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J Med Genet. 2018 Oct;55(10):675-684. doi: 10.1136/jmedgenet-2017-105224. Epub 2018 Aug 17.

Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM).

Wang K#1, Zhao S#2,3,4, Liu B2,3,4, Zhang Q1, Li Y2,3,4, Liu J2,3,5, Shen Y6, Ding X1, Lin J2,3,4, Wu Y2, Yan Z2,3,4, Chen J2,3,4, Li X2,7, Song X8, Niu Y2,7, Liu J1, Chen W2,3,4, Ming Y9, Du R8, Chen C9, Long B7, Zhang Y1, Tong X6, Zhang S2,10, Posey JE8, Zhang B6, Wu Z2,3,7, Wythe JD11,12,13, Liu P8, Lupski JR8,14,15, Yang X1, Wu N2,3,4.

Author information

1
Department of Interventional Neuroradiology, Beijing Neurosurgical Institute and Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
2
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing, China.
3
Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing, China.
4
Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
5
Department of Breast Surgical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
6
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, China.
7
Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
8
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
9
PET-CT Center, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
10
Department of Cardiology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
11
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas, USA.
12
Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, USA.
13
Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas, USA.
14
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
15
Texas Children's Hospital, Houston, Texas, USA.
#
Contributed equally

Abstract

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-β) 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-β and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.

KEYWORDS:

brain arteriovenous malformation (bavm); genetics heterogeneity; vasculogenesis; whole exome sequencing

Conflict of interest statement

Competing interests: JRL has stock ownership in 23andMe and Lasergen, is a paid consultant for Regeneron Pharmaceuticals and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered in the Baylor Genetics Laboratory (http://bmgl.com).

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