Expanding SNX14-Associated Movement Disorders in a Genotype–Phenotype Spectrum
Bibliographic record
Abstract
Background/Purpose: SNX14 is a sorting nexin protein that is involved in vesicular tethering during autophagy and vesicular trafficking at the endoplasmic reticulum and lysosomes. Biallelic variants in SNX14 are characterized by a global neurodevelopmental delay (NDD), muscular hypotonia, seizures, progressive cerebellar atrophy with ataxia, and craniofacial dysmorphia mirroring a lysosomal storage disorder. A Snx14-deficient mouse model presented severe motor disorders with Purkinje cell degeneration due to deficits in mitochondrial axonal transport and microtubule organization with reduced spastin. The pathomechanism and phenotypic variability of SNX14 deficiency in human remains elusive. Methods: Here, we collected detailed clinical and imaging data from unreported cases and previously published reports with biallelic variants in SNX14. Results: We identified 62 patients with biallelic SNX14 variants, including 22 unreported cases from 15 unrelated families, marking the largest patient cohort since 2015 with eight new variants. The wide clinical spectrum included ataxia (98%), global NDD (100%), and skeletal abnormalities (63%). We observed significantly less craniofacial dysmorphia in patients with novel N-terminal variants. Analyses of brain MRI studies revealed cerebellar atrophy (95%), cerebral atrophy (38%), and white matter hyperintensities (13%). We present novel phenotypes with movement disorders that included spastic quadriplegia, dysconjugate gaze, and intermittent exotropia. Genotype–phenotype correlations showed tentative associations in phenotype severity with reduced protein expression and primarily spastic neurological disorders clustered in the N-terminal region. Conclusion: Novel features reveal an expansion of the genotype–phenotype spectrum in SNX14 -related movement disorders and considerable overlap with vesicular trafficking disorders linked on a molecular basis. This provides groundwork for genetic counseling and support for patients and families. Publication History Article published online: 13 November 2023 © 2023. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany
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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) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.005 | 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".