Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. 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.
