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

An expanding number of monogenicdefects 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 adapt treatment. 207 children were recruited in 45 Paediatric centres through an international collaborative network(ESPGHAN GENIUSworking group) with a clinical presentation of severe VEO-IBD (n=185) or an anamnesissuggestive of a monogenicdisorder (n=22). Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitiswith perianal lesions, and colitisonly. 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. Molecular diagnosis was achieved in 66/207 children (32%): 61% with small bowel inflammation, 39% with colitisand perianal lesions and 18% with colitisonly. Targeted NGS pinpointed gene mutations causative of atypical presentations and identified large exonic copy number variationspreviously missed by WES. Our results lead us to propose an optimised diagnostic strategy to identify known monogeniccauses of severe IBD.