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

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2024年2月6日

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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,
Sen Liu,
Zihui Yan,
Xiaoxin Li,
Bowen Liu,
Yingzhao Huang,
Guangxi Gao,
Qing Liu,
Jianle Yang,
Xinyu Yang,
Aoran Maheshati,
Jihao Cai,
Yuanpeng Zhu,
Jie Wang,
Yang Yang,
Ziquan Li,
Guanfeng Lin,
Xiaohan Ye,
Pengfei Liu,
Guixing Qiu,
Wanlu Liu,
Chengtian Zhao,
Zhihong Wu,
Jianguo Zhang,
Nan Wu

摘要

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.