Background: Several recent referral center studies showed that a significant proportion (3–10%) of children with early-onset (EO, defined by an age at diagnosis <12 years) inflammatory bowel disease (IBD) present with an underlying monogenic disorder. Currently, more than sixty disorders of this type have been identified and their pathophysiological mechanisms are very heterogeneous. Most of them affect the intestinal epithelial barrier and are associated with defects in phagocytosis, immune deficiency, or are hyper- and auto-inflammatory disorders. However, they are all characterized by an EO intestinal inflammation.
Methods: Using a next-generation sequencing (NGS) of the 63 genes whose abnormalities are responsible for these disorders, and a targeted CGH array analysis of their chromosomal loci, 91 patients with an initial diagnosis of EO-IBD between 1988 and 2004 (54% of the whole EO-IBD cohort) issued from EPIMAD population-based registry were screened; 71 with Crohn's disease and 20 with ulcerative colitis.
Results: Analysis isolated 24 patients (26.4%) with very rare or not yet reported potential pathogenic variants in a total of 17 genes. Seven of them (7/91; 7.6%) had a genotype compatible with one of the tested disorders: Burton agammaglobulinemia, familial diarrhea, familial Cγ2 defect, hyper-IgM syndrome or Omenn syndrome. The remaining 17 patients (17/91; 18.7%) were heterozygous carriers of gene variants involved in autosomal recessive traits. The genotype identified in these patients were not likely to be the underlying cause of one of these disorders. However, it cannot be exclude that they may contribute to IBD as suggested by the unusually high prevalence of these genotypes.
Conclusions: Our study issued from a population-based registry, provides further evidence to recommend screening for inherited disorders using targeted NGS in children with an EO-IBD with the potential to enhance optimal selection of treatment options and adequate counseling of families. This study also indicates that targeted NGS used in this study may be an adequate and efficient tool for the reappraisal of the diagnosis in these patients.