A Heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy

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German Demidov , Steven Laurie , Willem De Ridder , Biljana Ermanoska , Vincent Timmerman , Jonathan Baets doi: https://doi.org/10.1101/2025.01.09.24319154 Liedewei Van de Vondel 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , Belgium 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium 3 Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp , Antwerp, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Liedewei Van de Vondel Jonathan De Winter 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , Belgium 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium 4 Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital , Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jonathan De Winter Alice Monticelli 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , Belgium 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Natacha Camacho 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tine Deconinck 5 Department of Medical Genetics, University of Antwerp and Antwerp University Hospital , Edegem, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Katrien Janssens 5 Department of Medical Genetics, University of Antwerp and Antwerp University Hospital , Edegem, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Goedele Malfroid 6 Department of Neurology, Geel General Hospital, Ziekenhuis Netwerk Kempen , Ziekenhuis Geel, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alicia Alonso-Jiménez 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , Belgium 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium 4 Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital , Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site German Demidov 7 Institute of Medical Genetics and Applied Genomics, University of Tübingen , Tübingen, Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Steven Laurie 8 Centro Nacional de Análisis Genómico (CNAG) , Baldiri Reixac 4, 08028 Barcelona, Spain 9 Universitat de Barcelona (UB) , Barcelona, Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site Willem De Ridder 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , Belgium 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium 4 Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital , Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Biljana Ermanoska 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , Belgium 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Vincent Timmerman 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium 3 Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp , Antwerp, Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jonathan Baets 1 Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp , Belgium 2 Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp , Antwerp, Belgium 4 Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital , Belgium Find this author on Google Scholar Find this author on PubMed Search for this author on this site For correspondence: jonathan.baets{at}uantwerpen.be Abstract Full Text Info/History Metrics Data/Code Preview PDF 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 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. Introduction While 80% of Rare Diseases (RD) are believed to be genetic, currently only 50-60% of RD patients receive a genetic diagnosis( 1 , 2 ). Detection of Single Nucleotide Variants (SNVs) and short insertions and deletions (indels) in Exome Sequencing (ES) data is standardized, while detection of larger variants (e.g. tandem repeats, copy number variants (CNVs) and structural variants (SVs)) is technically limited in short-read data. Microarrays can be used to evaluate CNVs but are seldomly performed for patients with late-onset disease. These shortcomings can be addressed by performing either (long-read) genome sequencing or by applying novel algorithms to existing ES data. Within the Solve-RD consortium( 3 ), a large-scale effort was performed to detect CNVs in ES, using three different algorithms (ClinCNV, ExomeDepth and Conifer) and a pre-defined list containing 615 genes associated with neuromuscular diseases( 4 ). Heterozygous loss-of-function variants in the SPTAN1 gene are associated with different disorders, including intellectual disability with or without peripheral neuropathy, hereditary motor neuropathy (HMN) with a variable severity and reduced penetrance, and recently also distal myopathy with variable severity( 5 – 7 ). SPTAN1 encodes α-II-spectrin, which exhibits widespread expression with an enrichment in neuronal tissues. In mice, homozygous knock-out of Sptan1 −/− is embryonically lethal, while heterozygous Sptan1 +/− mice display no phenotype( 8 ). Neuronal-specific knock-down of Sptan1 is critical in upholding neuronal structure( 9 , 10 ). α-II-spectrin oligomerizes with one of four different β-spectrins into heterotetramers, which together with actin, form a submembrane periodic cytoskeleton which is thought to infer mechanical resilience to axons through its ability to stretch and withstand cellular forces( 11 ). In this study, we describe the detection and interpretation of a heterozygous 9q34 deletion encompassing the SPTAN1 and DYNC2I2 genes and part of the GLE1 gene, in a multi-generational family with a childhood onset distal weakness. Materials and methods Genetic and clinical studies Experiments were approved by the University of Antwerp ethical committee. Known genetic causes for peripheral neuropathies were excluded in participants III:2 and IV:2 by an ES-based gene panel supplemented with Human Phenotype Ontology (HPO) based analysis. ES of III:2 was submitted to the Solve-RD consortium and analyzed within the European Reference Network for Rare Neuromuscular Disorders (ERN EURO-NMD)( 12 , 13 ). The identified CNV passed the filtering strategy and was reported for interpretation( 4 ). Segregation analysis was performed using SNP array (HumanCytoSNP-12 v2.1 BeadChip Kit, Illumina) with CNV Webstore 2.0 analysis, using DNA extracted from blood in 11 family members( 14 ). Clinical details were collected retrospectively for deceased individuals (I:1, I:2, II:1, II:2, II:3, III:3, IV:1). Individuals III:1, III:2 and IV:2 were clinically re-evaluated including Nerve Conduction Studies (NCS) and electromyography (EMG), muscle magnetic resonance imaging (MRI) was performed for patients III:2 and IV:2. Muscle biopsies were obtained respectively from the vastus lateralis (III:2) and the tibialis anterior (IV:2), and compared to a vastus lateralis biopsy from a control individual. Patient Fibroblasts, RT-qPCR, Western Blotting Fibroblasts were established from III:2 and an age-and-gender matched control and cultured in Dulbecco’s modified Eagle medium (DMEM) (ThermoFisher) with 10% Fetal Bovine Serum (FBS), 1% L-glutamine and 1% penicillin/streptomycin. RNA was extracted using the Universal RNA kit (Roboklon). cDNA was generated using the High-Capacity cDNA Reverse Transcription Kit (ThermoFisher). RT-qPCR was performed using the SYBR Green PCR Master Mix (ThermoFisher), SPTAN1 and GAPDH primers are available upon request. For western blotting, cell pellets were lysed with RIPA buffer and processed using the same protocol previously described( 6 ). Primary antibodies were anti-SPTAN1 (Abcam ab11755, 1:1000), anti-GLE1 (ThermoFisher 26466-1-AP, 1:1000), anti-GAPDH (Genetex GTX100118, 1:10 000). Muscle Biopsy Immunocytochemistry Seven micron cryosections of muscle tissue were fixated using ice-cold acetone and blocked using donkey serum (1:500) in PBS, and incubated overnight at 4°C with primary antibodies (anti-SPTAN1 (1:50, Abcam ab11755), anti-SPTB (1:500, Novocastra RBC2/3D5) and anti-SPTBN1 (ThermoFisher PA5-44905)). Secondary antibodies were incubated for 1 hour at 4°C, followed by autofluorescence blocking with 0,1% Sudan black for 10 minutes. Hoechst (1:20000) and phalloidin staining (1:25, Biotin) were performed. Images were acquired with a Zeiss LSM700 confocal microscope using a 20x/0.8 Plan Apochromat objective. Image analyses were performed in FIJI. Cells were segmented and masked using the Phalloidin signal as a region of interest to measure fluorescence intensity. Statistical Analysis Statistical analysis was performed using R. Values were normalized to the average of control replicates. The qPCR data was analyzed using the Pfaffl method and a two-sided Student’s t -test. For analysis of ICC experiments, a mixed linear model was first tested, but the variance between slides was neglectable, after which a One-Way Anova was performed. Results The CNV analysis identified a heterozygous deletion at locus 9q34 ( figure 1A ) in III:2, encompassing SPTAN1 and was therefore reported. The deletion was called by ClinCNV and ExomeDepth and visually inspected in IGV. Segregation analysis revealed that although all affected individuals carried the variant, non-penetrance was present in two individuals (pedigree available upon request). The SNP array located the left breakpoint within GLE1 and the right breakpoint to the intergenic region between DYNC2I2 and SET ( figure 1 ). The deletion was reported as a Variant of Unknown Significance (VUS) according to the ACMG guidelines( 15 ). Download figure Open in new tab Figure 1: Depiction of the CNV deletion size and location. Indication of de location of the identified Copy Number Variant (CNV) in the 9q34 region with coordinates in GRCh37, including part of GLE1, SPTAN1 and DYNC2I2. Patients exhibit varying degrees of early childhood onset lower limb distal weakness and foot abnormalities without marked disease progression or anticipation. Muscle weakness predominantly affected the anterior compartment of the distal lower limbs, selectively involved the extensor hallucis longus (EHL) muscle in one patient and foot dorsiflexion weakness in all affected participants. None showed evidence of proximal or bulbar muscle weakness. The extent of foot abnormalities ranged from pes cavus and hammertoes to distal arthrogryposis. None showed evidence of intellectual disability or facial dysmorphism. NCS and needle-EMG were inconclusive in three patients. Muscle MRI showed fatty infiltration of anterior and posterior compartments of the lower limbs in patient III:2 and bilateral absence of the EHL muscle in patient IV:2 ( figure 2A and B ). Muscle biopsy in III:2 and IV:2 showed myopathic changes, comprising a markedly increased number of internalized nuclei, increased fiber size variation with frequent fiber splitting and marked muscle fiber hypertrophy for participant IV:2 ( figure 2C and D ). Of note, patients II:3 and III:1 had a normal clinical and electrophysiological exam at ages 50-75 and are thus considered unaffected. Download figure Open in new tab Figure 2: Muscle MRI and muscle biopsy findings in patients III:2 and IV:2. (A) Axial T1-weighted images at the level of the thighs. (B) Axial T1-weighted images at the level of the calfs. Patient III:2 showing diffuse fatty infiltration and muscle atrophy of both the anterior and posterior compartment. Patient IV:2 showing bilateral absence of the EHL muscles indicated by white arrows. (C) Hematoxylin and eosin (H&E) staining on muscle biopsy (III:2 right m. vastus lateralis quadriceps femoris; IV:2 right m. tibialis anterior). Myopathic features seen in both participants with increased number of internalized nuclei seen in IV:2. (D) ATPase staining (pH 4,6) showing no fiber type disproportion or atrophy. SPTAN1 is a known dosage-sensitive gene and in the GnomAD v4 SV database small intronic but no exonic deletions in SPTAN1 occur ( 16 ). We hypothesized that the 9q34 deletion would lead to reduced levels of α-II-spectrin. Contrary to our assumption, α-II-spectrin levels in fibroblasts of III:2 are not reduced compared to control ( figure 3A ), but mRNA levels are (p = 0.0014, figure 3B ). Muscle biopsies similarly did not reveal a change in the intensity of the diffuse intracellular α-II-spectrin signal measured within the phalloidin-labeled muscle fibers ( figure 3C-D ). Neither were protein levels of β-I-spectrin reduced, a staining commonly used to assess muscle membrane integrity and binding partner of α-II-spectrin ( Supplemental figure 1 ). The genes adjacent to SPTAN1 and partially deleted in this variant, DYNC2I2 and GLE , are highly unlikely to be dosage-sensitive as both have a probability of being loss-of-function intolerant (pLi) score of 0( 17 ). Furthermore, more than 2000 exonic heterozygous deletions in DYNC2I2 are found in GnomAD v4. Recessive variants in GLE1 cause arthrogryposis multiplex congenita,( 18 ) and while a heterozygous loss-of-function variant was associated with Amyotrophic Lateral Sclerosis (ALS) in a single patient, this association has not been confirmed( 19 ). The partial C-terminal deletion of GLE1 in this family minimally includes exons 12-16 and maximally extends to exon 7. Western blot analysis on pellets from patient-derived lymphoblasts showed no evidence of a residual shorter fragment (data not shown), indicating that the deletion likely triggers nonsense-mediated decay. As GLE1 is likely not a Mendelian dosage-sensitive gene, the patients do not exhibit clinical signs of ALS, and the pedigree suggests a dominant inheritance pattern, the deletion of the GLE1 3’ exons is unlikely to contribute to the disease. Download figure Open in new tab Supplementary Figure 1: SPTB1 muscle biopsy staining. (A) SPTB1 intensity in ICC of muscle biopsies. (B) Representative ICC images of muscle biopsies, stained for DAPI (blue), SPTB1 (green), Phalloidin (red) and a merge image. Download figure Open in new tab Figure 3: Protein, RNA and ICC measurements in patient fibroblasts and muscle biopsy. (A) representative western blot of patient-derived fibroblasts compared to control. (B) qPCR data of patient-derived fibroblasts showing a reduction of SPTAN1 mRNA. (C) SPTAN1 intensity in ICC of muscle biopsies. (D) Representative ICC images of muscle biopsies, stained for DAPI (blue), SPTAN1 (green), Phalloidin (red) and a merge image. Discussion We identified a heterozygous 9q34 deletion in a family with distal myopathy through ES-based CNV analysis, warranting the addition of ES-based CNV screening to routine diagnostic practice. We propose that the heterozygous deletion of SPTAN1 underlies the observed myopathic abnormalities in the assessed family. SPTAN1 loss-of-function variants are known to cause HMN with reduced penetrance and have recently been reported to also cause childhood onset distal myopathy ( 7 ). Reduced penetrance and phenotypic variability are similarly observed here. This family closely resembles the reported SPTAN1 myopathy cohort with non-to slowly progressive distal weakness and feet abnormalities with onset in early childhood. Heterozygous deletion of SPTAN1 reduces mRNA levels in fibroblasts, but surprisingly, protein levels are unaffected in both fibroblasts and muscle. Protein and RNA levels were equally not significantly reduced in muscle tissue of loss-of-function carriers in a recently reported study ( 7 ). Correspondingly, a conditional knock-out of mouse Sptan1 under a myogenin driver does not result in a muscle phenotype in animals aged to six months( 20 ), although it is known that expression of α-II-spectrin in rat skeletal muscle cells have a changing expression pattern during development ( 21 ). In Drosophila , the spectrin complex was shown to have a role in the fusion of myoblast precursors into multi-nucleated myofibers ( 22 ). We hypothesize that an age-related haploinsufficiency of the spectrin complex might affect this role, thereby causing a developmental muscle phenotype. A further possibility is that the spectrin complex, known to act as a molecular scaffold in many cell types, has a role in upholding the nuclear localization in the myofiber, reflected in the internalized nuclei on the patients’ muscle biopsy. Further research into the developmental expression and muscle function of the spectrin complex will prove useful to gain insight into these possible mechanisms. Data Availability All data produced in the present study are available upon reasonable request to the authors. Acknowledgments & Funding Several authors are member 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. J.B. and V.T. 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). J.B. is supported by a Senior Clinical Researcher Mandate of the Research Fund – Flanders (FWO) under grant agreement N°1805021N. L.V.d.V. is supported by a predoctoral fellowship of the FWO under grant agreement N°11F0921N. J.D.W. is supported by the Goldwasser-Emsens fellowship. References 1. ↵ Hartley T , Lemire G , Kernohan KD , Howley HE , Adams DR , Boycott KM . New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases . Annu Rev Genomics Hum Genet . 2020 ; 21 : 351 – 72 . OpenUrl CrossRef PubMed 2. ↵ Wise AL , Manolio TA , Mensah GA , Peterson JF , Roden DM , Tamburro C , et al. Genomic medicine for undiagnosed diseases . The Lancet . 2019 ; 394 ( 10197 ): 533 – 40 . 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OpenUrl Abstract / FREE Full Text 22. ↵ Duan R , Kim JH , Shilagardi K , Schiffhauer ES , Lee DM , Son S , et al. Spectrin is a mechanoresponsive protein shaping fusogenic synapse architecture during myoblast fusion . Nat Cell Biol . 2018 ; 20 ( 6 ): 688 – 98 . OpenUrl CrossRef PubMed View the discussion thread. Back to top Previous Next Posted January 10, 2025. Download PDF Data/Code Email Thank you for your interest in spreading the word about medRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following A Heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy Message Subject (Your Name) has forwarded a page to you from medRxiv Message Body (Your Name) thought you would like to see this page from the medRxiv website. 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Share A Heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy Liedewei Van de Vondel , Jonathan De Winter , Alice Monticelli , Natacha Camacho , Tine Deconinck , Katrien Janssens , Goedele Malfroid , Alicia Alonso-Jiménez , German Demidov , Steven Laurie , Willem De Ridder , Biljana Ermanoska , Vincent Timmerman , Jonathan Baets medRxiv 2025.01.09.24319154; doi: https://doi.org/10.1101/2025.01.09.24319154 Share This Article: Copy Citation Tools A Heterozygous 9q34 deletion encompassing SPTAN1 as a cause of distal myopathy Liedewei Van de Vondel , Jonathan De Winter , Alice Monticelli , Natacha Camacho , Tine Deconinck , Katrien Janssens , Goedele Malfroid , Alicia Alonso-Jiménez , German Demidov , Steven Laurie , Willem De Ridder , Biljana Ermanoska , Vincent Timmerman , Jonathan Baets medRxiv 2025.01.09.24319154; doi: https://doi.org/10.1101/2025.01.09.24319154 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Area Genetic and Genomic Medicine Subject Areas All Articles Addiction Medicine (570) Allergy and Immunology (864) Anesthesia (302) Cardiovascular Medicine (4445) Dentistry and Oral Medicine (444) Dermatology (383) Emergency Medicine (609) Endocrinology (including Diabetes Mellitus and Metabolic Disease) (1515) Epidemiology (15236) Forensic Medicine (30) Gastroenterology (1127) Genetic and Genomic Medicine (6610) Geriatric Medicine (669) Health Economics (1000) Health Informatics (4549) Health Policy (1370) Health Systems and Quality Improvement (1613) Hematology (543) HIV/AIDS (1266) Infectious Diseases (except HIV/AIDS) (15926) Intensive Care and Critical Care Medicine (1104) Medical Education (623) Medical Ethics (147) Nephrology (668) Neurology (6613) Nursing (346) Nutrition (999) Obstetrics and Gynecology (1147) Occupational and Environmental Health (957) Oncology (3341) Ophthalmology (975) Orthopedics (369) Otolaryngology (420) Pain Medicine (436) Palliative Medicine (130) Pathology (665) Pediatrics (1694) Pharmacology and Therapeutics (693) Primary Care Research (714) Psychiatry and Clinical Psychology (5458) Public and Global Health (9244) Radiology and Imaging (2205) Rehabilitation Medicine and Physical Therapy (1370) Respiratory Medicine (1197) Rheumatology (596) Sexual and Reproductive Health (715) Sports Medicine (530) Surgery (713) Toxicology (99) Transplantation (289) Urology (265) (function(){function c(){var b=a.contentDocument||a.contentWindow.document;if(b){var d=b.createElement('script');d.innerHTML="window.__CF$cv$params={r:'a025451a8bac8468',t:'MTc3OTg4NzUzMw=='};var a=document.createElement('script');a.src='/cdn-cgi/challenge-platform/scripts/jsd/main.js';document.getElementsByTagName('head')[0].appendChild(a);";b.getElementsByTagName('head')[0].appendChild(d)}}if(document.body){var a=document.createElement('iframe');a.height=1;a.width=1;a.style.position='absolute';a.style.top=0;a.style.left=0;a.style.border='none';a.style.visibility='hidden';document.body.appendChild(a);if('loading'!==document.readyState)c();else if(window.addEventListener)document.addEventListener('DOMContentLoaded',c);else{var e=document.onreadystatechange||function(){};document.onreadystatechange=function(b){e(b);'loading'!==document.readyState&&(document.onreadystatechange=e,c())}}}})();