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Front Physiol. 2017 Jun 13;8:400. doi: 10.3389/fphys.2017.00400. eCollection 2017.

Candidate Gene Resequencing in a Large Bicuspid Aortic Valve-Associated Thoracic Aortic Aneurysm Cohort: SMAD6 as an Important Contributor.

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Faculty of Medicine and Health Sciences, Center of Medical Genetics, University of Antwerp and Antwerp University HospitalAntwerp, Belgium.
Cardiovascular Genetics, Department of Pediatrics, CHU Sainte-Justine, Université de MontrealMontreal, QC, Canada.
Department of Cardiac and Thoracic Vascular Surgery, University Hospital Schleswig-HolsteinLübeck, Germany.
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of MedicineBaltimore, MD, United States.
Department of Clinical pathology, Lviv National Medical University after Danylo HalytskyLviv, Ukraine.
Cardiovascular Research, SickKids University HospitalToronto, ON, Canada.
Cardiovascular Medicine Unit, Department of Medicine, Karolinska InstituteStockholm, Sweden.
Cardiothoracic Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska InstituteStockholm, Sweden.
Department of Clinical Genetics, Erasmus University Medical CenterRotterdam, Netherlands.
Assistance 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.
Department of Biology and Medical Genetics, 2nd Faculty of Medicine-Charles University and Motol University HospitalPrague, Czechia.
Institute of Clinical and Experimental MedicinePrague, Czechia.
Department of Human Genetics, Radboud University Medical CentreNijmegen, Netherlands.
Howard Hughes Medical InstituteBaltimore, MD, United States.


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.


SMAD6; bicuspid aortic valve; targeted gene panel; thoracic aortic aneurysm; variant burden test

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