Diagnostic Approach to Monogenic Inflammatory Bowel Disease in Clinical Practice: A Ten-Year Multicentric Experience

Abstract

Background and aims Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients’ management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis. Methods Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008–2017 who underwent a genetic workup were collected. Results Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT. Conclusion A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients’ management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes.

Effect of Exclusive Enteral Nutrition on the Disease Process, Nutrition Status, and Gastrointestinal Microbiota for Chinese Children With Crohn's Disease

“…In our study, we found that the patients in the CD‐RE group were older than the patients in the CD‐NRE group; in particular, there were more patients under 6 years of age in the CD‐NRE group. In recent years, researchers have defined CD diagnosis before the age of 6 as very early‐onset CD (VEO‐CD), 26 and we reported that VEO‐CD patients had poorer clinical outcomes than later‐onset CD patients (age at diagnosis: 10–17 years) 27 …”

Case Report: Refractory Autoimmune Gastritis Responsive to Abatacept in LRBA Deficiency

“…With this report we would stress the importance of prompt investigations for genetic immune dysregulation disease in children with early onset gastroenterological autoimmune disorders, as recommended by several studies (20,29,35). The simultaneous presence of autoimmune FIGURE 4 | Mechanism of action of abatacept in LRBA deficiency.…”

Advanced Understanding of Monogenic Inflammatory Bowel Disease

“…In recent years, several cohort studies have been conducted, using WES and targeted genome panel sequence (TGPS) to determine the prevalence of monogenic IBD in children (Table 1B) (35)(36)(37)(38)(39)(40)(41). Among these previous studies, the prevalence of monogenic IBD in children with IBD has varied greatly.…”

“…In these studies, 24 of 27 cases and 5 of 9 cases with monogenic IBD had IL10R signaling defects. The percentage of colitis with IL10R signaling defects in Asia is higher than in Europe (35)(36)(37)(38)(39)(40)(41).…”