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

作者：Fabienne, Charbit-Henrion; Marianna, Parlato; Sylvain, Hanein; Rémi, Duclaux-Loras; Jan, Nowak; Bernadette, Begue; Sabine, Rakotobe; Julie, Bruneau; Cécile, Fourrage; Olivier, Alibeu; Frédéric, Rieux-Laucat; Eva, Lévy; Marie-Claude, Stolzenberg; Fabienne, Mazerolles; Sylvain, Latour; Christelle, Lenoir; Alain, Fischer; Capucine, Picard; Marina, Aloi; Jorge Amil, Dias; Mongi Ben, Hariz; Anne, Bourrier; Christian, Breuer; Anne, Breton; Jiri, Bronsky; Stephan, Buderus; Mara, Cananzi

来源：Journal of Crohns & Colitis, 2018, 12(9): 1104-1112.

DOI：10.1093/ecco-jcc/jjy068

<jats:title>Abstract</jats:title>
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<jats:title>Background and Aims</jats:title>
<jats:p>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.</jats:p>
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<jats:title>Methods</jats:title>
<jats:p>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.</jats:p>
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<jats:title>Results</jats:title>
<jats:p>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.</jats:p>
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<jats:title>Conclusions</jats:title>
<jats:p>Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.</jats:p>
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• 出版日期2018-8-29
• 单位常州工学院