Telomere Length Measurement by Flow-FISH Distinguishes Dyskeratosis Congenita from Other Bone Marrow Failure Syndromes.
Bibliographic record
Abstract
Abstract This study was designed to evaluate the utility of flow-FISH telomere length measurement in white blood cells (WBC) as a screening test for Dyskeratosis congenita (DC). We studied 26 patients: 17 with DC, 1 silent carrier (clinically normal; mutation in TERC), 4 with the Hoyeraal-Hreidarsson variant (HH), and 4 with Revesz Syndrome. Five had mutations in DKC1, 5 in TERC, and 2 in TERT. 23 had hematologic abnormalities, 19 had 2 or 3 of the DC diagnostic triad (lacey pigmentation, dyskeratotic nails, and leukoplakia), and 4 had soft signs of DC. We evaluated 54 first-degree relatives of DC patients, 16 Fanconi Anemia patients (FA), 14 with Diamond-Blackfan Anemia (DBA), 5 with Shwachman Diamond Syndrome (SDS), and 10 with other possibly inherited cytopenias (Other). Telomere length was measured in granulocytes and lymphocyte subsets by automated multicolor flow-FISH; results were compared with age-matched values from 400 normal controls. “Very low (VL)” telomere length was defined as a mean telomere length below the normal first percentile for age and specific WBC type. We observed VL telomeres in all subsets in the silent carrier, all HH and Revesz patients, and 15/17 with DC. Eight of 51 DC relatives had VL telomeres in granulocytes versus 2/54 with VL telomeres in lymphocytes. The sensitivities for distinguishing a DC patient from an unaffected relative were 92% in lymphocytes and 96% in granulocytes; the specificities were 96% and 98%, respectively; the sensitivity and specificity for VL telomeres in both cell types were 96% and 96%. The silent carrier with a TERC mutation developed thrombocytopenia, hypocellular marrow, and a cytogenetic clone during follow-up. The 2 DC relatives with VL telomeres in lymphocytes were from a family without a known mutant gene; they may also be silent carriers. The latter possibility disqualified an HLA-matched sibling as a donor for DC-related aplastic anemia, because of engraftment concerns; another sibling donor with normal telomere length was selected. VL granulocyte telomeres were observed in 5/16 FA, 3/14 DBA, 1/5 SDS, and 1/10 Other patients, versus 2/16 FA, 1/14 DBA, 1/5 SDS, and 0/10 Other in lymphocytes, and in both lineages in only 1 each of FA, DBA, and SDS. The sensitivity and specificity for distinguishing DC from non-DC patients using VL telomeres in both lineages were 96% and 93%, respectively. Only DC patients had consistently VL telomeres in all cell subsets. Flow-FISH telomere length measurement provides a sensitive and specific method for identifying patients with DC among families, regardless of mutation status, and distinguishes patients with DC from those with other inherited or acquired marrow failure syndromes. It may also help to detect silent carriers, and facilitate identification of mutations in other telomere biology genes. Our data suggest that the diagnostic triad, soft physical findings and/or bone marrow failure may not be required for the diagnosis of DC. Correct diagnosis of DC will enhance genetic counseling and hematologic management.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.002 | 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".