De novo mutations of <i>SCN1A</i> are responsible for arthrogryposis broadening the <i>SCN1A</i>-related phenotypes
Bibliographic record
Abstract
Background Arthrogryposis multiplex congenita (AMC) is the direct consequence of reduced fetal movements. AMC includes a large spectrum of diseases which result from variants in genes encoding components required for the formation or the function of the neuromuscular system. AMC may also result from central nervous involvement. SCN1A encodes Nav1.1, a critical component of voltage-dependent sodium channels which underlie action potential generation and propagation. Variants of SCN1A are known to be responsible for Dravet syndrome, a severe early-onset epileptic encephalopathy. We report pathogenic heterozygous missense de novo variants in SCN1A in three unrelated individuals with AMC. Methods Whole-exome sequencing was performed from DNA of the index case of AMC families. Heterozygous missense variants in SCN1A (p.Leu893Phe, p.Ala989Thr, p.Ile236Thr) were identified in three patients. Sanger sequencing confirmed the variants and showed that they occurred de novo. Results AMC was diagnosed from the second trimester of pregnancy in the three patients. One of them developed drug-resistant epileptic seizures from birth. We showed that SCN1A is expressed in both brain and spinal cord but not in skeletal muscle during human development. The lack of motor denervation as established by electromyographic studies or pathological examination of the spinal cord or skeletal muscle in the affected individuals suggests that AMC is caused by brain involvement. Conclusion We show for the first time that SCN1A variants are responsible for early-onset motor defect leading to AMC indicating a critical role of SCN1A in prenatal motor development and broadening the phenotypic spectrum of variants in SCN1A .
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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 | 0.001 | 0.003 |
| 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 | 0.001 |
| 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".