Interpretation of XIAP Variants of Uncertain Significance in Paediatric Patients with Refractory Crohn's Disease

Iksoo Chang, Seongjun Park, Hye Jin Lee, Inki Kim, Sojung Park, Mi Kyoung Ahn, Juhwan Lee, Mooseok Kang, In Jeoung Baek, Young Hoon Sung, Chan Gi Pack, Hyo Jeong Kang, Kunsong Lee, Ho Joon Im, Eul Ju Seo, Kyung Mo Kim, Suk Kyun Yang, Kyuyoung Song, Seak Hee Oh

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3 Scopus citations


Background and Aims: Mutations in XIAP can lead to the development of treatment-refractory severe paediatric Crohn's disease [CD], for which haematopoietic stem cell transplantation is the primary therapeutic option. The interpretation of variants of uncertain significance [VUSs] in XIAP needs to be scrutinized. Methods: Targeted next-generation sequencing was performed for 33 male paediatric patients with refractory CD admitted at a tertiary referral hospital. To obtain functional data, biomolecular cell assays and supercomputing molecular dynamics simulations were performed. Results: Nine unrelated male patients harboured hemizygous XIAP variants. Four known pathogenic variants and one novel pathogenic variant [p.Lys168Serfs∗12] were identified in five patients, and two novel VUSs [p.Gly205del and p.Pro260Ser] and one known VUS [p.Glu350del] were identified in the remaining four. Among children with VUSs, only the subject with p.Gly205del exhibited defective NOD2 signalling. Using molecular dynamics simulation, we determined that the altered backbone torsional energy of C203 in XIAP of p.G205del was ~2 kcal/mol, suggesting loss of zinc binding in the mutant XIAP protein and poor coordination between the mutant XIAP and RIP2 proteins. Elevated auto-ubiquitination of zinc-depleted p.G205del XIAP protein resulted in XIAP protein deficiency. Conclusion: A high prevalence of XIAP deficiency was noted among children with refractory CD. Advanced functional studies decreased the subjectivity in the case-level interpretation of XIAP VUSs and directed consideration of haematopoietic stem cell transplantation.

Original languageEnglish
Pages (from-to)1291-1304
Number of pages14
JournalJournal of Crohn's and Colitis
Issue number8
StatePublished - 1 Aug 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn's and Colitis Organisation. All rights reserved. For permissions, please email:


  • Crohn's disease
  • XIAP
  • molecular dynamics
  • variant of uncertain significance


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