P440: Decoding the GANAB enigma: Novel insights into pediatric cystic kidney disease
Bibliographic record
Abstract
Autosomal-dominant polycystic kidney disease (ADPKD) is predominantly linked to PKD1 or PKD2 mutations. Pathogenic GANAB variants, which encode neutral alpha-glucosidase AB, cause ADPKD type 3 (OMIM 600666). Since the gene-disease association was first reported in 20167, 18 kindreds have been described. We describe a 5-year-old male who initially presented with hypotonia, hypermobility, developmental delay, soft skin in distal extremities, macrocephaly and pulmonary stenosis. A condition resembling Ehlers-Danlos syndrome was suspected, but genetic testing was negative. He also had five urinary tract infections between ages before age 5 and needed neurosurgery for a tethered spinal cord at age 4. Other abnormalities uncovered in the process include kidney cysts, a pituitary microadenoma, and small cyst in the filum terminale of the spinal cord. His brother has kidney cysts and a history of cystic hydrocephalus that required neurosurgical intervention. His mother has kidney and hepatic cysts and was also diagnosed with Adie’s pupil (abnormal pupillary response to light). Whole exome sequencing revealed a novel pathogenic GANAB variant (c.2575C>T; p.Gln859Ter) shared by the two siblings and their mother, in keeping with ADPKD type 3; no other variants were identified that could explain the extended neurophenotype of the two brothers. Located on the 22nd exon (out of 24), this variant is predicted to lead to nonsense-mediated decay. The only neurological abnormality for patients with GANAB variants is intracranial aneurysms in three individuals from one family; it is unclear if the other known cases all underwent neuroimaging. The fact that the two boys both have cysts affecting various brain regions suggests that it may be a rare manifestation of this condition. On that basis, we recommend that all patients diagnosed with ADPKD type 3 should undergo neuroimaging. It is unknown if the other non-cystic phenotypes documented in this kindred are causally linked to the GANAB variant.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| 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".