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

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, Zhengye Zhao, Guilin Chen, Yuchen Niu, Xiangjie Yin, Yuhong Hu, Xiaochen Zhang, Pengfei Liu, Guixing Qiu, Wanlu Liu, Chengtian Zhao, Zhihong Wu (), Jianguo Zhang () and Nan Wu ()
Additional contact information
Sen Zhao: Peking Union Medical College and Chinese Academy of Medical Sciences
Hengqiang Zhao: Peking Union Medical College and Chinese Academy of Medical Sciences
Lina Zhao: 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
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
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
Zhengye Zhao: Peking Union Medical College and Chinese Academy of Medical Sciences
Guilin Chen: Peking Union Medical College and Chinese Academy of Medical Sciences
Yuchen Niu: Peking Union Medical College and Chinese Academy of Medical Sciences
Xiangjie Yin: Peking Union Medical College and 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
Guixing Qiu: Peking Union Medical College and 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
Jianguo Zhang: Peking Union Medical College and Chinese Academy of Medical Sciences
Nan Wu: Peking Union Medical College and Chinese Academy of Medical Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45442-5

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