50P Monoallelic DAG1 truncating variants in patients with hyperCKemia
Bibliographic record
Abstract
Dystroglycan is an essential component of the dystrophin-glycoprotein complex that links the actin-associated cytoskeleton to the extracellular matrix (ECM). Dystroglycan, encoded by the DAG1 gene, is proteolytically cleaved into α-Dystroglycan, a highly glycosylated protein that binds to ECM ligands, and β-Dystroglycan, a transmembrane protein non-covalently linked to α-Dystroglycan. Biallelic variants in DAG1 cause primary dystroglycanopathies with a wide phenotypic variability. Through exome sequencing we identified heterozygous truncating DAG1 variants in 18 individuals from 10 unrelated families. Five variants were stop gains and five were frameshift; with the majority localized in α-Dystroglycan (90%). Segregation analysis was available for seven families, with one variant being de novo, three dominantly inherited and three inherited from an asymptomatic parent. WGS performed in six patients excluded the presence of additional deep intronic DAG1 variants. The most common clinical features were the presence of high CK levels (18/18), myalgia (9/18) and muscle hypertrophy (3/18). Mild levels of learning or social difficulties were also observed in some patients (4/18). Histological analysis was performed in eight patients and showed the presence of mild dystrophic or myopathic changes. Dystroglycan immunostaining, either β-Dystroglycan or α-Dystroglycan, was reduced in four out of five patients. RNAseq data from muscle biopsies from two unrelated patients showed the expression of both wild-type and truncated alleles, indicating that nonsense-mediated decay is not triggered by these alleles. To date, few studies have reported the presence of heterozygous truncating DAG1 variants in asymptomatic or pauci-symptomatic individuals. Here, we describe 18 additional individuals with AD DAG1 hyperCKemia with mild muscular manifestations. Expression of both the truncated and wild-type alleles argues against haploinsufficiency as the underlying pathomechanisms in DAG1 -AD individuals.
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 distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".