’s disease, of which three were compound heterozygous carriers for a 333-bp deletion and an additional single-nucleotide variant, and one was homozygous for the 333-bp deletion in IL10RA. Based on these cases with heterozygous pathogenic variants in IL10RA, the possibility of another large fragment deletion that can be missed by whole-exon sequencing or gene panels should be considered, particularly when serum IL-10 is increased in patients with VEO-IBD.