Description:
<jats:title>Summary</jats:title><jats:p>Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (<jats:styled-content style="fixed-case">IBD</jats:styled-content>) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset <jats:styled-content style="fixed-case">IBD</jats:styled-content> (<jats:styled-content style="fixed-case">VEO</jats:styled-content>‐<jats:styled-content style="fixed-case">IBD</jats:styled-content>) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset <jats:styled-content style="fixed-case">IBD</jats:styled-content> and <jats:styled-content style="fixed-case">VEO</jats:styled-content>‐<jats:styled-content style="fixed-case">IBD</jats:styled-content> thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic <jats:styled-content style="fixed-case">IBD</jats:styled-content> as well as key questions and future directions of <jats:styled-content style="fixed-case">IBD</jats:styled-content> research.</jats:p>