De novo missense variants in the RPEL3 domain of PHACTR4 in individuals with overlapping congenital anomalies
Bibliographic record
Abstract
PHACTR4 is proposed to play a role in embryonic development but has yet to be associated with human disease. Here, we report the detailed clinical features of two individuals for whom molecular diagnostic testing was undertaken at a large diagnostic laboratory and who were found to harbor rare, damaging de novo missense variants in the conserved RPEL3 domain of PHACTR4. We also present aggregate information on additional individuals in whom missense variants in the same PHACTR4 gene region were detected. All presented with overlapping phenotypes. Features present in at least half of these individuals included cleft palate, ophthalmologic abnormalities, hearing impairment, dysmorphic facial features, digital anomalies, renal/urinary anomalies, growth delay, microcephaly, abnormal brain imaging, and neurodevelopmental abnormalities; some individuals had additional unique findings as well. The proposed cellular function of PHACTR4 and information from related genes with variants in an RPEL domain suggest that PHACTR4 is a promising candidate gene for human disease. We hope that this report will promote additional research interest in the PHACTR4 gene and lead to the publication of additional cases, to potentially establish a causative relationship and to further delineate the phenotypic and variant spectrum of a PHACTR4-related disorder.
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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".