Pseudohypoparathyroidism type 1a and the <i>GNAS</i> p.R231H mutation: Somatic mosaicism in a mother with two affected sons
Bibliographic record
Abstract
Pseudohypoparathyrodism (PHP) is a disorder caused by mutations in the guanine nucleotide-binding α-subunit (GNAS). We sought to determine the genetic origin of PHP1a in one affected family. We identified the previously reported Gsα R231H mutation in family members affected with PHP1a. DNA analysis found that the two clinically affected sons are heterozygous for the mutation. The sons have PHP1a, manifesting obesity, intellectual disability, hypogonadism, hypothyroidism and elevated PTH levels. Initial DNA sequencing did not detect the mutation in either parent. However, their mother displayed some features of PHP, including elevated PTH levels and asymmetrical metacarpal shortening. Using molecular cloning, we detected the mutation at low levels in the mother's leukocyte DNA, consistent with somatic mosaicism and her mildly affected status. Thus, we have identified additional cases of PHP1a caused by the Gsα R231H mutation. In this family, the mother has a milder phenotype due in part to somatic mosaicism, whereas the two affected sons have full PHP1a. Though somatic mosaicism for activating GNAS mutations is known to occur in McCune-Albright syndrome, this is the first report confirming somatic mosaicism for a hypofunctioning GNAS mutation in a PHP kindred.
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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 | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| 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".