Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study

Abstract

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. (© The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)Blood. 2015 Jan 22;125(4):639-48. (PMID: 25349174); N Engl J Med. 2009 Nov 19;361(21):2033-45. (PMID: 19890111); Nat Rev Gastroenterol Hepatol. 2015 May;12(5):293-302. (PMID: 25782092); Nat Genet. 2014 Oct;46(10):1135-1139. (PMID: 25217960); J Pediatr Gastroenterol Nutr. 2017 Mar;64(3):378-384. (PMID: 27253662); Nat Methods. 2010 Apr;7(4):248-9. (PMID: 20354512); Gastroenterology. 2010 Sep;139(3):770-8. (PMID: 20537998); Lancet. 2010 Oct 9;376(9748):1272. (PMID: 20934598); Nat Protoc. 2009;4(7):1073-81. (PMID: 19561590); Front Pediatr. 2016 Sep 14;4:98. (PMID: 27683652); Arch Dis Child. 2014 Jan;99(1):35-8. (PMID: 24108068); J Allergy Clin Immunol. 2016 Oct;138(4):1142-1151.e2. (PMID: 27484032); Nat Methods. 2016 Feb;13(2):109-10. (PMID: 26820543); Nat Med. 2014 Dec;20(12):1410-1416. (PMID: 25329329); Nucleic Acids Res. 2001 Jan 1;29(1):308-11. (PMID: 11125122); Am J Gastroenterol. 2010 Oct;105(10):2262-75. (PMID: 20551941); Pediatrics. 2017 Aug;140(2):. (PMID: 28724572); Inflamm Bowel Dis. 2017 Dec;23(12):2109-2120. (PMID: 28930861); Nature. 2016 Aug 17;536(7616):285-91. (PMID: 27535533); Eur J Immunol. 2014 Oct;44(10):2854-61. (PMID: 25154746); J Allergy Clin Immunol. 2014 Feb;133(2):529-34. (PMID: 24139496); Gastroenterology. 2014 Nov;147(5):990-1007.e3. (PMID: 25058236); Front Immunol. 2014 Nov 03;5:531. (PMID: 25404929); Hum Genet. 2014 Mar;133(3):299-310. (PMID: 24142340); Nat Genet. 2014 Aug;46(8):812-814. (PMID: 25038750); Gut. 2013 Dec;62(12):1795-805. (PMID: 24203055); Curr Opin Pediatr. 2013 Dec;25(6):708-14. (PMID: 24240290); J Allergy Clin Immunol. 2012 Aug;130(2):481-8.e2. (PMID: 22721650); Science. 2014 Sep 26;345(6204):1623-1627. (PMID: 25213377); Science. 2015 Jul 24;349(6246):436-40. (PMID: 26206937); EMBO Mol Med. 2018 Apr;10(4):. (PMID: 29567797); J Allergy Clin Immunol. 2014 Nov;134(5):1131-41.e9. (PMID: 24942515); Nat Methods. 2014 Apr;11(4):361-2. (PMID: 24681721); Nat Genet. 2014 Mar;46(3):310-5. (PMID: 24487276); Nature. 2015 Oct 1;526(7571):68-74. (PMID: 26432245); Blood. 2015 Jan 22;125(4):591-9. (PMID: 25359994); Int J Colorectal Dis. 2016 Jun;31(6):1235-6. (PMID: 26584814); J Med Genet. 2014 Nov;51(11):748-55. (PMID: 25194001); Gastroenterology. 2017 Aug;153(2):609-611.e3. (PMID: 28683258); Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943); Inflamm Bowel Dis. 2013 Dec;19(13):2820-8. (PMID: 24216686). Linking ISSN: 18739946. Subset: MEDLINE; Grant Information: 339407 International ERC_ European Research Council Date of Electronic Publication: 20180829. Current Imprints: Publication: 2015- : Oxford : Oxford University Press; Original Imprints: Publication: Amsterdam : Elsevier Science <br />