AUTHOR=Gillis Elisabeth , Kumar Ajay A. , Luyckx Ilse , Preuss Christoph , Cannaerts Elyssa , van de Beek Gerarda , Wieschendorf Björn , Alaerts Maaike , Bolar Nikhita , Vandeweyer Geert , Meester Josephina , Wünnemann Florian , Gould Russell A. , Zhurayev Rustam , Zerbino Dmytro , Mohamed Salah A. , Mital Seema , Mertens Luc , Björck Hanna M. , Franco-Cereceda Anders , McCallion Andrew S. , Van Laer Lut , Verhagen Judith M. A. , van de Laar Ingrid M. B. H. , Wessels Marja W. , Messas Emmanuel , Goudot Guillaume , Nemcikova Michaela , Krebsova Alice , Kempers Marlies , Salemink Simone , Duijnhouwer Toon , Jeunemaitre Xavier , Albuisson Juliette , Eriksson Per , Andelfinger Gregor , Dietz Harry C. , Verstraeten Aline , Loeys Bart L. ,  Mibava Leducq Consortium 

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

JOURNAL=Frontiers in Physiology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2017.00400

DOI=10.3389/fphys.2017.00400

ISSN=1664-042X

ABSTRACT=<p>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 <italic>NOTCH1, SMAD6</italic>, and <italic>MAT2A</italic>. 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., <italic>GATA5, NOS3</italic>) or in syndromic (e.g., <italic>TGFBR1/2, TGFB2/3</italic>) or non-syndromic (e.g., <italic>ACTA2</italic>) 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 (<italic>n</italic> = 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 (<italic>n</italic> = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was <italic>SMAD6</italic> (<italic>p</italic> = 0.002), with 2.5% (<italic>n</italic> = 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 <italic>SMAD6</italic> mutations to the etiology of the BAV/TAA phenotype.</p>