Identification of Compound Heterozygous <i>CYP11A1</i> Variants via Reanalysis of Clinical Sequencing Data
Bibliographic record
Abstract
A molecular diagnosis is currently achievable in approximately 50% of patients assessed by clinical geneticists at tertiary care centres. Next-Generation Sequencing Panels contain a defined group of genes associated with a clinically defined set of phenotypes. Most clinical sequencing providers streamline their wet-bench workflows by sequencing the entire exome or genome, followed by targeted bioinformatic extraction of variant data from a pre-specified gene set. Thus, additional data on these patients remain available but are only reviewed by special request. We interrogated clinical-grade sequencing data on two out of three affected members of a family with childhood-onset adrenal insufficiency in whom an autosomal recessive condition was suspected. Review of clinome data identified heterozygosity for CYP11A1 variants c.644T>C; p.(Phe215Ser) and c.1187G>A; p.(Arg396Lys) in both affected sibs. Long-read whole genome sequencing of the proband showed these variants were in trans, confirming compound heterozygosity and resolving the molecular etiology of the clinical diagnosis.
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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 | 0.002 | 0.007 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.003 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".