Abstract
We report a family affected with childhood onset distal muscle weakness with a heterozygous chromosome 9q34 deletion encompassing the SPTAN1 gene. The deletion was detected through exome-sequencing based copy number variant (CNV) detection, segregates in four patients and is non-penetrant in two other relatives. Electromyography, muscle MRI and muscle biopsy revealed a myopathic disease phenotype. Cellular consequences of the deletion were investigated using qPCR and western blotting on patient-derived fibroblasts, which revealed a reduction of RNA but not protein levels. Immunocytochemistry was performed on muscle tissue which did not reveal reduction of α-II-spectrin. SPTAN1 loss-of-function variants have previously been reported to cause distal hereditary motor neuropathy and recently distal myopathy. Here, we confirm the role of SPTAN1 haploinsufficiency as a cause of distal myopathy. We propose an age-dependent lack of α-II-spectrin and suggest CNV detection in repurposed exome sequencing as an important diagnostic tool.
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Data availability
The genetic data is available after registration through the RD-Connect GPAP (https://platform.rd-connect.eu/). All other data is available from the authors upon reasonable request.
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Acknowledgements
Several authors are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD, project N°870177). We thank the participating patients and relatives for their cooperation in this study.
Funding
JB and VT are part of the μNEURO Research Centre of Excellence of the University of Antwerp. This work was supported by the EU Horizon 2020 program (Solve-RD under grant agreement N°779257). JB is supported by a Senior Clinical Researcher Mandate of the Research Fund – Flanders (FWO) under grant agreement N°1805021N. LVdV is supported by a predoctoral fellowship of the FWO under grant agreement N°11F0921N and the Peripheral Nerve Society Laura Feltri Basic Research Fellowship. JDW is supported by the Goldwasser-Emsens fellowship.
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LVdV performed and designed experiments and wrote the manuscript. JDW collected clinical data and aided in manuscript writing. AM and NC performed experiments. TD and KJ performed diagnostic validation of the variant. GM, AAJ, WDR collected clinical data. GD, SL conducted experiments within Solve-RD. WDR, BE and VT designed experiments, aided in manuscript writing. JB designed experiments, reviewed data and performed manuscript writing.
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All experiments performed in this study were approved by the University of Antwerp ethical committee. Informed consent was obtained from all patients that were evaluated.
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Van de Vondel, L., De Winter, J., Monticelli, A. et al. A heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy. Eur J Hum Genet (2025). https://doi.org/10.1038/s41431-025-01938-2
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DOI: https://doi.org/10.1038/s41431-025-01938-2
