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Hadjinicolaou A, Ngo KJ, Conway DY, et al. De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy. Acta Neuropathol Commun. 2021;9(1):194doi: 10.1186/s40478-021-01277-5.
Hadjinicolaou, A., Ngo, K. J., Conway, D. Y., Provias, J. P., Baker, S. K., Brady, L. I., Bennett, C. L., La Spada, A. R., Fogel, B. L., & Yoon, G. (2021). De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy. Acta neuropathologica communications, 9(1), 194. https://doi.org/10.1186/s40478-021-01277-5
Hadjinicolaou, Aristides, et al. "De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy." Acta neuropathologica communications vol. 9,1 (2021): 194. doi: https://doi.org/10.1186/s40478-021-01277-5
Hadjinicolaou A, Ngo KJ, Conway DY, Provias JP, Baker SK, Brady LI, Bennett CL, La Spada AR, Fogel BL, Yoon G. De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy. Acta Neuropathol Commun. 2021 Dec 18;9(1):194. doi: 10.1186/s40478-021-01277-5. PMID: 34922620; PMCID: PMC8684165.
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Acta Neuropathol Commun. 2021 Dec 18;9(1):194. doi: 10.1186/s40478-021-01277-5.

De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy.

Acta neuropathologica communications

Aristides Hadjinicolaou, Kathie J Ngo, Daniel Y Conway, John P Provias, Steven K Baker, Lauren I Brady, Craig L Bennett, Albert R La Spada, Brent L Fogel, Grace Yoon

Affiliations

  1. Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
  2. Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, USA.
  3. Department of Pathology and Molecular Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada.
  4. Department of Medicine, Divisions of Physical Medicine and Neurology, McMaster University, Hamilton, ON, Canada.
  5. Department of Pediatrics, McMaster University Medical Centre, Hamilton, ON, Canada.
  6. Department of Pathology and Laboratory Medicine, University of California, Irvine, USA.
  7. Department of Neurology and Department of Biological Chemistry, UC Institute for Neurotherapeutics, University of California, Irvine, USA.
  8. Departments of Neurology and Human Genetics, David Geffen School of Medicine, Clinical Neurogenomics Research Center, University of California Los Angeles, 695 Charles E. Young Dr. South, Gonda Room 6554A, Los Angeles, CA, 90095, USA. [email protected].
  9. Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. [email protected].
  10. Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. [email protected].

PMID: 34922620 PMCID: PMC8684165 DOI: 10.1186/s40478-021-01277-5

Abstract

Pathogenic variants in SETX cause two distinct neurological diseases, a loss-of-function recessive disorder, ataxia with oculomotor apraxia type 2 (AOA2), and a dominant gain-of-function motor neuron disorder, amyotrophic lateral sclerosis type 4 (ALS4). We identified two unrelated patients with the same de novo c.23C > T (p.Thr8Met) variant in SETX presenting with an early-onset, severe polyneuropathy. As rare private gene variation is often difficult to link to genetic neurological disease by DNA sequence alone, we used transcriptional network analysis to functionally validate these patients with severe de novo SETX-related neurodegenerative disorder. Weighted gene co-expression network analysis (WGCNA) was used to identify disease-associated modules from two different ALS4 mouse models and compared to confirmed ALS4 patient data to derive an ALS4-specific transcriptional signature. WGCNA of whole blood RNA-sequencing data from a patient with the p.Thr8Met SETX variant was compared to ALS4 and control patients to determine if this signature could be used to identify affected patients. WGCNA identified overlapping disease-associated modules in ALS4 mouse model data and ALS4 patient data. Mouse ALS4 disease-associated modules were not associated with AOA2 disease modules, confirming distinct disease-specific signatures. The expression profile of a patient carrying the c.23C > T (p.Thr8Met) variant was significantly associated with the human and mouse ALS4 signature, confirming the relationship between this SETX variant and disease. The similar clinical presentations of the two unrelated patients with the same de novo p.Thr8Met variant and the functional data provide strong evidence that the p.Thr8Met variant is pathogenic. The distinct phenotype expands the clinical spectrum of SETX-related disorders.

© 2021. The Author(s).

Keywords: Axonal neuropathy; Neurodegeneration; SETX; Senataxin

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