Exome Sequencing for cerebral palsies: Opening windows for differential diagnosis
Bibliographic record
Abstract
DNA sequencing technologies played a critical role in the last two decades in expanding our understanding of genetic spectrum behind neurodevelopmental disorders. Recently, induction MPS in the area of medical genetics provided chance for differential diagnosis and/or reverse phenotyping of cerebral palsies and many other developmental disorders. Here we present how ES through MPS has identified causative mutations and showed scope for further characterization of the neurodevelopmental disorders. Here we report and discuss four cases (5Y to 12Y) who were diagnosed as CP with mild or moderate ID. Whole Exome libraries were constructed using Exome RDY panel and sequenced on Ion Proton. The reads generated were aligned to hg19 and variants were annotated and prioritized using Ion Reporter. In Cases-I & II a homozygous mutation in PMM2 gene (NM_000303.2, c.710C>T, p.THR237ARG) and a novel nonsense mutation in gene SLC35A2 (NM_005660.2, c.1024C>T, p.Arg342Ter) which are known to cause congenital disorder of glycosylation type Ia (MIM: 212065) and type IIm SOMATIC MOSAIC (MIM: 300896) were identified, respectively. In case-III (two male siblings) ES identified a novel Frame Shift (FS) mutation in APRATAXIN (APTX) gene (NM_001195248.1, c.638delG, p.Arg213fs, rs150886026) which are known to cause ATAXIA-OCULOMOTOR APRAXIA 1; AOA1 (MIM: 208920). Brain imaging in Case-IV is suggestive of Joubert syndrome with hearing loss, we identified a missense mutation in AHI1 gene (NM_001134830.1, c.2023G>A, p.Asp675Asn) and also a nonsense mutation in gene GJB2 (NM_004004.5, c.71G>A, p.Trp24Ter) which explains the hearing impairment in the case. Mutations in cases and parent(s) were confirmed on 3500 Genetic Analyzer revealed Autosomal recessive or X-linked dominant and somatic mosaicism pattern of inheritance. Reverse phenotyping was convincing for Case I & II. Case III phenotype was delineated by the identification of responsible gene /mutation. Complex phenotype of Case IV was characterized as revealed by genotyping. Our work suggests genotype first approach will be beneficial for prompt & precise diagnosis and reverse phenotyping of neurodevelopmental disorders.
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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 | 0.002 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.001 | 0.002 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".