P754 X-linked inhibitor of apoptosis protein genetic variants in paediatric-onset inflammatory bowel disease
Bibliographic record
Abstract
Background: Inflammatory bowel disease (IBD) has a multifactorial aetiology, with complex interactions between genetic and environmental factors. Recent studies have suggested an increasing spectrum of human monogenic diseases that can present with IBD-like intestinal inflammation. Mutations in X-linked inhibitor of apoptosis protein (XIAP) result in an X-linked recessive disorder whose phenotype is highly heterogeneous with respect to age at presentation and severity of disease and is poorly understood. Due to X chromosome inactivation heterozygous female carriers can also be symptomatic. Although a severe phenotype with infantile onset disease and predisposition to hemophagocytic lymphohistiocytosis (HLH) or X-linked lymphoproliferative syndrome (XLP) is recognized, one recent study has reported XIAP variants in 4% of male pediatric IBD patients. Methods: 1250 individual Hospital for Sick Children pediatric IBD patients have undergone whole exome sequencing in collaboration with the Regeneron Genetics Center. Within the cohort, 39 variants were called across the XIAP gene – 29 of which were high quality, rare (maf <0.01), protein coding variants predicted to be deleterious. 13 of these variants were present in 15 affected patients all of which have been Sanger validated. Case notes were retrospectively reviewed to ascertain phenotypic features of IBD in these 15 pediatric patients. Results: Of the 15 patients (80% males), 14 (93%) were diagnosed with IBD. 13 (92%) of these with Crohn's disease and 1 (7%) with ulcerative colitis. At the time of diagnosis, CD involved small bowel and colon (L3) in 50% children, colon (L2) in 14% and ileum (L1) in 28%. 21% of the children had perianal disease, with a further 21% having extra intestinal manifestations of IBD (erythema nodosum, fevers, large joint arthritis). A further infant was diagnosed with primary HLH and received a bone marrow transplant. This infant did have some gastrointestinal involvement with diffuse damage noted in the colonic mucosa and frequent apoptotic cells. 14% of these children had a first degree relative with IBD. 21% underwent ileocaecal resection with 57% progressing to biologic therapy. Patient samples, monocytes, are now undergoing a functional test to determine tumour necrosis factor (TNF) production of monocytes in response to NOD2 stimulation by muramyl dipeptides (L18-MDP) for the functional diagnosis of XIAP deficiency. Conclusions: Analysis of this large pediatric cohort confirms the highly varied phenotypic spectrum of IBD associated with XIAP mutations. Functional studies may more completely explain the observed variation.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".