Unraveling the genetic architecture of congenital vertebral malformation with reference to the developing spine
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Published:2024-02-06
Issue:1
Volume:15
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Zhao SenORCID, Zhao Hengqiang, Zhao Lina, Cheng Xi, Zheng Zhifa, Wu Mengfan, Wen Wen, Wang Shengru, Zhou ZixiangORCID, Xie Haibo, Ruan DengfengORCID, Li QingORCID, Liu Xinquan, Ou ChengzhuORCID, Li Guozhuang, Zhao Zhengye, Chen Guilin, Niu Yuchen, Yin Xiangjie, Hu YuhongORCID, Zhang Xiaochen, Liu Sen, Yan Zihui, Li Xiaoxin, Liu Bowen, Huang Yingzhao, Gao Guangxi, Liu Qing, Yang Jianle, Yang Xinyu, Maheshati Aoran, Cai Jihao, Zhu Yuanpeng, Wang Jie, Yang Yang, Li Ziquan, Lin Guanfeng, Ye Xiaohan, Liu Pengfei, Qiu Guixing, Liu WanluORCID, Zhao ChengtianORCID, Wu Zhihong, Zhang Jianguo, Wu NanORCID,
Abstract
AbstractCongenital 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.
Funder
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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