Fetal pathogenesis of scoliosis suggested by asymmetry of gene expression in paravertebral muscles

Background The malfunction of paravertebral muscles may contribute to the development of idiopathic scoliosis. Several candidate genes have been linked to scoliosis, but the underlying mechanisms and cell types remain unclear.

We included 40 idiopathic scoliosis cases and 19 controls. Muscle biopsies were obtained bilaterally in the cases, and at least unilaterally in the controls. RNA sequencing, differential gene expression analysis and gene set enrichment analysis were performed between cases and controls, and between convex and concave sides in the cases. Hounsfield units (HU) in paravertebral muscles from preoperative CT were assessed at biopsy sites in cases.

Qualified transcriptome analysis included 56 samples (30 convex, 26 concave) from 35 scoliosis cases and 22 samples from 17 controls. Among 14,212 expressed genes included in the downstream analysis, 22 differentially expressed genes were identified between cases and controls and 16 between convex and concave sides. Scoliosis cases showed decreased fetal muscle and immune cells. Convex side showed decreased fibro-adipogenic progenitors, endothelial cell types, satellite cells and myeloid cells and increased fetal skeletal muscle cells. Morphological asymmetry was verified by the HU findings.

These results indicated asymmetry of gene expression profiles and suggests a fetal developmental origin of idiopathic scoliosis, with increased muscle mass pushing convexity. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was funded by Swedish Research Council The Stockholm County Council Center for Innovative Medicine Karolinska Institutet HRH Crown Princess Lovisas Association for Child Healthcare Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Swedish Ethical Review Authority in Stockholm. Case (Dnr) number 2017/2374-31, 2018/1457-32, 2022/00700-02, 2024/05452-02. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Shared first authorship between Tian Cheng and Gamze Yazgeldi Gunaydin Conflict-of-interest statement The authors have no conflict of interests.