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Unraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine

Author

Listed:
  • Sen Zhao

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Baylor College of Medicine)

  • Hengqiang Zhao

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Lina Zhao

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Xi Cheng

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Zhifa Zheng

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Mengfan Wu

    (Ocean University of China)

  • Wen Wen

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Shengru Wang

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Zixiang Zhou

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Haibo Xie

    (Ocean University of China)

  • Dengfeng Ruan

    (Zhejiang University)

  • Qing Li

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Xinquan Liu

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Chengzhu Ou

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Guozhuang Li

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Zhengye Zhao

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Guilin Chen

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Yuchen Niu

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Xiangjie Yin

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Yuhong Hu

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Xiaochen Zhang

    (Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Pengfei Liu

    (Baylor College of Medicine
    Baylor Genetics)

  • Guixing Qiu

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Wanlu Liu

    (Zhejiang University)

  • Chengtian Zhao

    (Ocean University of China)

  • Zhihong Wu

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences)

  • Jianguo Zhang

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

  • Nan Wu

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Beijing Key Laboratory for Genetic Research of Skeletal Deformity
    Chinese Academy of Medical Sciences)

Abstract

Congenital vertebral malformation, affecting 0.13–0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord at early developmental stages and myoblast/myocytes at late stages, highlighting their critical roles in the developing spine. Our work provides insights into the developmental biology of the human spine and the pathogenesis of spine malformation.

Suggested Citation

  • Sen Zhao & Hengqiang Zhao & Lina Zhao & Xi Cheng & Zhifa Zheng & Mengfan Wu & Wen Wen & Shengru Wang & Zixiang Zhou & Haibo Xie & Dengfeng Ruan & Qing Li & Xinquan Liu & Chengzhu Ou & Guozhuang Li & Z, 2024. "Unraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45442-5
    DOI: 10.1038/s41467-024-45442-5
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    References listed on IDEAS

    as
    1. Mary E. Dickinson & Ann M. Flenniken & Xiao Ji & Lydia Teboul & Michael D. Wong & Jacqueline K. White & Terrence F. Meehan & Wolfgang J. Weninger & Henrik Westerberg & Hibret Adissu & Candice N. Baker, 2016. "High-throughput discovery of novel developmental phenotypes," Nature, Nature, vol. 537(7621), pages 508-514, September.
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