Abstract
The craniovertebral junction (CVJ) is an anatomically complex region of the axial skeleton that provides protection of the brainstem and the upper cervical spinal cord. Structural malformation of the CVJ gives rise to life-threatening neurological deficits, such as quadriplegia and dyspnea. Unfortunately, genetic studies on human subjects with CVJ malformation are limited and the pathogenesis remains largely elusive. In this study, we recruited 93 individuals with CVJ malformation and performed exome sequencing. Manual interpretation of the data identified three pathogenic variants in genes associated with Mendelian diseases, including CSNK2A1, MSX2, and DDX3X. In addition, the contribution of copy number variations (CNVs) to CVJ malformation was investigated and three pathogenic CNVs were identified in three affected individuals. To further dissect the complex mutational architecture of CVJ malformation, we performed a gene-based rare variant association analysis utilizing 4371 in-house exomes as control. Rare variants in LGI4 (carrier rate = 3.26%, p = 3.3 × 10–5) and BEST1 (carrier rate = 5.43%, p = 5.77 × 10–6) were identified to be associated with CVJ malformation. Furthermore, gene set analyses revealed that extracellular matrix- and RHO GTPase-associated biological pathways were found to be involved in the etiology of CVJ malformation. Overall, we comprehensively dissected the genetic underpinnings of CVJ malformation and identified several novel disease-associated genes and biological pathways.
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Datasets are available from the corresponding author on reasonable request.
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Acknowledgements
This research was funded in part by the Beijing Municipal Excellent Talents Training Fund (2018000020124G142 to Z.L.), the Science and Technology Innovation Capacity Building-advanced discipline construction project (1192070315 to F.J.), the National Natural Science Foundation of China (81930068 and 81772299 to Z.W., 81822030 and 82072391 to N.W., 81672123 and 81972037 to T.J.Z.), Beijing Natural Science Foundation (JQ20032 to N.W., 7191007 to Z.W.), CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-051 to J.Z. and N.W., 2021-I2M-1-052 to Z.W.). We thank Dr. Zan Chen for his contribution in recruiting CVJ malformation patients.
Funding
This research was funded in part by the Beijing Municipal Excellent Talents Training Fund (2018000020124G142 to Z.L.), the Science and Technology Innovation Capacity Building-advanced discipline construction project (1192070315 to F.J.), the National Natural Science Foundation of China (81930068 and 81772299 to Z.W., 81822030 and 82072391 to N.W., 81672123 and 81972037 to T.J.Z.), Beijing Natural Science Foundation (JQ20032 to N.W., 7191007 to Z.W.), CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1-051 to J.Z. and N.W., 2021-I2M-1-052 to Z.W.).
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Terry Jianguo Zhang, Fengzeng Jian and Nan Wu contributed to the study conception and design. Material preparation, data collection and analysis were performed by Zhenlei Liu, Hengqiang Zhao, Huakang Du, Siyi Cai, Sen Zhao, Yuchen Niu, Xiaoxin Li, Bowen Liu, Yingzhao Huang, Jiashen Shao, Lian Liu, Ye Tian, Zhihong Wu, Hao Wu and Yue Hu. The first draft of the manuscript was written by Zhenlei Liu, Hengqiang Zhao, Huakang Du and Siyi Cai, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Liu, Z., Du, H., Zhao, H. et al. Dissection of mendelian predisposition and complex genetic architecture of craniovertebral junction malformation. Hum Genet 142, 89–101 (2023). https://doi.org/10.1007/s00439-022-02474-5
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DOI: https://doi.org/10.1007/s00439-022-02474-5