Advanced Understanding of Monogenic Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD) is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract and comprise three major subgroups of Crohn's disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBDU). Recent advances in genomic technologies have furthered our understanding of IBD pathogenesis. It includes differentiation rare monogenic disorders exhibiting IBD and IBD-like inflammation (monogenic IBD) from patients with the common polygenic form of IBD. Several novel genes responsible for monogenic IBD have been elucidated, and the number of reports has increased due to advancements in molecular functional analysis. Identification of these pathogenic genetic mutations has helped in elucidating the details of the immune response associated with gastrointestinal inflammation and in providing individualized treatments for patients with severe IBD that is often unresponsive to conventional therapy. The majority of monogenic IBD studies have focused on young children diagnosed <6 years of age (very early-onset IBD); however, a recent study revealed high prevalence of monogenic IBD in older children aged >6 years of age as well. Meanwhile, although patients with monogenic IBD generally show co-morbidities and/or extraintestinal manifestation at the time of diagnosis, cases of IBD developing as the initial symptom with unremarkable prodromal symptoms have been reported. It is crucial that the physicians properly match genetic analytical data with clinical diagnosis and/or differential diagnosis. In this review, we summarize the essential clues that may physicians make a correct diagnosis of monogenic disease, including classification, prevalence and clinical phenotype based on available literatures.

Gut-associated cGMP mediates colitis and dysbiosis in a mouse model of an activating mutation in GUCY2C

“…Monogenic intestinal epithelium defects contributing to pediatric inflammatory bowel disease (IBD) have been described and are not readily amenable to current treatment regimens ( Leung and Muise, 2018 ; Nambu and Muise, 2021 ). Among the genes associated with very early–onset IBD are mutations in the receptor guanylyl cyclase C gene ( GUCY2C ; Bose et al, 2020 ; Crowley et al, 2020 ).…”

A Machine Learning Approach to Identifying Causal Monogenic Variants in Inflammatory Bowel Disease

“…Currently, linking the clinical phenotype to monogenic variants suffers from the dual challenge of lack of standardization in the medical record and the clinical heterogeneity of diseases, such as monogenic IBD. 29 Previous work has linked earlier onset and extra-intestinal manifestations with monogenic disease. 3 In our machine learning models, neither sex nor age at diagnosis was statistically associated strongly enough with monogenic cases to warrant inclusion in our prioritization pipeline.…”

Role of ultrasound in the diagnosis of very early-onset inflammatory bowel disease in children: a report of three cases

“…Furthermore, the type of IBD is generally classified into ulcerative colitis (UC), Crohn's disease (CD), or unclassified (IBD-unclassified) [8]. In children with VEO-IBD, IBD-unclassified is reportedly more common than older-onset IBD [9]. Recently, some cases of VEO-IBD have been included as a monogenic disorder in a unique category of IBD that accompanies immuno-deficiency syndromes, hematological disorders or other genetic diseases [6,[9][10][11][12].…”

“…In children with VEO-IBD, IBD-unclassified is reportedly more common than older-onset IBD [9]. Recently, some cases of VEO-IBD have been included as a monogenic disorder in a unique category of IBD that accompanies immuno-deficiency syndromes, hematological disorders or other genetic diseases [6,[9][10][11][12]. This category is more resistant to conventional therapy and requires specific treatments such as stem cell blood transplantation [3,5,6].…”