Frequency of Deleterious Pathogenic/Likely Pathogenic Germline Variants in Related and Unrelated Allogeneic Hematopoietic Cell Transplant Donors for Patients with Myelodysplastic Syndrome
Bibliographic record
Abstract
Introduction Up to 15% of myelodysplastic syndrome (MDS) patients have pathogenic (P) or likely pathogenic (LP) germline variants (PGVs) underlying their disease. PGVs in allogeneic hematopoietic cell transplant (allo-HCT) donor cells may impact outcomes. Around 5% of related donors (RDs) share PGVs with recipients, the rate of PGVs in unrelated donors (UDs) is unknown. Objective We quantified PGVs in recipient-donor pairs for patients undergoing RD or UD allo-HCT for MDS. Methods Paired peripheral blood samples from MDS patients undergoing allo-HCT and RDs or UDs underwent 30X whole genome sequencing (WGS) in prior CIBMTR studies. Variants were called in 40 hematologic cancer predisposition genes. Quality filtered variants were culled by a 0.005 gnomAD allele frequency (AF) cutoff, adjusted to 0.05 for genes with high AF P/LP variants ( CHEK2, DDX41 ). Intronic variants were removed, except in genes with known P/LP intronic variants ( DKC1, FANCI, GATA2 , NF1, TERT ). Variants with >25 somatic occurrences in COSMIC were removed. P/LP variants were manually curated for pathogenicity per established guidelines. Shared PGVs in RD and recipients were confirmed germline. PGVs in UD and recipients were considered likely germline if variants known to have minimal somatic variation. Results Total 494 patients with paired recipient-donor WGS were included, 97 patients had RDs and 397 patients had UDs as their stem cell source. PGVs were found in 15% (75/494) of recipients with MDS, most commonly in DDX41 (20%, 15/75), RUNX1 (17%, 13/75), and CHEK2 (8%, 6/75). In RDs, 5% (5/97) of donors had PGVs. The PGV was shared between the donor and recipient in 80% (4/5) of cases and in 20% (1/5), the recipient lacked the donor PGV. Among UDs, 4% (16/397) had PGVs identified. In 19% (3/16) of UDs with a PGV the recipient had a separate, unshared PGV (Table 1). Conclusion We identified PGVs in a significant number of allo-HCT donors for MDS patients, with similar rates in RDs as prior literature. Rates of PGVs were comparable between UDs or RDs. Future work will assess PGVs and allo-HCT outcomes.
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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 | 0.002 |
| 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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 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".