P698: A streamlined testing of mosaic maternal isodicentric supernumerary chromosome 15q11.2q13 [idic(15)]
Bibliographic record
Abstract
Chromosome microarray is a first tier test for patients with developmental delay, autism and congenital abnormalities. When microarray detects loss or gain in the15q11.2q13 Prader-Willi/Angelman critical region (PWACR), further cytogenetic (karyotype and FISH) and molecular techniques are required for accurate diagnosis. A maternally derived 15q gain establishes a diagnosis of maternal 15q duplication syndrome characterized by hypotonia, developmental delays, intellectual disability, autism spectrum disorder and epilepsy. However, a paternally derived 15q gain has more variable effects from asymptomatic to sleep concerns, developmental delay, autistic features, and congenital anomalies. Determining the parental origin of a 15q gain is critical for patient diagnosis, management and genetic counseling. Around 60-80% of maternal duplication syndrome cases are caused by supernumerary idic(15) with four copies of 15q11.2q13 and 20-40% cases are due to maternal interstitial duplication of 15q11.2q13 with three copies of the 15q region. Both supernumerary idic(15) and interstitial duplication of 15q contain the minimal PWACR between low copy repeats BP2 and BP3. Tetrasomy idic(15) tends to be associated with more severe phenotypes than trisomy 15q duplication, suggesting that there is a gene dosage effect. The majority of idic(15) cases contain one supernumerary chromosome idic(15) (tetrasomy). Cases with two or three supernumerary chromosomes idic(15) (hexasomy or octosomy) are rare but more studies of such cases will contribute to better understanding of gene dosage effect on phenotype. A 4 year old girl presented with developmental speech delay. Her gross motor milestones were normal, but she had an unsteady gait at 4 years. She currently has receptive and expressive language delays and struggles with age-appropriate social interactions. She has been in good health and is nondysmorphic. Family history is negative for any intellectual disability. High resolution CytoScan HD Array (ThermoFisher) analysis of peripheral blood DNA detected a mosaic gain of 5.775 Mb in 15q11.2q13.1, denoted as arr[hg19] 15q11.2q13.1(22,770,421-28,545,601)x3∼4, which contained type 1 PWACR region between BP1 and BP3. Karyotype analysis was performed on blood from proband and parents. Parental karyotypes were normal. The proband had three cell lines: 21 of 30 cells had one supernumerary chromosome idic(15), 2 of 30 cells had two supernumerary chromosomes idic(15) and seven cells were normal. Hence she has mosaic de novo idic(15), mos 47,XX,+idic(15)(q13)[21]dn/48,XX,+idic(15)(q13)x2 [2]dn/46,XX[7]. Metaphase and interphase FISH analyses of proband and parental blood samples, using CytoCell SNRPN probe at 15q11.2 and 15qter subtelomere probe (clone 154P1) showed that each idic(15) contained two SNRPN loci but no signal for 15qter probe, which confirmed the de novo supernumerary chromosome idic(15) in proband. Interphase FISH showed that 82% of cells contained one idic(15) (tetrasomy 15q), 5% of cells had two idic(15) (hexasomy 15q) and 13% of cells were normal, ie, nuc ish(SNRPNx4)[82]dn/(SNRPNx6)[5]dn/(SNRPNx2)[13]. Methylation MLPA (MRC Holland) analysis of the proband DNA revealed that the methylation ratio was ∼75%, indicating that there were one copy of paternal 15q and ∼three copies of maternal 15q. Therefore, the idic(15) was derived from maternal chromosome 15. We have diagnosed this patient with mosaic idic(15) maternal duplication syndrome, with mosaicism for tetrasomy idic (15), hexasomy idic (15), and a normal cell line. Mosaic idic(15) cases are rare. The effects of the idic(15) may be somewhat milder due to the presence of the normal cell line and also depending on tissue distribution, especially in the brain.
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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 | 0.000 | 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".