Frontiers in Physiology (Jun 2017)
Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor
- Elisabeth Gillis,
- Ajay A. Kumar,
- Ilse Luyckx,
- Christoph Preuss,
- Elyssa Cannaerts,
- Gerarda van de Beek,
- Björn Wieschendorf,
- Björn Wieschendorf,
- Maaike Alaerts,
- Nikhita Bolar,
- Geert Vandeweyer,
- Josephina Meester,
- Florian Wünnemann,
- Russell A. Gould,
- Rustam Zhurayev,
- Dmytro Zerbino,
- Salah A. Mohamed,
- Seema Mital,
- Luc Mertens,
- Hanna M. Björck,
- Anders Franco-Cereceda,
- Andrew S. McCallion,
- Lut Van Laer,
- Judith M. A. Verhagen,
- Ingrid M. B. H. van de Laar,
- Marja W. Wessels,
- Emmanuel Messas,
- Guillaume Goudot,
- Michaela Nemcikova,
- Alice Krebsova,
- Marlies Kempers,
- Simone Salemink,
- Toon Duijnhouwer,
- Xavier Jeunemaitre,
- Juliette Albuisson,
- Per Eriksson,
- Gregor Andelfinger,
- Harry C. Dietz,
- Harry C. Dietz,
- Aline Verstraeten,
- Bart L. Loeys,
- Bart L. Loeys,
- Mibava Leducq Consortium
Affiliations
- Elisabeth Gillis
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Ajay A. Kumar
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Ilse Luyckx
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Christoph Preuss
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de MontrealMontreal, QC, Canada
- Elyssa Cannaerts
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Gerarda van de Beek
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Björn Wieschendorf
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Björn Wieschendorf
- Department of Cardiac and Thoracic Vascular Surgery, University Hospital Schleswig-HolsteinLübeck, Germany
- Maaike Alaerts
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Nikhita Bolar
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Geert Vandeweyer
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Josephina Meester
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Florian Wünnemann
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de MontrealMontreal, QC, Canada
- Russell A. Gould
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineBaltimore, MD, United States
- Rustam Zhurayev
- Department of Clinical pathology, Lviv National Medical University after Danylo HalytskyLviv, Ukraine
- Dmytro Zerbino
- Department of Clinical pathology, Lviv National Medical University after Danylo HalytskyLviv, Ukraine
- Salah A. Mohamed
- Department of Cardiac and Thoracic Vascular Surgery, University Hospital Schleswig-HolsteinLübeck, Germany
- Seema Mital
- Cardiovascular Research, SickKids University HospitalToronto, ON, Canada
- Luc Mertens
- Cardiovascular Research, SickKids University HospitalToronto, ON, Canada
- Hanna M. Björck
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska InstituteStockholm, Sweden
- Anders Franco-Cereceda
- Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska InstituteStockholm, Sweden
- Andrew S. McCallion
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineBaltimore, MD, United States
- Lut Van Laer
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Judith M. A. Verhagen
- Department of Clinical Genetics, Erasmus University Medical CenterRotterdam, Netherlands
- Ingrid M. B. H. van de Laar
- Department of Clinical Genetics, Erasmus University Medical CenterRotterdam, Netherlands
- Marja W. Wessels
- Department of Clinical Genetics, Erasmus University Medical CenterRotterdam, Netherlands
- Emmanuel Messas
- 0Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou; Université Paris Descartes, Paris Sorbonne Cité; Institut National de la Santé et de la Recherche Médicale, UMRSParis, France
- Guillaume Goudot
- 0Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou; Université Paris Descartes, Paris Sorbonne Cité; Institut National de la Santé et de la Recherche Médicale, UMRSParis, France
- Michaela Nemcikova
- 1Department of Biology and Medical Genetics, 2nd Faculty of Medicine-Charles University and Motol University HospitalPrague, Czechia
- Alice Krebsova
- 2Institute of Clinical and Experimental MedicinePrague, Czechia
- Marlies Kempers
- 3Department of Human Genetics, Radboud University Medical CentreNijmegen, Netherlands
- Simone Salemink
- 3Department of Human Genetics, Radboud University Medical CentreNijmegen, Netherlands
- Toon Duijnhouwer
- 3Department of Human Genetics, Radboud University Medical CentreNijmegen, Netherlands
- Xavier Jeunemaitre
- 0Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou; Université Paris Descartes, Paris Sorbonne Cité; Institut National de la Santé et de la Recherche Médicale, UMRSParis, France
- Juliette Albuisson
- 0Assistance Publique–Hôpitaux de Paris, Hôpital Européen Georges Pompidou; Université Paris Descartes, Paris Sorbonne Cité; Institut National de la Santé et de la Recherche Médicale, UMRSParis, France
- Per Eriksson
- Cardiovascular Medicine Unit, Department of Medicine, Karolinska InstituteStockholm, Sweden
- Gregor Andelfinger
- Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de MontrealMontreal, QC, Canada
- Harry C. Dietz
- McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineBaltimore, MD, United States
- Harry C. Dietz
- 4Howard Hughes Medical InstituteBaltimore, MD, United States
- Aline Verstraeten
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Bart L. Loeys
- Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium
- Bart L. Loeys
- 3Department of Human Genetics, Radboud University Medical CentreNijmegen, Netherlands
- Mibava Leducq Consortium
- DOI
- https://doi.org/10.3389/fphys.2017.00400
- Journal volume & issue
-
Vol. 8
Abstract
Bicuspid aortic valve (BAV) is the most common congenital heart defect. Although many BAV patients remain asymptomatic, at least 20% develop thoracic aortic aneurysm (TAA). Historically, BAV-related TAA was considered as a hemodynamic consequence of the valve defect. Multiple lines of evidence currently suggest that genetic determinants contribute to the pathogenesis of both BAV and TAA in affected individuals. Despite high heritability, only very few genes have been linked to BAV or BAV/TAA, such as NOTCH1, SMAD6, and MAT2A. Moreover, they only explain a minority of patients. Other candidate genes have been suggested based on the presence of BAV in knockout mouse models (e.g., GATA5, NOS3) or in syndromic (e.g., TGFBR1/2, TGFB2/3) or non-syndromic (e.g., ACTA2) TAA forms. We hypothesized that rare genetic variants in these genes may be enriched in patients presenting with both BAV and TAA. We performed targeted resequencing of 22 candidate genes using Haloplex target enrichment in a strictly defined BAV/TAA cohort (n = 441; BAV in addition to an aortic root or ascendens diameter ≥ 4.0 cm in adults, or a Z-score ≥ 3 in children) and in a collection of healthy controls with normal echocardiographic evaluation (n = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was SMAD6 (p = 0.002), with 2.5% (n = 11) of BAV/TAA patients harboring causal variants, including two nonsense, one in-frame deletion and two frameshift mutations. All six missense mutations were located in the functionally important MH1 and MH2 domains. In conclusion, we report a significant contribution of SMAD6 mutations to the etiology of the BAV/TAA phenotype.
Keywords
