Background Adolescent idiopathic scoliosis (AIS) is a genetically heterogeneous disease characterised by three-dimensional deformity of the spine in the absence of a congenital spinal anomaly or neurological musculoskeletal disorder. The clinical variability and incomplete penetrance of some genes linked with AIS indicate that this disease constitutes an oligogenic trait.
Objective We aimed to explore the oligogenic nature of this disease and identify novel AIS genes.
Methods We analysed rare damaging variants within AIS-associated genes by using exome sequencing in 40 AIS trios and 183 sporadic patients.
Results Multiple variants within AIS-associated genes were identified in eight AIS trios, and five individuals harboured rare damaging variants in the FLNB gene. The patients showed more frequent oligogenicity than the controls. In the gene-based burden test, the top signal resided in FLNB. In functional studies, we found that the AIS-associated FLNB variants altered the protein’s conformation and subcellular localisation and its interaction with other proteins (TTC26 and OFD1) involved in AIS. The most compelling evidence of an oligogenic basis was that the number of rare damaging variants was recognised as an independent prognostic factor for curve progression in Cox regression analysis.
Conclusion Our data indicate that AIS is an oligogenic disease and identify FLNB as a susceptibility gene for AIS.
- adolescent idiopathic scoliosis
- exome sequencing
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HJ, SL and KH contributed equally.
Contributors HJ, SL and KH contributed equally to this work. CW, FY and XZ are cocorresponding authors. HJ, SL, JH and FY conceived and designed the study. EX, JM, YM, JZ and RG collected the blood sample and clinical data. HJ, SL and KH performed the experiments. TL conducted in silico analysis. TL, RG and CW analysed the data. HJ and XZ wrote the manuscript. All authors reviewed and approved the manuscript.
Funding This work was supported by the National Natural Science Foundation of China (number 81772305) and Shanghai Sailing Program (19YF1447800).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All studies on human subjects were approved by ethics committee of Shanghai Changzheng Hospital, Shanghai. Written informed consent was obtained from all the participants. All the procedures were performed under the Declaration of Helsinki and relevant policies in China.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request.
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