RARE-22. GERMLINE PATHOGENIC VARIANT c.1552G>A;p.E518K IN DGCR8 CONFERS SUSCEPTIBILITY FOR SCHWANNOMATOSIS AND THYROID TUMORS
Bibliographic record
Abstract
Abstract Germline mutations in DICER1 cause a pleiotropic susceptibility syndrome characterized by the development of pediatric or early-onset tumors including pleuropulmonary blastoma, Wilms tumors, pineoblastomas, multinodular goiter (MNG) and thyroid cancers. Somatic mutations in the other two microprocessors DROSHA and DGCR8 have been found in Wilms Tumors and pineoblastomas. We present here two families with peripheral schwannomatosis and thyroid tumors carrying a germline variant c.1552G>A;p.E518K in DGCR8. Family one had six affected members with early-onset MNG and five of them developed schwannomatosis. All five members were heterozygous for the variant. One of the carriers had also been diagnosed with a choroid plexus papilloma at 7 years old. The common second event in all tumors tested was the loss of chromosome 22 at the somatic level. In family two, a 35-year-old male was diagnosed with a peripheral schwannoma at the age of 12. Since then, he has developed seven extra peripheral schwannomas (one of which was an ancient schwannoma) and papillary thyroid cancer. DGCR8 lies on chromosome 22q, adjacent to the three schwannoma genes: LZTR1, SMARCB1 and NF2. The variant, c.1552G>A;p.E518K localizes to the first RNA-binding domain of DGCR8 and structural modelling predicts that it abolishes proper binding of RNA. It is also a hotspot somatic mutation in Wilms tumors. Using miRNA profiling, we show that this variant disrupts global microRNA production and DGCR8 mutated tumors show a specific miRNA profile different from DGCR8 wild type tumors. These findings reinforce DGCR8 as a novel susceptibility gene for schwannomatosis and thyroid tumors.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.008 | 0.001 |
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".