108 A NOVEL COL1A1 MUTATION IN INFANTILE CORTICAL HYPEROSTOSIS (CAFFEY DISEASE) EXPANDS THE SPECTRUM OF COLLAGEN-RELATED DISORDERS
Bibliographic record
Abstract
Infantile cortical hyperostosis (Caffey disease) is an autosomal dominant disorder characterized by episodes of localized rapid bone formation, which are usually limited to the first 2 years of life. We performed a genome-wide screen for genetic linkage in an affected family and mapped the genetic locus of Caffey disease to chromosome 17q21 (2-point LOD score: 6.78). Fourteen candidate genes within the linked region were sequenced. Affected individuals and obligate carriers were heterozygous for a missense mutation (3041C>T) in exon 42 of COL1A1, which was predicted to alter the amino acid sequence (R836C) of the triple helical domain of the α1(I) chain of type I collagen. The same mutation was identified in the affected members of an unrelated family with Caffey disease, and it occurred most likely as a de novo mutation in identical twins, each affected by this disorder. The mutation was not present in > 300 chromosomes from healthy individuals. Dermal fibroblast cultures from an affected individual showed abnormal disulfide-bonded dimeric α1(I) chains. Two-dimensional SDS-PAGE analysis showed that these dimers dissociated after reduction of disulfide bonds into α1(I)9 chains that likely contained the R836C mutation. Electron microscopic analysis of collagen fibrils from an affected individual showed decreased number of fibrils, increased variability of size and shape of fibrils, and increased material interspersed between fibrils. Mutations in COL1A1 have been previously shown to cause Ehlers-Danlos syndrome (EDS) and osteogenesis imperfecta; we therefore re-examined our patients for features of these disorders. Individuals with R836C mutation showed joint laxity, soft skin, and inguinal hernias, similar to EDS type III, while fracture rates were only 1.6 per patient and bone densitometry was normal. Our findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.
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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) | 0.001 | 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 | 0.001 | 0.000 |
| 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".