Systematic functional validation of IKAROS variants from patients and laboratory-generated mutations
Bibliographic record
Abstract
ABSTRACT: The transcription factor IKAROS plays an important role in lymphocyte development, differentiation, and as a tumor suppressor. To date, >70 IKAROS germ line heterozygous variants have been reported in patients with primary immunodeficiency (PID)/inborn errors of immunity (IEI) and leukemia, and this number continues to grow. Germ line IKAROS loss- and gain-of-function mutations have been linked to immunodeficiency, immune dysregulation, and hematologic malignancies, with a broad spectrum of clinical manifestations. Routine next-generation sequencing approaches in patients with PID/IEI have facilitated the identification of IKAROS variants, including several cases with variants of uncertain significance (VUS). To determine the VUS' functional behavior, we systematically generated constructs recapitulating those changes and tested IKAROS functions in vitro. We also conducted an in-depth examination of the C-terminal dimerization domain using alanine-scanning mutagenesis to identify amino acids critical for dimerization and other functions. This work provides a comprehensive description of the biologic impact of 81 previously unreported and/or untested IKAROS variants, including 33 patient-detected germ line VUS and 48 laboratory-generated mutations in the dimerization domain. Among them, 15 of the patient-detected variants, primarily mapping to IKAROS DNA-binding or dimerization domains, and at least 21 of the laboratory-generated mutations, impaired IKAROS function and could explain or result in human disease. VUS located in between IKAROS DNA binding and dimerization domains were less likely to be functionally deleterious. Of note, both positive and negative functional data herein generated can be relevant for patients carrying these IKAROS variants, helping to establish a diagnosis and guide treatment decisions.
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How this classification was reachedexpand
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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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) | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".