A13 WHOLE EXOME SEQUENCING OF OVER 1000 PEDIATRIC IBD PATIENTS FROM A SINGLE CENTRE IDENTIFIES MONOGENIC FORMS OF IBD.
Bibliographic record
Abstract
Inflammatory bowel disease (IBD) has a multifactorial aetiology, with complex interactions between genetic and environmental factors. Recent studies suggest an increasing spectrum of monogenic disease in the very young. The prevalence of these mutations in older children is unknown. To determine the incidence of monogenic forms of IBD in a typical cohort of pediatric IBD patients and identify any phenotypic characteristics suggestive of a monogenic cause. 2,431 unique participants underwent whole exome sequencing (WES), including 1,098 IBD probands. This data was interrogated for a panel of 51 genes known to be associated with monogenic IBD. The Genome Analysis Toolkit (GATK) was used to identify highly penetrant rare variants of interest. Sanger sequencing verified variant genotypes. A clinical database was reviewed to ascertain phenotypic characteristics. A single centre retrospective study identified 1,098 index cases, diagnosed over a 12 year period (2003–2015) who underwent WES. 2431 unique participants (302 trios, 31 quads, 29 affected siblings). Of sequenced affected cases, 60% CD, 40% UC/IBD-U. 16% < 6.9 years, 22% 7–10.9 years, 62% > 11 years. Across the 51 genes, 19 protein coding variants predicted to be deleterious were identified in 54 patients, which were high quality and rare (maf <0.01). XIAP, DOCK8 and CYBB were the most commonly identified gene variants within the cohort. Overall, approximately 4.9% of patients in a typical cohort of Pediatric IBD patients were found to have monogenic disease. WES of this largest pediatric cohort to date confirms the highly varied phenotypic spectrum of IBD associated with monogenic disease. Whilst many children with causal VEOIBD mutations were diagnosed < 1 year of age, a significant number of older children were identified. Characterising genotypic-phenotypic features may provoke earlier recognition which will allow novel therapeutic approaches in this paediatric IBD population. None
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.000 | 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 teacher head, 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".