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Original research
Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS)
  1. Sen Zhao1,2,
  2. Yuanqiang Zhang1,2,3,
  3. Weisheng Chen1,2,3,4,
  4. Weiyu Li5,
  5. Shengru Wang1,2,6,
  6. Lianlei Wang1,2,3,
  7. Yanxue Zhao1,2,
  8. Mao Lin1,2,3,
  9. Yongyu Ye2,7,
  10. Jiachen Lin1,2,3,
  11. Yu Zheng8,
  12. Jiaqi Liu2,9,
  13. Hengqiang Zhao1,2,3,10,
  14. Zihui Yan1,2,3,
  15. Yongxin Yang11,
  16. Yingzhao Huang1,2,
  17. Guanfeng Lin1,
  18. Zefu Chen1,2,
  19. Zhen Zhang1,2,
  20. Sen Liu1,2,
  21. Lichao Jin1,2,
  22. Zhaoyang Wang1,2,
  23. Jingdan Chen2,
  24. Yuchen Niu2,12,
  25. Xiaoxin Li2,12,
  26. Yong Wu2,
  27. Yipeng Wang1,2,
  28. Renqian Du4,
  29. Na Gao1,
  30. Hong Zhao1,
  31. Ying Yang1,
  32. Ying Liu1,
  33. Ye Tian1,
  34. Wenli Li1,
  35. Yu Zhao1,
  36. Jia Liu1,
  37. Bin Yu1,
  38. Na Zhang1,
  39. Keyi Yu1,
  40. Xu Yang1,
  41. Shugang Li1,
  42. Yuan Xu1,
  43. Jianhua Hu1,
  44. Zhe Liu13,
  45. Jianxiong Shen1,2,
  46. Shuyang Zhang2,14,
  47. Jianzhong Su10,
  48. Anas M Khanshour15,
  49. Yared H Kidane15,
  50. Brandon Ramo16,
  51. Jonathan J Rios15,17,
  52. Pengfei Liu4,18,
  53. V. Reid Sutton4,18,19,
  54. Jennifer E Posey4,
  55. Zhihong Wu2,6,12,
  56. Guixing Qiu1,2,6,12 Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study,
  57. Carol A Wise15,17,
  58. Feng Zhang5,
  59. James R Lupski4,19,20,21,
  60. Jianguo Zhang1,2,6,
  61. Nan Wu1,2,4,6
  1. 1Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
  2. 2Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China
  3. 3Graduate School, Peking Union Medical College, Beijing, China
  4. 4Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  5. 5Obstetrics and Gynecology Hospital, NHC Key Laboratory of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), School of Life Sciences, Shanghai, China
  6. 6Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
  7. 7Department of Orthopedic Surgery, First Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangzhou, China
  8. 8School of Finance, Southwestern University of Finance and Economics, Chengdu, Sichuan, China
  9. 9Department of Breast Surgical Oncology, National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
  10. 10School of Ophthalmology & Optometry and Eye Hospital, School of BiomedicalEngineering, Wenzhou Medical University, Wenzhou, Zhejiang, China
  11. 11Machine Intelligence Group, University of Edinburgh, Edinburgh, UK
  12. 12Medical Research Center, Peking Union Medical College Hospital, Peking UnionMedical College and Chinese Academy of Medical Sciences, Beijing, China
  13. 13Laboratory of Clinical Genetics, Peking Union Medical College Hospital, Peking UnionMedical College and Chinese Academy of Medical Sciences, Beijing, China
  14. 14Department of Cardiology, Peking Union Medical College Hospital, Peking UnionMedical College and Chinese Academy of Medical Sciences, Beijing, China
  15. 15Center for Pediatric Bone Biology and Translational Research, Scottish Rite for Children, Dallas, Texas, USA
  16. 16Department of Orthopaedic Surgery, Scottish Rite for Children, Dallas, Texas, USA
  17. 17McDermott Center for Human Growth and Development, Department of Pediatrics and Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
  18. 18Baylor Genetics, Houston, Texas, USA
  19. 19Texas Children's Hospital, Houston, Texas, USA
  20. 20Departments of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
  21. 21Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA
  1. Correspondence to Dr Nan Wu, Department of orthopaedic surgery; Beijing Key Laboratory for Genetic Research of Skeletal Deformity; Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; dr.wunan{at}pumch.cn; Dr Jianguo Zhang, Department of orthopaedic surgery; Beijing Key Laboratory for Genetic Research of Skeletal Deformity; Key Laboratory of Big Data for Spinal Deformities, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; zhangjianguo{at}pumch.cn

Abstract

Background Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening.

Methods In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited.

Results After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis.

Conclusion ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

  • genetics
  • clinical genetics
  • diagnostics
  • molecular genetics
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Footnotes

  • CAW, FZ, JRL, JZ and NW are joint senior authors.

  • Twitter @LiuPF, @poseypod

  • SZ, YZ, WC, WL and SW contributed equally.

  • Contributors NW, JZ and SZ conceived of the project and designed the study. SZ, YZ, WC, WL, SW, LW, LJ, ZW, JC and GL collected and interpreted the data. YZ, YY, JL, HZ, ZY, ZC and JS conducted the statistical analysis. SZ, YZ, YW, ML, JL, YY, YH, ZZ, SL, XL, RD, ZL and YN conducted the bioinformatic analyses. JZ, GQ, YW, NG, HZ, YY, YL, YT, WL, YZ, JL, BY, NZ, KY, XY, SL, YX, JH, JS and SZ recruited the patients. SZ, YZ, ZW and NW wrote the first draft of the manuscript, and AMK, YK, BR, JJR, PL, VRS, JEP, CAW, FZ and JRL critically revised the work for important intellectual content. All authors provided crucial input on several iterations of the manuscript and approved the final version.

  • Funding This research was funded in part by the National Natural Science Foundation of China (81822030 to NW, 81930068 and 81772299 to ZW, 81672123 and 81972037 to JZ, 31625015, 31571297 and 31771396 to FZ, 81871746 to YW and 81772301 to GQ), Beijing Natural Science Foundation (7191007 to ZW), CAMS Initiative Fund for Medical Sciences (2016-I2M-3-003 to GQ and NW, 2016-I2M-2-006 and 2017-I2M-2-001 to ZW), Tsinghua University-Peking Union Medical College Hospital Initiative Scientific Research Program (to NW), the National Key Research and Development Program of China (No. 2018YFC0910506 to N.W. and Z.W., No. 2016YFC0901501 to SZ), and the National Undergraduates Innovation and Training Program of Peking Union Medical College (2019zlgc0627 to SZ), CAMS Innovation Fund for Graduates (2018-1002-01-09 to YZ). Also supported by the US National Institutes of Health, National Institute of Neurological Disorders and Stroke (NINDS R35 NS105078 to JRL), National Human Genome Research Institute/National Heart, Lung, and Blood Institute (NHGRI/NHLBI UM1 HG006542 to Baylor-Hopkins Center for Mendelian Genomics), the National Human Genome Research Institute (NHGRI K08 HG008986 to JEP), TX Scottish Rite Hospital Research Fund (to CAW), Foundation Cotrel (to CAW), and P01 HD084387 (to CAW).

  • Competing interests JRL has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals and Novartis and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (by comparative genomic hybridisation microarray and/or single-nucleotide polymorphism arrays), clinical exome sequencing and whole-genome sequencing offered in the Baylor Genetics Laboratory (http://bmgl.com).

  • Patient consent for publication Not required.

  • Ethics approval Written informed consent was provided by each participant in the two cohorts. Approval for the study was obtained from the ethics committee at Peking Union Medical College Hospital (JS-098), the institutional review board of the University of Texas Southwestern Medical Center (STU 112010-150) and Baylor College of Medicine (H-29697).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. The datasets analyzed during the current study are available from the corresponding author on reasonable request.

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