Monozygotic twins with chromosome 22q11 deletion and discordant phenotypes: updates with an epigenetic hypothesis
Bibliographic record
Abstract
he completion of the human genome sequence affords novel approaches to studies on contiguous gene deletion syndromes. These syndromes are caused by a deletion and loss of one copy of a set of contiguous genes on a given chromosome. Here, the syndromic phenotypes are often attributed to haploinsufficiency of a number of deleted genes. One such syndrome deals with deletion of 22q11.2. It is the most common microdeletion syndrome with a frequency of 1:4000 live births. 1 This high frequency has been attributed to low copy repeats (LCR) on chromosome 22, 2 with most cases (85-90%) representing de novo mutations. Also, the critical common region is relatively large (>1.5-3.0 Mb), may involve >30 genes, and there is no evidence of any correlation between the size of the deletion and the observed syndromic phenotypes. In fact, the clinical phenotype of the 22q11 deletion syndrome is characterised by extensive variability. It includes velocardiofacial syndrome (VCFS), DiGeorge syndrome (DGS), and associated physical, developmental, neurological, and neuropsychiatric phenotypes. This phenotypic variability associated with the 22q11 deletion is an exception to all the other contiguous gene syndromes. More puzzling are recent reports that monozygotic twins (p>0.99) with 22q11 deletions have discordant phenotypes. In this discussion we will review all published cases of monozygotic twins concordant for del 22q11 and assess phenotypic discordance/concordance between them. More important, we will discuss an epigenetic explanation for their discordance that is compatible with modern molecular understanding of the human genome, the sequence features of this region of chromosome 22, and the "second hit" hypothesis involving genetic and/or epigenetic somatic events.
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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) | 0.001 | 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 | 0.001 |
| 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".