Bone Marrow Failure Associated With Short Telomeres and Digenic Variants of Uncertain Significance in Telomere Biology Genes
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Bibliographic record
Abstract
Telomere Biology Disorders (TBD) are a group of heritable disorders characterized by short telomeres. We report two patients that presented with bone marrow failure (BMF), who were identified to have low telomere length (TL) and variants of uncertain significance (VUS) in two different telomere genes inherited from their parents. At age 6, Patient 1 had stage 4 neuroblastoma. He was treated with chemotherapy, surgery, immunotherapy, and autologous stem cell rescue. At age 10, he developed pancytopenia. Bone marrow biopsy revealed hypocellular marrow and der (1; 7), associated with myelodysplastic syndrome. Germline genetic evaluation showed a pathogenic variant in DNAJC21 (from father) and VUS in NAF1 (c.1375C > T) (from father) and RTEL1 (c.533T > C) (from mother). The patient was found to have very low TL (VLTL) (< 1st percentile) in 4/6 white blood cell subsets. The patient's mother was found to have borderline low TL (VLTL) ( 1 and < 10th percentiles) in 4/6 subsets and VLTL in 1/6 subsets. Father had VLTL in 1/6 but normal TL in other subsets. Neither parent reported any symptoms of TBD. Patient 2 presented with a depressed skull fracture at age 15. He was found incidentally to have pancytopenia. Bone marrow biopsy showed hypocellular marrow and no cytogenetic abnormalities. The patient had VLTL in all 6/6 subsets. Genetic evaluation showed VUSs in TERT (c.3158-80G > A) (from mother), TINF2 (c.814T > C) (from mother) and SRP72 (c.1928C > T) (from father). Mother was also found to have VLTL in all 6 subsets but has reported good health except for premature graying of hair. These two patients presented with BMF, identified to have VUSs in more than one TBD-associated gene with functional evidence of shortened telomeres, highlighting the potential for a digenic mode of inheritance. Synergy between two VUSs could contribute to a penetrant phenotype and resulting in earlier or more severe onset of disease.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.000 | 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 it