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An Author Correction to this article was published on 22 June Very-early-onset inflammatory bowel disease VEO-IBD is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in patients median age-at-diagnosis of 3. Inflammatory bowel disease IBD represents a heterogeneous group of disorders characterized by a dysregulated immune response toward commensal gut bacteria leading to chronic relapsing intestinal inflammation 1 , 2.
Patients with VEO-IBD present with a higher rate of pancolitis, and subgroups present with severely fistulising disease, resistance to conventional immunosuppressive treatments and immune defects associated with increased lethality 6 , 7. Several Mendelian disorders present with IBD and IBD-like intestinal inflammation and have an onset during infancy or within the first 6 years of life 8 , 9.
The majority of these conditions are autosomal recessive or X-linked inherited primary immunodeficiencies PIDs. A simple differential diagnosis based on phenotypic associations is often difficult and a sequential work-up based on candidate genes is time consuming. Identifying the underlying disease-causing variants in VEO-IBD patients is important because it can directly influence patient management and inform on the appropriate treatment strategy, e.
Genome-wide association studies focusing on pediatric-onset cases 24 , 25 identified risk loci that, at the time, were not associated with adult-onset disease but all have since been robustly associated in adult-IBD cohorts More recently, three studies focusing on patients with an age at disease onset greater than 6 years, reported a weak, but statistically significant, negative relationship between polygenic risk score and the age at CD and UC diagnoses 27 , 28 , We include patients in whom a Mendelian disorder is unexpected due to clinical presentation, or were mutation negative following screening of specific VEO-IBD genes selected based on patient presentation e.
