title: Targeted Sequencing and Immunological Analysis Reveal the Involvement of Primary Immunodeficiency Genes in Pediatric IBD: a Japanese Multicenter Study.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan. ysasahara@med.tohoku.ac.jp.
authors.forename: Yoji
authors.identifier: 0000-0003-0030-1535
authors.initials: Y
authors.lastname: Sasahara
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kikuchi
authors.affiliation: Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Miyagi, Japan.
authors.forename: Humihiko
authors.initials: H
authors.lastname: Kakuta
authors.affiliation: Department of Gastroenterology, Yamagata Prefectural Central Hospital, Yamagata, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kashiwabara
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ishige
authors.affiliation: Department of Pediatrics, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Department of Pathology and Laboratory Medicine, Hirosaki City Hospital, Aomori, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Pediatrics, Toyama University School of Medicine, Toyama, Japan.|Department of Pediatrics, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hoshino
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Kanegane
authors.affiliation: Department of General Pediatrics, Miyagi Children's Hospital, Sendai, Miyagi, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Abukawa
authors.affiliation: Department of Pediatrics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
mesh_terms: D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007109:Immunity / Q000235:genetics*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D015212:Inflammatory Bowel Diseases / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D040582:Inheritance Patterns; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053709:Interleukin-10 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007564:Japan; D008297:Male; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction; D000073359:Exome Sequencing; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D053709:Interleukin-10 Receptor alpha Subunit; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D016753:Interleukin-10
keywords: Very early-onset inflammatory bowel disease; pediatric gastroenterology; primary immunodeficiency; targeted sequencing