Likely foregut endoderm origin for a postzygotic mutation affecting the RNase IIIb domain of DICER1
Bibliographic record
Abstract
In 2016, we reported a child with bilateral lung cysts and left lung type II pleuropulmonary blastoma (PPB), classic phenotypes of DICER1 syndrome; we identified a DICER1 hotspot mutation c.5425G>A, p.Gly1809Arg in both a lung cyst and PPB, but the variant was absent in other tissues studied. A somatic mutation (c.1966C>T, p.Arg656Ter) was identified in the PPB, and mosaicism was suspected.1 The child has since developed multinodular goitre (MNG) with cystic thyroid nodules. We have now detected p.Gly1809Arg in the thyroid lesions, while various other tissues were negative. The exquisite localisation of the variant confirms mosaicism and strongly suggests it arose in embryonic foregut endoderm between gestational days 16 and 26. Mosaicism is a phenomenon where two genetically distinct populations of cells arise following postzygotic acquisition in one cell of a de novo mutation.2 DICER1 syndrome is a paediatric multitumour predisposition syndrome caused typically by germline loss-of-function DICER1 variants, but some predisposing mosaic DICER1 mutations have also been described.1 3 4 DICER1 encodes an endoribonuclease that processes hairpin precursors into mature microRNAs that, in turn, post-transcriptionally regulate target messenger RNA expression. Syndromic tumours result from acquisition of a somatic, second variant that typically affects DICER1’s critical RNase IIIb cleavage domain. These variants are referred to as ‘hotspot mutations’ and include NM_177438.3: c.5425G>A, p.Gly1809Arg. Common phenotypes of DICER1 syndrome include PPB, MNG, cystic nephroma and Sertoli-Leydig cell tumour. Previously, to assess mosaicism 1 in multiple tissues obtained when the patient’s age ranged from 11 months to age 15 years, DNA was analysed using a Fluidigm Access Array and the HaloPlex HS Target Enrichment System, followed by deep sequencing. However, the results were inconclusive because no completely normal lung tissue was available for study, the p.Gly1809Arg variant was not found in DNA derived from saliva, head hair or blood …
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.004 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 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".