Human ASXL1 Deficiency Causes Epigenetic Dysfunction, Combined Immunodeficiency and EBV–Associated Hodgkin Lymphoma
Bibliographic record
Abstract
ABSTRACT Inborn errors of immunity (IEI) are a group of disorders caused by deleterious variants in immune-related genes, including some that function as epigenetic regulators. Additional sex combs-like 1 (ASXL1) is an epigenetic modifier that has not previously been linked to an IEI. Somatic ASXL1 variants are found in clonal hematopoiesis and hematologic neoplasms, while heterozygous germline variants cause Bohring–Opitz syndrome. We present a new IEI caused by biallelic germline variants in ASXL1 . The patient had a complex and unusual history of disease progression notable for persistent cutaneous vaccine-strain rubella granulomas initially manifesting in early childhood, chronic macrocytosis and mild bone marrow cellular hypoplasia, and Epstein Barr virus– associated Hodgkin lymphoma in adolescence. Detailed immunophenotyping revealed progressive loss of B-cells, hypogammaglobinemia, and T-cell lymphopenia with severe skewing toward a memory phenotype and elevated expression of T-cell exhaustion and senescence markers. Molecular investigations confirmed ASXL1 protein deficiency in the patient’s T-cells and fibroblasts. The T-cells exhibited marked loss of DNA methylation, increased epigenetic aging, and CD8 T-cell dysfunction. These aberrations were ameliorated by lentivirus-mediated transduction with wild-type ASXL1 , confirming the pathogenicity of ASXL1 variants. This study defines a novel human IEI caused by ASXL1 deficiency, a diagnosis that should be considered in individuals with chronic viral infections, virus-associated hematologic malignancies, and combined immunodeficiency. Furthermore, our findings provide fresh insights into the mechanisms underlying the roles of human ASXL1 in T-cell function as well as in the development and maintenance of lymphomas.
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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 | 0.000 |
| 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) | 0.001 | 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".