Exome Sequencing Identifies PINCH2 Mutations in Early Onset Autosomal Recessive LGMD with Severe Cardiomyopathy and Triangular Tongues (S46.001)
Bibliographic record
Abstract
OBJECTIVE: Utilize whole exome sequencing for molecular identification in undiagnosed siblings with limb girdle muscular dystrophy (LGMD). BACKGROUND: LGMD is a heterogeneous group of inherited disorders leading to progressive muscle degeneration and often associated with cardiac complications. A large portion of patients with LGMD remain genetically undiagnosed. DESIGN/METHODS: We investigated affected adult siblings with a childhood onset LGMD with macroglossia and calf enlargement using genetic, imaging and pathological testing. RESULTS: The patients demonstrated severe quadriparesis with a broad based triangular tongue and biventricular cardiac dysfunction. Musculoskeletal Magnetic Resonance (MR) demonstrates bilateral, symmetric, severe atrophy and fat infiltration in proximal, distal and trunk musculature. Cardiac MR shows biventricular dilatation and systolic dysfunction along with subepicardial pattern of delayed enhancement in the inferior and inferolateral walls of the left ventricle indicating fibrosis. After negative genetic evaluation for known LGMD genes, we performed whole exome sequencing of the affected siblings and identified shared compound heterozygous missense mutations in exon 5 (c.C356T; p.P119L and c.C342G; p.N114K) and exon 11 (c.T1034C; p.L345P) in PINCH2 (also known as LIMS2), which segregated appropriately in the family. Muscle biopsy showed dystrophic features and the z-line pattern of PINCH2 staining seen in control was disrupted. PINCH2 is an important member of the IPP (ILK, Parvin, PINCH) heterotrimeric complex, essential for signaling through integrin adhesion receptors that regulates cell migration, spreading and adhesion, and is found in skeletal and cardiac muscle cells in mouse and zebrafish models. The IPP complex stabilizes expression of the component proteins by reducing proteasomal degradation. PINCH1 may compensate for loss of PINCH2 in some tissues, suggesting that potential therapy may involve upregulation of PINCH1 to stabilize the IPP complex in patients with PINCH2 mutations. CONCLUSIONS: We identify patients with a severe LGMD with cardiomyopathy and triangular tongues. Although well established in animal models, this is the first report of defective PINCH2 causing LGMD with cardiomyopathy in humans.
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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".