Very early-onset inflammatory bowel disease: gaining insight through focused discovery.
Ontology highlight
ABSTRACT:
SUBMITTER: Moran CJ
PROVIDER: S-EPMC6165626 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundChildren with very early onset inflammatory bowel diseases (VEO-IBD) often have a refractory and severe disease course. A significant number of described VEO-IBD-causing monogenic disorders can be attributed to defects in immune-related genes. The diagnosis of the underlying primary immunodeficiency (PID) often has critical implications for the treatment of patients with IBD-like phenotypes.MethodsTo identify the molecular etiology in 5 patients from 3 unrelated kindred with IBD-like symptoms, we conducted whole exome sequencing. Immune workup confirmed an underlying PID.ResultsWhole exome sequencing revealed 3 novel CARMIL2 loss-of-function mutations in our patients. Immunophenotyping of peripheral blood mononuclear cells showed reduction of regulatory and effector memory T cells and impaired B cell class switching. The T cell proliferation and activation assays confirmed defective responses to CD28 costimulation, consistent with CARMIL2 deficiency.ConclusionOur study highlights that human CARMIL2 deficiency can manifest with IBD-like symptoms. This example illustrates that early diagnosis of underlying PID is crucial for the treatment and prognosis of children with VEO-IBD.
| S-EPMC6799948 | biostudies-literature
Project description:Immunogenetics of Very Early Onset Inflammatory Bowel Disease
| PRJNA671449 | ENA
Project description:Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.
| S-EPMC5376484 | biostudies-literature
Project description:Inflammatory bowel disease (IBD) is treated with a variety of immunomodulating and immunosuppressive therapies; however, for the majority of cases, these therapies are not targeted for specific disease phenotypes. Monogenic IBD with causative genetic defect is the exception and represents a disease cohort where precision therapeutics can be applied. With the advent of rapid genetic sequencing platforms, these monogenic immunodeficiencies that cause inflammatory bowel disease are increasingly being identified. This subpopulation of IBD called very early onset inflammatory bowel disease (VEO-IBD) is defined by an age of onset of less than six years of age. Twenty percent of VEO-IBDs have an identifiable monogenic defect. The culprit genes are often involved in pro-inflammatory immune pathways, which represent potential avenues for targeted pharmacologic treatments. This review will provide an overview of the current state of disease-specific targeted therapies, as well as empiric treatment for undifferentiated causes of VEO-IBD.
| S-EPMC10059893 | biostudies-literature
Project description:Background and aimsDysbiosis of the gut microbiota is a well-known correlate of the pathogenesis of inflammatory bowel disease [IBD]. However, few studies have examined the microbiome in very early-onset [VEO] IBD, which is defined as onset of IBD before 6 years of age. Here we focus on the viral portion of the microbiome-the virome-to assess possible viral associations with disease processes, reasoning that any viruses potentially associated with IBD might grow more robustly in younger subjects, and so be more detectable.MethodsVirus-like particles [VLPs] were purified from stool samples collected from patients with VEO-IBD [n = 54] and healthy controls [n = 23], and characterized by DNA and RNA sequencing and VLP particle counts.ResultsThe total number of VLPs was not significantly different between VEO-IBD and healthy controls. For bacterial viruses, the VEO-IBD subjects were found to have a higher ratio of Caudovirales vs to Microviridae compared to healthy controls. An increase in Caudovirales was also associated with immunosuppressive therapy. For viruses infecting human cells, Anelloviridae showed higher prevalence in VEO-IBD compared to healthy controls. Within the VEO-IBD group, higher levels of Anelloviridae DNA were also positively associated with immunosuppressive treatment. To search for new viruses, short sequences enriched in VEO-IBD samples were identified, and some could be validated in an independent cohort, although none was clearly viral; this provides sequence tags to interrogate in future studies.ConclusionsThese data thus document perturbations to normal viral populations associated with VEO-IBD, and provide a biomarker-Anelloviridae DNA levels-potentially useful for reporting the effectiveness of immunosuppression.
| S-EPMC7648169 | biostudies-literature
Project description:Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.
| S-EPMC8423350 | biostudies-literature
Project description:Background/aimsInformation on pediatric inflammatory bowel disease (PIBD) and very early onset IBD (VEOIBD) are sparse in India, where IBD is emerging. We aimed to evaluate characteristics of VEOIBD and later onset PIBD (LO-PIBD) in India.MethodsWe performed retrospective analysis of a large, prospectively maintained IBD registry. PIBD was divided in to VEOIBD ( < 6 years) and LO-PIBD (6-17 years). Demographic data, disease characteristics and treatment were compared between the PIBD groups and with other Asian/Western studies as well as the adult patients of the registry.ResultsOf 3,752 IBD patients, 292 (7.8%) had PIBD (0-17 years) (175 Crohn's disease [CD], 113 ulcerative colitis [UC], 4 IBD-undifferentiated; 22 VEOIBD [7.5%], and 270 LO-PIBD [92.5%]). VEOIBD patients had more severe disease compared to LO-PIBD in both UC (P= 0.003) and CD (P< 0.001). Familial IBD was more common in VEOIBD (13.6%) compared to LO-PIBD (9.2%). Ileal disease (L1) was an independent risk factor for diagnostic delay in pediatric CD. Diagnostic delay ( > 6 months) was significantly lower in VEOIBD (40.9%) than in LO-PIBD (78.8%) (P< 0.001). Compared to other Asian and Western studies, extensive UC (72.5%) and complicated CD (stricturing/penetrating: 42.7%) were relatively more common. Perianal CD was relatively less frequent (7.4%). PIBD had a significantly higher number of complicated and ileal CD and extensive UC comparison to adult cohort of the registry.ConclusionsVEOIBD has more aggressive phenotype than LO-PIBD. Disease appears distinct from other Asian and Western studies and adult onset disease, with more complicated CD and extensive UC.
| S-EPMC8566832 | biostudies-literature
Project description:Background and aimsOver 80 monogenic causes of very early onset inflammatory bowel disease [VEOIBD] have been identified. Prior reports of the natural history of VEOIBD have not considered monogenic disease status. The objective of this study is to describe clinical phenotypes and outcomes in a large single-centre cohort of patients with VEOIBD and universal access to whole exome sequencing [WES].MethodsPatients receiving IBD care at a single centre were prospectively enrolled in a longitudinal data repository starting in 2012. WES was offered with enrollment. Enrolled patients were filtered by age of diagnosis <6 years to comprise a VEOIBD cohort. Monogenic disease was identified by filtering proband variants for rare, loss-of-function, or missense variants in known VEOIBD genes inherited according to standard Mendelian inheritance patterns.ResultsThis analysis included 216 VEOIBD patients, followed for a median of 5.8 years. Seventeen patients [7.9%] had monogenic disease. Patients with monogenic IBD were younger at diagnosis and were more likely to have Crohn's disease phenotype with higher rates of stricturing and penetrating disease and extraintestinal manifestations. Patients with monogenic disease were also more likely to experience outcomes of intensive care unit [ICU] hospitalisation, gastrostomy tube, total parenteral nutrition use, stunting at 3-year follow-up, haematopoietic stem cell transplant, and death. A total of 41 patients [19.0%] had infantile-onset disease. After controlling for monogenic disease, patients with infantile-onset IBD did not have increased risk for most severity outcomes.ConclusionsMonogenic disease is an important driver of disease severity in VEOIBD. WES is a valuable tool in prognostication and management of VEOIBD.
| S-EPMC9455789 | biostudies-literature
Project description:Integrin alpha–V (ITGAV) forms heterodimers with beta subunits to regulate several cellular processes including transforming growth factor β (TGF-β) signaling. We examined three unrelated families with common disease features including two children born with congenital brain anomalies and later development of immune dysregulation, atopy, and colitis, and three fetuses with brain and developmental defects. Using whole exome and RNA sequencing and functional studies, we demonstrate that biallelic ITGAV variants caused abnormal splicing or mislocalized protein that led to dysregulated TGF-β signaling in these families. Furthermore, knockout itgav (-/-) zebrafish embryos developed brain defects with loss of microglia and juvenile itgav (-/-) zebrafish developed colitis. Together, we show the critical role of ITGAV in immune regulation and gut and brain homeostasis and disease pathogenesis.
2024-09-30 | GSE248975 | GEO
Project description:Severe forms of inflammatory bowel disease (IBD) that develop in very young children can be caused by variants in a single gene. We performed whole-exome sequence (WES) analysis to identify genetic factors that might cause granulomatous colitis and severe perianal disease, with recurrent bacterial and viral infections, in an infant of consanguineous parents.We performed targeted WES analysis of DNA collected from the patient and her parents. We validated our findings by a similar analysis of DNA from 150 patients with very-early-onset IBD not associated with known genetic factors analyzed in Toronto, Oxford, and Munich. We compared gene expression signatures in inflamed vs noninflamed intestinal and rectal tissues collected from patients with treatment-resistant Crohn's disease who participated in a trial of ustekinumab. We performed functional studies of identified variants in primary cells from patients and cell culture.We identified a homozygous variant in the tripartite motif containing 22 gene (TRIM22) of the patient, as well as in 2 patients with a disease similar phenotype. Functional studies showed that the variant disrupted the ability of TRIM22 to regulate nucleotide binding oligomerization domain containing 2 (NOD2)-dependent activation of interferon-beta signaling and nuclear factor-?B. Computational studies demonstrated a correlation between the TRIM22-NOD2 network and signaling pathways and genetic factors associated very early onset and adult-onset IBD. TRIM22 is also associated with antiviral and mycobacterial effectors and markers of inflammation, such as fecal calprotectin, C-reactive protein, and Crohn's disease activity index scores.In WES and targeted exome sequence analyses of an infant with severe IBD characterized by granulomatous colitis and severe perianal disease, we identified a homozygous variant of TRIM22 that affects the ability of its product to regulate NOD2. Combined computational and functional studies showed that the TRIM22-NOD2 network regulates antiviral and antibacterial signaling pathways that contribute to inflammation. Further study of this network could lead to new disease markers and therapeutic targets for patients with very early and adult-onset IBD.
| S-EPMC4842103 | biostudies-literature