A recurrent germline mutation in the <i>PIGA</i> gene causes Simpson‐Golabi‐Behmel syndrome type 2
Bibliographic record
Abstract
Hypomorphic germline mutations in the PIGA (phosphatidylinositol glycan class A) gene recently were recognized as the cause of a clinically heterogeneous spectrum of X-linked disorders including (i) early onset epileptic encephalopathy with severe muscular hypotonia, dysmorphism, multiple congenital anomalies, and early death ("MCAHS2"), (ii) neurodegenerative encephalopathy with systemic iron overload (ferro-cerebro-cutaneous syndrome, "FCCS"), and (iii) intellectual disability and seizures without dysmorphism. Previous studies showed that the recurrent PIGA germline mutation c.1234C>T (p.Arg412*) leads to a clinical phenotype at the most severe end of the spectrum associated with early infantile lethality. We identified three additional individuals from two unrelated families with the same PIGA mutation. Major clinical findings include early onset intractable epileptic encephalopathy with a burst-suppression pattern on EEG, generalized muscular hypotonia, structural brain abnormalities, macrocephaly and increased birth weight, joint contractures, coarse facial features, widely spaced eyes, a short nose with anteverted nares, gingival overgrowth, a wide mouth, short limbs with short distal phalanges, and a small penis. Based on the phenotypic overlap with Simpson-Golabi-Behmel syndrome type 2 (SGBS2), we hypothesized that both disorders might have the same underlying cause. We were able to confirm the same c.1234C>T (p.Arg412*) mutation in the DNA sample from an affected fetus of the original family affected with SGBS2. We conclude that the recurrent PIGA germline mutation c.1234C>T leads to a recognizable clinical phenotype with a poor prognosis and is the cause of SGBS2.
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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 | 0.001 | 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 | 0.001 | 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".