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 (>1.5-3.0Mb), may involve >30 genes, and there is no evidence of any correlation between the size of the deletion and the observed syndromic phenotypes.3 In fact, the clinical phenotype of the 22q11 deletion syndrome is characterised by extensive variability.4 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. SUMMARY OF CASE REPORTS Twin pair 1Twin pair 1 5 was born to a 32 year old mother of European ancestry, at a gestational age of 38 weeks, weighing 2200 g (twin 1) and 2800 g (twin 2), apparently from a single placenta.Although the facial features of the male twins were similar and related to DGS, only twin 1 had a heart murmur at week 1 and a diagnosis of tetralogy of Fallot was made at week 8. Twin 1 also had slow development, more pronounced nasal speech, and more marked toe deformity.There is no family history of congenital heart disease or other handicap.High resolution cytogenetic analysis on 100 metaphases on each of the twins was compatible with a single de novo deletion event leading to a 46,XY,del(22)(q11.21q11.23)karyotype in both twins.Four hypervariable DNA polymorphisms and nine red cell antigens established that the twins are 99.998%monozygotic.The authors argue that the discordant phenotype cannot be explained by genotypic differences alone.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".