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
  • 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. [email protected].
  • 29. Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 30. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 31. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 32. Howard Hughes Medical Institute, Baltimore, MD, USA. [email protected].
  • 33. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • 34. Department of Pediatrics, Division of Pediatric Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
  • # 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.