Identification of a Second‐Hit Brain Somatic <scp> <i>DEPDC5</i> </scp> Variant Supports Causality of a <scp> <i>DEPDC5</i> </scp> Germline Variant of Uncertain Significance. Time for a Classification Update?
Bibliographic record
Abstract
Germline variants in DEPDC5 are a cause of familial focal epilepsy with variable foci. Affected individuals may have focal cortical dysplasia if a second brain somatic variant occurs. As access to brain tissue is limited, the second somatic hit in the brain is usually presumed if a clear pathogenic germline variant is present. Here, we present a patient with structural focal epilepsy due to focal cortical dysplasia. He underwent epilepsy surgery at age 2 months. Clinical genetic testing revealed a germline variant of uncertain significance (VUS) DEPDC5 c.920T>G, p. (Leu307Arg). We hypothesized that if the proband's germline DEPDC5 variant was disease-causal, a second somatic variant may be identifiable in affected cortical tissue. DNA was extracted from archived brain formalin-fixed paraffin-embedded tissue and subjected to deep gene panel analysis. This revealed an additional somatic pathogenic variant in DEPDC5, which was confirmed using droplet digital PCR. Identification of the second somatic hit in brain tissue (DEPDC5 c.982C>T, p.(Arg328*)) confirmed the two-hit situation in this patient and supported disease causality of the germline variant. In conclusion, testing tissue for somatic variants may be clinically relevant at a patient-specific level if a germline VUS affects a gene where a two-hit mechanism is known.
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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 | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| 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".