Clinical, radiographic and molecular characterization of two unrelated families with multicentric osteolysis, nodulosis, and arthropathy
Bibliographic record
Abstract
BACKGROUND: Multicentric osteolysis nodulosis and arthropathy (MONA) is a rare autosomal recessive disorder characterized by marked progressive bone loss and joint destruction resulting in skeletal deformities. MONA is caused by MMP2 deficiency. Here we report clinical and molecular analyses of four patients in two families from Pakistan and Finland. METHODS: Clinical analyses including radiography were completed and blood samples were collected. The extracted DNA was subjected to whole-exome analysis or target gene sequencing. Segregation analyses were performed in the nuclear pedigree. Pathogenicity prediction scores for the selected variants and conservation analyses of affected amino acids were observed. RESULTS: The phenotype in the four affected individuals was consistent with multicentric osteolysis or MONA, as the patients had multiple affected joints, osteolysis of hands and feet, immobility of knee joint and progressive bone loss. Long-term follow up of the patients revealed the progression of the disease. We found a novel MMP2 c.1336 + 2T > G homozygous splice donor variant segregating with the phenotype in the Pakistani family while a MMP2 missense variant c.1188 C > A, p.(Ser396Arg) was homozygous in both Finnish patients. In-silico analysis predicted that the splicing variant may eventually introduce a premature stop codon in MMP2. Molecular modeling for the p.(Ser396Arg) variant suggested that the change may disturb MMP2 collagen-binding region. CONCLUSION: Our findings expand the genetic spectrum of Multicentric osteolysis nodulosis and arthropathy. We also suggest that the age of onset of this disorder may vary from childhood up to late adolescence and that a significant degree of intrafamilial variability may be present.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| 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".