An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Bolton, Chrissy; Smillie, Christopher S.; Pandey, Sumeet; Elmentaite, Rasa; Wei, Guojian; Argmann, Carmen; Aschenbrenner, Dominik; James, Kylie R.; McGovern, Dermot; Macchi, Marina; Cho, Judy H.; Shouval, Dror S.; Kammermeier, Jochen; Koletzko, Sibylle; Bagalopal, Krithika; Capitani, Melania; Cavounidis, Athena; Pires, Elisabete; Weidinger, Carl; McCullagh, James; Arkwright, Peter D.; Haller, Wolfram; Siegmund, Britta; Peters, Lauren; Jostins, Luke; Travis, Simon; Anderson, Carl A.; Snapper, Scott B.; Klein, Christoph; Schadt, Eric E.; Xavier, Ramnik J.; Teichmann, Sarah A.; Muise, Aleixo M.; Regev, Aviv; Uhlig, Holm H.

doi:10.1053/j.gastro.2021.11.014

Cited by 49 publications

(36 citation statements)

References 52 publications

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“…Some caution must be taken in the interpretation of exome sequencing data, at least in part due to identification of many variants of unknown significance and difficulties of in silico modelling of the functional impact of multiple variants 40,41 . Next generation sequencing has also enabled identification of numerous monogenic forms of inflammatory bowel disease caused by genes directly interacting with NOD2, including loss of function variation in RIPK2, XIAP and CARD9 42 . NOD2 has recently been included in a collated panel of monogenic IBD genes which are investigated as part of whole genome sequencing in very-early onset IBD (and selected other cases) in the United Kingdom 43 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

NOD2in Crohn’s Disease—Unfinished Business

Ashton

Seaby

Beattie

et al. 2022

Journal of Crohn's and Colitis

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Studies of Crohn’s disease consistently implicate NOD2 as the most important gene in disease pathogenesis since first being identified in 2001. Since this point, genome-wide association, next-generation sequencing, and functional analyses have all confirmed a key role for NOD2, but despite this, NOD2 also has significant unresolved complexity. More recent studies have reinvigorated an early hypothesis that NOD2 may be a single-gene cause of disease, and the distinct ileal stricturing phenotype seen with NOD2-related disease presents an opportunity for personalised diagnosis, disease prediction and targeted therapy. The genomics of NOD2 has much that remains unknown, including the role of rare variation, phasing of variants across the haplotype block and the role of variation in the NOD2-regulatory regions. Here, we discuss the evidence and the unmet needs of NOD2-research, based on recently published evidence, and suggest methods that may meet these requirements.

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Section: Accepted Manuscriptmentioning

confidence: 99%

NOD2in Crohn’s Disease—Unfinished Business

Ashton

Seaby

Beattie

et al. 2022

Journal of Crohn's and Colitis

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“…On the other hand, rare deleterious variants directly causing intestinal inflammation were identified using advanced sequencing technologies (3,4). To date, nearly a 100 distinct monogenic disorders associated with IBD were characterized, resulting from deleterious and rare mutations in genes important for immune responses, epithelial cell function, or both (5,6). Consequently, in many of these diseases intestinal inflammation is accompanied by an immunodeficiency state, manifesting as recurrent or atypical infections.…”

Section: Introductionmentioning

confidence: 99%

RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features

et al. 2022

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PurposeReceptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulator of necroptosis and inflammatory responses. We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from RIPK1 mutations.MethodsWhole exome and Sanger sequencing was performed in two IBD patients. Mass cytometry time of flight (CyTOF) was conducted for in-depth immunophenotyping on one of the patient’s peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn’s disease.ResultsThe patients presented with severe colitis and perianal fistulas in the first months of life, without severe/atypical infections. Genetic studies identified pathogenic genetic variants in RIPK1 (Patient 1, A c.1934C>T missense mutation in Exon 11; Patient 2, c.580G>A missense mutation residing in Exon 4). Protein modeling demonstrated that the mutation in Patient 1 displaces a water molecule, potentially disrupting the local environment, and the mutation in Patient 2 may lead to disruption of the packing and conformation of the kinase domain. Immunofluorescence RIPK1 staining in rectal biopsies demonstrated no expression for Patient 1 and minimal expression for Patient 2, compared to controls and patients with active Crohn’s disease. Using CyTOF unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8+ T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient’s immune cells exhibited decreased IL-6 production in response to lipopolysaccharide (LPS) across multiple cell types including T cells, B cells and innate immune cells.ConclusionsMutations in RIPK1 should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1’s role in inflammasome activation, but also in epithelial cells, it is unclear whether IL1 blockade or allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency.

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“…Finally, atlases also allow us to move from the level of individual risk genes to the modules and programs in which they participate, thus helping decipher gene function, nominate causal processes, and related diseases with similar morbidities at the level of programs, even when the underlying genes are distinct 29 . This is illustrated in monogenic and polygenic IBD 39 , in which programs involving M cells are enriched in both forms of the disease 39 . Single-cell atlases can also reveal cellular subtypes that are shared across tissues or are unique in particular locations or disease contexts, such as recent surveys of mouse 40 and human 41 fibroblasts.…”

Section: From Disease-associated Genes To Cells Of Actionmentioning

confidence: 99%

Impact of the Human Cell Atlas on medicine

Rood¹,

Maartens

Hupalowska³

et al. 2022

Nat Med

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103

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Table 1 | A selection of key experimental methods for construction of cell atlases at different levels of biological organization 1. Clinical data Clinical-trial data; health records; disease registries; patient registries Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Cited by 49 publications

References 52 publications

NOD2in Crohn’s Disease—Unfinished Business

NOD2in Crohn’s Disease—Unfinished Business

RIPK1 mutations causing infantile-onset IBD with inflammatory and fistulizing features

Impact of the Human Cell Atlas on medicine

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