C003 The influence of CAG-CCG repeat sequence variants on the phenotype of HD patients with small expansions
Bibliographic record
Abstract
Background Chorea is less frequent in patients with small CAG repeat alleles (CAG36-39).1 Synonymous sequence variants within the HTT CAG-CCG repeat region such as the loss of the CAA interruption (LOI), are modifiers of HD onset and penetrance, particularly in symptomatic carriers with small CAG repeat alleles.2 However, phenotypic differences other than earlier age at onset are not described. Aims We investigated how sequence variants influence the phenotype in patients with small CAG expansions. Methods We included 125 carriers with uninterrupted CAG36-39 in Paris (n=50) and in Vancouver (n=75). We amplified the region of interest by PCR and sequenced the amplicons with Illumina MiSeq (Paris) and clonal Sanger sequencing of the HTT repeat tract (Vancouver). Results We found 29 carriers with the LOI variant (23%). Patients with the LOI variant had a non significant earlier mean age at onset than those with the canonical sequence (59 years vs 61 years), depite comparable proportions of different CAG sizes in both groups. The full triad of motor, cognitive and psychiatric involvement was more frequent in LOI patients (100% vs. 36%; p<0.05), but there was no difference regarding the absence of chorea which was frequent in both groups (17% in patients with the LOI and 28% in patients with the canonical sequence). Conclusions In the largest phenotyped small expansion cohort with DNA sequence data from two reference centers to date, the LOI is potentially a severity factor of clinical manifestations. Specific phenotypic traits like chorea frequency appear to be more related to CAG size than structure. References Heinzmann A, Sayah S, Lejeune F, Hahn V, Teichmann M, Monin M, et al. Huntington’s disease with small CAG repeat expansions. Mov Disord. 2023 Jul;38(7):1294–306. Findlay Black H, Wright GEB, Collins JA, Caron N, Kay C, Xia Q, et al. Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range. Genet Med [Internet]. 2020 Aug 3 [cited 2020 Oct 2]; Available from: http://www.nature.com/articles/s41436-020-0917-z.
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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 | 0.000 | 0.001 |
| 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) | 0.007 | 0.001 |
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".