Whole-Genome Study of a Multigenerational Family with Essential Tremor
Bibliographic record
Abstract
BACKGROUND: Essential tremor (ET) is a common movement disorder with ˜5% prevalence in individuals above the age of 65, but in rare cases, it arises during childhood. Growing evidence suggests the role of cerebellum in the disease mechanism. ET is highly heritable, however, poor replication of risk loci point to its significant heterogeneity. Thus, it is important to genetically investigate kindreds with a strong aggregation of ET. METHODS: We conducted a clinical and whole-genome investigation of a large Caucasian Canadian family, in which six out of eight patients are affected by childhood-onset ET in four consecutive generations. Eight family members were available for study, including three patients affected by ET. Whole-genome sequencing (WGS) was conducted for the four most informative individuals, followed by Sanger sequencing in the entire kindred. RESULTS: We searched for rare variants absent in the eldest unaffected individual, but present in the patients (two siblings and their third-degree relative). Our stringent whole-genome filtering approach revealed a rare heterozygous p. Arg90Gln substitution in TCP10L (rs151233771) in all three investigated patients. Sanger sequencing confirmed the p. Arg90Gln variant and revealed its absence in the rest of the family members. CONCLUSIONS: Whole-genome data of the family with ET resulted in a single candidate gene mapped to 21q22.11 locus (TCP10L) with the highest brain expression in cerebellum. Our study encourages future replication studies to validate the genetic link between TCP10L and ET, and suggests the p. Arg90Gln variant for functional investigation.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".