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Basic science
Original research
Exome sequencing of 112 trios identifies recessive genetic variants in brain arteriovenous malformations
  1. Mingqi Zhang1,
  2. Xinghuan Ding2,
  3. Qianqian Zhang3,
  4. Jian Liu1,
  5. Yisen Zhang1,
  6. Ying Zhang1,
  7. Zhongbin Tian1,
  8. Wenqiang Li1,
  9. Wei Zhu1,
  10. Huibin Kang1,
  11. Zhongxiao Wang1,
  12. Xinzhi Wu1,
  13. Chao Wang1,
  14. Xinjian Yang1,
  15. Kun Wang1
  1. 1 Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
  2. 2 Department of Neurosurgery, Beijing Ditan Hospital, Capital Medical University, Beijing 100070, China
  3. 3 Department of Cerebrovascular Disease, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Henan Provincial Neurointerventional Engineering Research Center and Henan International Joint Laboratory of Cerebrovascular Disease, Zhengzhou 450000, Henan, China
  1. Correspondence to Dr Kun Wang, Department of Interventional Neuroradiology, Beijing TianTan Hospital and Beijing Neurosurgical Institute, Capital Medical University, No.119, South 4th Ring West Road, Fengtai District, Beijing 100070, China; wangkun650{at}126.com; Dr Xinjian Yang, Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, No.119, South 4th Ring West Road, Fengtai District, Beijing 100070, China; yangxinjian{at}voiceoftiantan.org

Abstract

Background Brain arteriovenous malformation (BAVM) is a main cause of cerebral hemorrhage and hemorrhagic stroke in adolescents. Morphologically, a BAVM is an abnormal connection between cerebrovascular arteries and veins. The genetic etiology of BAVMs has not been fully elucidated. In this study, we aim to investigate potential recessive genetic variants in BAVMs by interrogation of rare compound heterozygous variants.

Methods We performed whole exome sequencing (WES) on 112 BAVM trios and analyzed the data for rare and deleterious compound heterozygous mutations associated with the disease.

Results We identified 16 genes with compound heterozygous variants that were recurrent in more than one trio. Two genes (LRP2, MUC5B) were recurrently mutated in three trios. LRP2 has been previously associated with BAVM pathogenesis. Fourteen genes (MYLK, HSPG2, PEAK1, PIEZO1, PRUNE2, DNAH14, DNAH5, FCGBP, HERC2, HMCN1, MYH1, NHSL1, PLEC, RP1L1) were recurrently mutated in two trios, and five of these genes (MYLK, HSPG2, PEAK1, PIEZO1, PRUNE2) have been reported to play a role in angiogenesis or vascular diseases. Additionally, abnormal expression of the MYLK protein is related to spinal arteriovenous malformations.

Conclusion Our study indicates that rare recessive compound heterozygous variants may underlie cases of BAVM. These findings improve our understanding of BAVM pathology and indicate genes for functional validation.

  • arteriovenous malformation
  • genetic
  • hemorrhage

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/neurintsurg-2020-016469

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Contributors Study concept and design: Kun Wang, Xinjian Yang. Acquisition of data and technique support: Mingqi Zhang, Xinghuan Ding, Qianqian Zhang, Zhongxiao Wang, Xinzhi Wu, Chao Wang. Analysis and interpretation of data: Jian Liu, Yisen Zhang, Ying Zhang, Zhongbin Tian, Huibin Kang. Drafting or revising the manuscript: Mingqi Zhang, Xinghuan Ding, Wei Zhu, Wenqiang Li. Final approval of the version to be published: Kun Wang, Xinjian Yang. Agreement to be accountable for all aspects of the work: Mingqi Zhang.

    • Funding This work was supported by National Key Research and Development Plan of China (grant number: 2016YFC1300800), the National Natural Science Foundation of China (grant numbers: 81671139, 81901178, 81 801 156 and 81801158), the Excellent Talent Training Program of Dongcheng District, Beijing (grant number: 2019-DCT-M-15), the Youth Innovation Project of Beijing Neurosurgical Institute (code: 2019004) and Beijing Tiantan Hospitals Authority Youth Programme (code: QML20190503).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.