Journal
JOURNAL OF CROHNS & COLITIS
Volume 12, Issue 9, Pages 1104-1112Publisher
OXFORD UNIV PRESS
DOI: 10.1093/ecco-jcc/jjy068
Keywords
Genetics and molecular epidemiology; paediatrics; VEO-IBD; monogenic disorders; TNGS
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Funding
- Investissement d'Avenir [ANR-10-IAHU-01]
- Fondation des Maladies Rares
- Association Francois Aupetit
- INSERM
- Polish National Science Centre [2015/16/T/NZ5/00168]
- [ERC-2013-AdG-339407-IMMUNOBIOTA]
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Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. Methods: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. Results: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.
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