Variants in CAPN3 Causing Autosomal Dominant Limb–Girdle Muscular Dystrophy Combined With Calpain‐3 Deficiency
Bibliographic record
Abstract
Abstract: Limb–girdle muscular dystrophy Type 2A/R1 or calpain‐3 deficiency is the most common autosomal recessive limb–girdle muscular dystrophy. However, in recent years, autosomal dominant cases and families with calpain‐3 deficiency have been reported, and there is an emerging interest in looking for single variants in the calpain‐3 gene in mildly to moderately affected patients with limb–girdle muscular dystrophy without biallelic gene variants in CAPN3. Here, we report four cases with creatine kinase levels above 1500 U/L, mild‐to‐moderate proximal weakness, waddling gait, and scapular winging. Two patients, a son and his father, are heterozygous for the CAPN3 variant c.304C>T; p.(Pro102Ser), which has previously been reported in patients with compound heterozygous variants in CAPN3. The third and fourth patients were heterozygous for c.1371C>G; p.(Asn457Lys) and c.1490C>T; p.Ala497_Glu508del, respectively, neither of which has been reported before. All four patients had a near‐complete loss of calpain‐3 as determined by western blotting. While inherited autosomal dominant calpainopathy has now been firmly established, additional single cases of dominant calpainopathy are likely to emerge; some will be associated with clinical findings from parents or siblings, while others will arise from spontaneous mutations, but nevertheless with similar clinical findings of mild‐to‐moderate proximal weakness, increased level of creatine kinase, and near‐complete loss of calpain‐3 protein in affected individuals. This report expands the known number of variants causing dominant calpainopathy from 8 to 11 that appears to exclusively reside in two out of four domains that make up calpain‐3. This information could aid in determining whether a CAPN3 variant of unknown significance is pathological.
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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 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".