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Nat Genet. 2019 Jan;51(1):42-50. doi: 10.1038/s41588-018-0265-y. Epub 2018 Nov 19.

ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm.

Author information

1
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
2
Howard Hughes Medical Institute, Baltimore, MD, USA.
3
Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine Research Centre, Université de Montréal, Montreal, Quebec, Canada.
4
The Jackson Laboratory, Bar Harbor, ME, USA.
5
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6
Heart and Vascular Institute, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
7
Oregon National Primate Research Center, Portland, OR, USA.
8
Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
9
Center for Medical Genetics, Faculty of Medicine and Health Sciences, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium.
10
Center for Molecular Medicine, Department of Medicine Solna, University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
11
Department of Cardiac and Thoracic Vascular Surgery, University Hospital Lübeck, Lübeck, Germany.
12
Wilmer Eye Institute in the Department of Ophthalmology at the Johns Hopkins University School of Medicine, Baltimore, MD, USA.
13
The Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA.
14
Rex Hospital, Raleigh, NC, USA.
15
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
16
Cardiovascular Research Institute, Massachussets General Hospital, Charlestown, MA, USA.
17
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
18
Thoracic Aortic Center, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
19
Cardiovascular Research Center, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
20
Division of Cardiovascular and Thoracic Surgery, Duke University Medical Center, Durham, NC, USA.
21
Thoracic Aortic Center and Cardiovascular Genetics Program, Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
22
Division of Cardiology, The Hospital for Sick Children, Labatt Family Heart Centre, Toronto, Ontario, Canada.
23
Department of Molecular Medicine and Surgery, University Hospital Solna, Karolinska Institutet, Stockholm, Sweden.
24
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
25
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
26
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
27
Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada.
28
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. andy@jhmi.edu.
29
Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. andy@jhmi.edu.
30
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. andy@jhmi.edu.
31
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. hdietz@jhmi.edu.
32
Howard Hughes Medical Institute, Baltimore, MD, USA. hdietz@jhmi.edu.
33
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. hdietz@jhmi.edu.
34
Department of Pediatrics, Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. hdietz@jhmi.edu.

Abstract

Bicuspid aortic valve (BAV) is a common congenital heart defect (population incidence, 1-2%)1-3 that frequently presents with ascending aortic aneurysm (AscAA)4. BAV/AscAA shows autosomal dominant inheritance with incomplete penetrance and male predominance. Causative gene mutations (for example, NOTCH1, SMAD6) are known for ≤1% of nonsyndromic BAV cases with and without AscAA5-8, impeding mechanistic insight and development of therapeutic strategies. Here, we report the identification of variants in ROBO4 (which encodes a factor known to contribute to endothelial performance) that segregate with disease in two families. Targeted sequencing of ROBO4 showed enrichment for rare variants in BAV/AscAA probands compared with controls. Targeted silencing of ROBO4 or mutant ROBO4 expression in endothelial cell lines results in impaired barrier function and a synthetic repertoire suggestive of endothelial-to-mesenchymal transition. This is consistent with BAV/AscAA-associated findings in patients and in animal models deficient for ROBO4. These data identify a novel endothelial etiology for this common human disease phenotype.

PMID:
30455415
PMCID:
PMC6309588
[Available on 2019-05-19]
DOI:
10.1038/s41588-018-0265-y

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