Discovering the Developmental Basis of Trachea‐Esophageal Birth Defects: Evidence for Endosome‐opathies
Bibliographic record
Abstract
The trachea and esophagus (TE) arise from a common foregut tube during embryonic development. Disruptions in TE morphogenesis cause congenital trachea‐esophageal defects (TEDs) such as esophageal atresia, tracheoesophageal fistula and tracheoesophageal clefts. TEDs occur in approximately 1 in 3500 births, but their etiology is poorly understood. We have established the www.CLEARconsortium.org ; a multidisciplinary team of clinicians, geneticists, bioinformaticians, stem cell and developmental biologists using patient genome sequencing, animal models and iPSC‐derived human organoids to discover the genetic and developmental basis of trachea‐esophageal birth defects. Using the complementary advantages of Xenopus and mouse models we have defined the conserved molecular and cellular mechanisms that regulate normal TE morphogenesis. We show that downstream of Hedgehog/Gli signaling endosome‐mediated epithelial remodeling regulates TE morphogenesis which when disrupted results in tracheoesophageal clefts similar to human Pallister Hall syndrome patients. Proband‐parent trio genome sequencing identified an enrichment of potential damaging de novo variants in genes encoding membrane/vesicular‐trafficking proteins, suggesting a common “endosome‐opathy” pathway. Ongoing CRISPR mutagenesis screens in Xenopus tropicalis assessing candidate causative variants from patients confirms that the endosome protein Itsn1 is essential for TE morphogenesis, suggesting that the ITSN1 variant is likely pathogenic in the patient. Finally, leveraging results from animal models we have generated multi‐lineage human esophageal organoids from iPSCs with patient mutations to identify how mutations impact human esophageal differentiation. Together these results significantly advance our understanding of TEDs with the goal of revealing phenotype‐genotype associations that will inform prognosis and clinical treatment.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| 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".