Abstract
Purpose
Pediatric inflammatory bowel disease (IBD) is a heterogeneous disorder caused by multiple factors. Although genetic and immunological analyses are required for a definitive diagnosis, no reports of a comprehensive genetic study of a Japanese population are available.
Methods
In total, 35 Japanese patients <16 years of age suffering from IBD, including 27 patients aged <6 years with very early-onset IBD, were enrolled in this multicenter study. Exome and targeted gene panel sequencing was performed for all patients. Mutations in genes responsible for primary immunodeficiency diseases (PID) and clinical and immunological parameters were evaluated according to disease type.
Results
We identified monogenic mutations in 5 of the 35 patients (14.3 %). We identified compound heterozygous and homozygous splice-site mutations in interleukin-10 receptor A (IL-10RA) in two patients, nonsense mutations in X-linked inhibitor of apoptosis protein (XIAP) in two patients, and a missense mutation in cytochrome b beta chain in one patient. Using assays for protein expression levels, IL-10 signaling, and cytokine production, we confirmed that the mutations resulted in loss of function. For each patient, genotype was significantly associated with clinical findings. We successfully treated a patient with a XIAP mutation by allogeneic cord blood hematopoietic stem cell transplantation, and his symptoms were ameliorated completely.
Conclusions
Targeted sequencing and immunological analysis are useful for screening monogenic disorders and selecting curative therapies in pediatric patients with IBD. The genes responsible for PID are frequently involved in pediatric IBD and play critical roles in normal immune homeostasis in the gastrointestinal tract.
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Acknowledgments
The authors thank all of our patients and their parents for participating in this study. We thank Drs. H Kumagai, M Sasaki, T Saitoh, T Nanbu, N Abe, and J Suzuki for providing patients’ samples and clinical data. We also thank M Uchiyama, N Ichinoi, H Kudoh, and R Satoh for technical assistance.
This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (26461562), a grant from the Japanese Ministry of Health, Labour and Welfare (H26-037) and a grant from the Japan Agency for Medical Research and Development (J150001095) to YS.
Authorship Contributions
TS and YS designed and performed the research, analyzed data, and wrote the manuscript. AH and HK performed the research. HK, TK, TI, YN, and DA provided patients’ samples and clinical data. MT performed pathological evaluations. AK and SK provided scientific advice.
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All authors declare that they have no conflict of interest and have nothing to disclose.
Ethical Approval
This study was approved by the Ethics Committee of the Tohoku University Graduate School of Medicine on 30th September 2013. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendment or comparable ethical standards.
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Written informed consent was obtained from all individual participants or their guardians included in this study.
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Suzuki, T., Sasahara, Y., Kikuchi, A. et al. Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: a Japanese Multicenter Study. J Clin Immunol 37, 67–79 (2017). https://doi.org/10.1007/s10875-016-0339-5
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DOI: https://doi.org/10.1007/s10875-016-0339-5