Late-Onset Sacsinopathy Diagnosed by Exome Sequencing and Comparative Genomic Hybridization
Why this work is in the frame
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Bibliographic record
Abstract
The molecular diagnosis of adult-onset autosomal recessive cerebellar ataxias remains challenging because of genetic heterogeneity. However, recently developed molecular genetic techniques will potentially revolutionize the diagnostic approach. Here we set out to define the genetic basis of the ataxia in two brothers with no molecular diagnosis. Clinical evaluation was followed by whole-exome second-generation sequencing and comparative genomic hybridization to determine the diagnosis. Whole-exome sequencing identified a hemizygous novel spastic ataxia of Charlevoix-Saguenay (SACS) stop-codon mutation in both brothers (c.13048G→T, p.E4350*) that was present in the mother, but not the father. Comparative genomic hybridization revealed a 0.7-Mb deletion on chromosome 13q12.12 in both brothers, which included SACS and was heterozygous in the asymptomatic father. The milder phenotype, caused by a whole-gene deletion and a stop-codon mutation in SACS, indicates a loss-of-function mechanism in late-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), and illustrates the importance of chromosomal rearrangements in the investigation of adult-onset ataxia.
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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 | 0.000 | 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 it