期刊
JOURNAL OF MEDICAL GENETICS
卷 55, 期 10, 页码 675-684出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jmedgenet-2017-105224
关键词
brain arteriovenous malformation (bavm); whole exome sequencing; genetics heterogeneity; vasculogenesis
资金
- National Natural Science Foundation of China [81671139, 81220108007, 81501852]
- Beijing Nova Program [Z161100004916123]
- National Key Research and Development Plan of China [2016YFC1300800, 2016YFC090150, 2016YFC0901501]
- 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine
- CAMS Initiative Fund for Medical Sciences [2016-I2M-3-003]
- Beijing Natural Science Foundation [7172175]
- Central Level Public Interest Program for Scientific Research Institute [2016ZX310177]
- Fundamental Research Funds for the Central Universities [3332016006]
- Distinguished Youth Foundation of Peking Union Medical College Hospital [JQ201506]
- Beijing Nova Program Interdisciplinary Collaborative Project [xxjc201717]
- American Heart Association [16GRNT31330023]
- National Key Research and Development Program of China, Stem Cell and Translational Research [2016YFA0100500]
- National Institute of Neurological Disorders and Stroke [NINDS R01N058529]
- National Human Genome Research Institute/National Heart, Lung, and Blood Institute [NHGRI/NHLBI UM1 HG006542]
- National Human Genome Research Institute [NHGRI K08 HG008986]
- PUMC Youth Fund
Background Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM. Methods We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model. Results We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene, ENG, and three damaging variants in novel candidate genes: PITPNM3, SARS and LEMD3, which we then functionally validated in zebrafish. In addition, eight likely pathogenic heterozygous variants (TIMP3, SCUBE2, MAP4K4, CDH2, IL17RD, PREX2, ZFYVE16 and EGFR) were identified in eight patients, and 16 patients carried one or more variants of uncertain significance. Potential oligogenic inheritance (MAP4K4 with ENG, RASA1 with TIMP3 and SCUBE2 with ENG) was identified in three patients. Regulation of sma- and mad-related proteins (SMADs) (involved in bone morphogenic protein (BMP)/transforming growth factor beta (TGF-beta) signalling) and vascular endothelial growth factor (VEGF)/vascular endotheliual growth factor recepter 2 (VEGFR2) binding and activity (affecting the VEGF signalling pathway) were the most significantly affected biological process involved in the pathogenesis of BAVM. Conclusions Our study highlights the specific role of BMP/TGF-beta and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据