Homozygous missense variant in <i>C2orf69</i> causes early-onset neurodegeneration, leukoencephalopathy and autoinflammation
Bibliographic record
Abstract
Biallelic pathogenic variants in C2orf69 cause a fatal autosomal recessive multisystem disorder characterized by recurrent autoinflammation, hypomyelination, progressive neurodegeneration, microcephaly, failure to thrive, liver dysfunction, respiratory chain defects and accumulation of glycogen in skeletal muscle. No missense variants in C2orf69 have been reported to date. We report a 6-year-old boy with microcephaly, global developmental delays, lower limb spasticity with hyperreflexia, epilepsy, abnormal brain MRI, failure to thrive, recurrent fevers and transaminitis. Whole-exome sequencing identified a homozygous missense c.320 C>G, p.(Pro107Arg) variant of uncertain significance (VUS) in C2orf69. Skeletal muscle biopsy showed active and chronic muscle fibre degeneration with deposits of periodic acid–Schiff-positive material in affected tissues, consistent with abnormal glycogen storage. Mitochondrial respiratory assays were normal in muscle tissue. Primary patient fibroblasts showed normal levels of mRNA expression but significantly reduced levels of endogenous C2ORF69 protein and GBE1 by Western blot. We report a patient with a homozygous missense variant in C2orf69, causing loss of function. Depletion of endogenous GBE1 in affected cells can be considered a biomarker for this disorder and assist in the interpretation of VUS in C2orf69. This expands the clinical and genetic spectrum of C2orf69-related 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 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".