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
Data availability statement
Data are available upon reasonable request.
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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.