Dissection of mendelian predisposition and complex genetic architecture of craniovertebral junction malformation

被引:0
|
作者
Zhenlei Liu
Huakang Du
Hengqiang Zhao
Siyi Cai
Sen Zhao
Yuchen Niu
Xiaoxin Li
Bowen Liu
Yingzhao Huang
Jiashen Shao
Lian Liu
Ye Tian
Zhihong Wu
Hao Wu
Yue Hu
Terry Jianguo Zhang
Fengzeng Jian
Nan Wu
机构
[1] Xuanwu Hospital,Department of Neurosurgery
[2] Capital Medical University,Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases
[3] Spine Center,Key Laboratory of Big Data for Spinal Deformities
[4] China International Neuroscience Institute (China-INI),undefined
[5] Peking Union Medical College Hospital,undefined
[6] Peking Union Medical College and Chinese Academy of Medical Sciences,undefined
[7] Beijing Key Laboratory for Genetic Research of Skeletal Deformity,undefined
[8] Chinese Academy of Medical Sciences,undefined
来源
Human Genetics | 2023年 / 142卷
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学科分类号
摘要
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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页码:89 / 101
页数:12
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