Journal article
Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy
Genetics in medicine, Vol.27(6), 101399
06/2025
DOI: 10.1016/j.gim.2025.101399
PMID: 40023774
Abstract
Heterozygous pathogenic variants in SPTAN1 cause a diverse spectrum of neurogenetic disorders ranging from peripheral and central nervous system involvement to complex syndromic presentations. We set out to investigate the role of SPTAN1 in genetically unsolved hereditary myopathies.
Through international collaboration we identified 14 families with distal weakness and heterozygous SPTAN1 loss-of-function variants. Clinical data, electrophysiology, muscle CT or MRI and muscle biopsy findings were collected and standardized. SPTAN1 protein, mRNA expression analysis and cDNA sequencing was performed on muscle tissue from two participants.
Five families showed autosomal dominant mode of inheritance, while in nine patients the variant was shown to be de novo, including 2 pairs of monozygotic twins. In two families, further segregation analysis was not possible. All affected participants presented with early childhood onset distal weakness and foot abnormalities. Muscle MRI or CT in 10 patients showed fatty infiltration of the distal lower limb anterior compartment and/or selective involvement of the extensor hallucis longus muscle. Muscle biopsy revealed myopathic changes in 7 patients. Finally, we provide proof for nonsense mediated decay in muscle tissue derived from two patients.
We present evidence linking heterozygous SPTAN1 loss-of-function variants to childhood-onset distal myopathy in 14 unrelated families.
Details
- Title: Subtitle
- Heterozygous loss-of-function variants in SPTAN1 cause an early childhood onset distal myopathy
- Creators
- Jonathan De Winter - University of AntwerpLiedewei Van de Vondel - University of AntwerpBiljana Ermanoska - University of AntwerpAlice Monticelli - University of AntwerpArnaud Isapof - Hôpital Armand-TrousseauEnzo Cohen - InsermTanya Stojkovic - Sorbonne UniversitéPeter Hackman - Folkhälsans ForskningscentrumMridul Johari - Harry Perkins Institute of Medical ResearchJohanna Palmio - Tampere University HospitalMegan A. Waldrop - Nationwide Children's HospitalAlayne P. Meyer - Nationwide Children's HospitalStefan Nicolau - Nationwide Children's HospitalKevin M. Flanigan - Nationwide Children's HospitalAna Töpf - Newcastle UniversityJordi Diaz-Manera - Newcastle UniversityVolker Straub - Newcastle UniversityCheryl Longman - Queen Elizabeth University HospitalCatherine A. McWilliam - Queen Elizabeth University HospitalRotem Orbach - National Institute of Neurological Disorders and StrokeSumit Verma - Emory UniversityRegina Laine - Boston Children's HospitalSandra Donkervoort - National Institutes of HealthCarsten G. Bonnemann - National Institute of Neurological Disorders and StrokeAdriana Rebelo - University of MiamiStephan Züchner - University of MiamiTiffany Grider - University of IowaMichael E. Shy - University of IowaIsabelle Maystadt - Institute of Pathology and GeneticsFlorence Demurger - Centre hospitalier Bretagne AtlantiqueAnita Cairns - Queensland Children’s HospitalSarah Beecroft - Pawsey Supercomputing Research CentreChiara Folland - Harry Perkins Institute of Medical ResearchWillem De Ridder - Antwerp University HospitalGina Ravenscroft - The University of Western AustraliaGisèle Bonne - InsermBjarne Udd - Tampere University HospitalJonathan Baets - University of Antwerp
- Resource Type
- Journal article
- Publication Details
- Genetics in medicine, Vol.27(6), 101399
- DOI
- 10.1016/j.gim.2025.101399
- PMID
- 40023774
- NLM abbreviation
- Genet Med
- ISSN
- 1098-3600
- eISSN
- 1530-0366
- Publisher
- Elsevier Inc; NEW YORK
- Grant note
- European UnionResearch Fund-FlandersMarie Sklo-dowska Curie Postdoctoral fellowshipSenior Clinical Researcher mandate of the Research Fund-FlandersTampere University Hospital Support FoundationTampere University HospitalNational Institutes of Neurological Disorders and StrokeNational Institutes of Health (NIH)Muscular Dystrophy Association and Charcot Marie Tooth AssociationMuscular Dystrophy UKNational Institute of Neurologic Disorders and StrokeNIHNIHR Newcastle Biomedical Research CentreEuropean Reference Network for Rare Neurologic Diseases (ERN-RND): 739510 European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD): 870177 Sanofi GenzymeUltragenyxLGMD2l Research FundSamantha J. Brazzo FoundationLGMD2D FoundationKurt+Peter Foundation
This work was supported by the Goldwasser-Emsens fellowship and Solve-RD project from the European Union's Horizon 2020 Research and Innovation Programme under grant agreement number 779257 (Solve-RD).L.V.d.V. is supported by a predoctoral fellowship of the Research Fund-Flanders under grant agreement number 11F0921N. B.E. is currently supported by Marie Sklo-dowska Curie Postdoctoral fellowship 101107344. J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund-Flanders under grant agreement number 1805021N. J.P. is supported by the Tampere University Hospital Support Foundation, Tampere University Hospital(number MK339). S.Z. is supported by a National Institutes of Neurological Disorders and Stroke grant number 5R01NS072248. M.E.S. receives support from the National Institutes of Health (NIH), Muscular Dystrophy Association and Charcot Marie Tooth Association and likes to discloseconsulting Agreements with Alnylam Pharmaceuticals,A pplied therapeutics, Novartis, Takeda. C.B. received sup-port from intramural funds from the National Institute of Neurologic Disorders and Stroke, NIH. A.T., J.D.M., and V.S. are supported by the NIHR Newcastle Biomedical Research Centre. Several authors are part of the mu NEUROResearch Centre of Excellence of the University of Antwerp. Several authors are member of the European Reference Network for Rare Neurologic Diseases (ERN-RND, project number 739510) and of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD, project number 870177). MYO-SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2l Research Fund, Samantha J. Brazzo Foundation, LGMD2D Foundation and Kurt+Peter Foundation, Muscular Dystrophy UK, andCoalition to Cure Calpain 3.
- Language
- English
- Electronic publication date
- 02/26/2025
- Date published
- 06/2025
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984798363502771
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