2. Academic Validation
  3. ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm

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

  • Nat Genet. 2019 Jan;51(1):42-50. doi: 10.1038/s41588-018-0265-y.
Russell A Gould # 1 2,  Hamza Aziz # 1 2,  Courtney E Woods # 1,  Manuel Alejandro Seman-Senderos 1,  Elizabeth Sparks 1,  Christoph Preuss 3 4,  Florian Wünnemann 3,  Djahida Bedja 5 6,  Cassandra R Moats 5 7,  Sarah A McClymont 8,  Rebecca Rose 1,  Nara Sobreira 1,  Hua Ling 8,  Gretchen MacCarrick 1,  Ajay Anand Kumar 9,  Ilse Luyckx 9,  Elyssa Cannaerts 9,  Aline Verstraeten 9,  Hanna M Björk 10,  Ann-Cathrin Lehsau 11,  Vinod Jaskula-Ranga 12,  Henrik Lauridsen 13,  Asad A Shah 14,  Christopher L Bennett 1 2,  Patrick T Ellinor 15 16,  Honghuang Lin 17,  Eric M Isselbacher 18,  Christian Lacks Lino Cardenas 19,  Jonathan T Butcher 13,  G Chad Hughes 20,  Mark E Lindsay 21,  Baylor-Hopkins Center for Mendelian Genomics,  MIBAVA Leducq Consortium,  Luc Mertens 22,  Anders Franco-Cereceda 23,  Judith M A Verhagen 24,  Marja Wessels 25,  Salah A Mohamed 11,  Per Eriksson 10,  Seema Mital 25,  Lut Van Laer 9,  Bart L Loeys 9 26,  Gregor Andelfinger 4 27,  Andrew S McCallion 28 29 30,  Harry C Dietz 31 32 33 34
Affiliations

Affiliations

  • 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.
  • # Contributed equally.
PMID: 30455415 DOI: 10.1038/s41588-018-0265-y
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.

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