A novel transmembrane <i>CXCR4</i> variant that expands the WHIM genotype-phenotype paradigm
Bibliographic record
Abstract
Variants in the C-X-C motif chemokine receptor 4 gene (CXCR4) are associated with a rare autosomaldominant combined immunodeficiency, WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome.1,2 The CXCR4/C-X-C motif chemokine ligand 12 (CXCL12) axis is a master regulator of immune cell bone marrow homing and egress 3-5 and B-cell development.6 Previously known pathogenic nonsense, frameshift, and missense variants identified in individuals with WHIM syndrome (CXCR4 WHIM ) have been localized to the intracellular C-terminal region of CXCR4, a G protein-coupled receptor.2 We describe 4 unrelated patients, designated P1 to P4, with variable clinical presentations including leukopenia, hypercellular bone marrow, recurrent infections, hypogammaglobulinemia, and susceptibility to human papillomavirus, harboring a novel heterozygous CXCR4 variant (c.250G>C; p.D84H), designated as CXCR4 D84H , in the second transmembrane domain of the receptor.We performed comprehensive ex vivo and in vitro functional characterization of cells harboring CXCR4 D84H in parallel with in silico molecular modeling to determine pathogenicity of the newly discovered variant.See supplemental Methods for detailed methods, including supplemental Table 1A-B.The studies were approved by institutional review board (IRB) of the respective institutions, including institutional review of Duke University (IRB number Pro00066839), Belarusian Research Center for Pediatric Oncology (IRB number 200809-RD), and University Medical Center Freiburg (IRB number 354/19).Table 1 and supplemental Table 2A summarize the clinical and laboratory characteristics and immunophenotyping data for P1 to P4.P1 is a female aged 40 years with plantar warts since childhood, recurrent vulvovaginal and anal dysplasia, and carcinoma in situ for 20 years.Cytopenia, including neutropenia, were first documented at age 15 years.She had Epstein-Barr virus in childhood from which she recovered and was
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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".