TY - JOUR
T1 - Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor
AU - MIBAVA Leducq Consortium
AU - Gillis, Elisabeth
AU - Kumar, Ajay A.
AU - Luyckx, Ilse
AU - Preuss, Christoph
AU - Cannaerts, Elyssa
AU - Beek, Gerarda van de
AU - Wieschendorf, Björn
AU - Alaerts, Maaike
AU - Bolar, Nikhita
AU - Vandeweyer, Geert
AU - Meester, Josephina
AU - Wünnemann, Florian
AU - Gould, Russell A.
AU - Zhurayev, Rustam
AU - Zerbino, Dmytro
AU - Mohamed, Salah A.
AU - Mital, Seema
AU - Mertens, Luc
AU - Björck, Hanna M.
AU - Franco-Cereceda, Anders
AU - McCallion, Andrew S.
AU - Van Laer, Lut
AU - Verhagen, Judith M.A.
AU - van de Laar, Ingrid M.B.H.
AU - Wessels, Marja W.
AU - Messas, Emmanuel
AU - Goudot, Guillaume
AU - Nemcikova, Michaela
AU - Krebsova, Alice
AU - Kempers, Marlies
AU - Salemink, Simone
AU - Duijnhouwer, Toon
AU - Jeunemaitre, Xavier
AU - Albuisson, Juliette
AU - Eriksson, Per
AU - Andelfinger, Gregor
AU - Dietz, Harry C.
AU - Verstraeten, Aline
AU - Loeys, Bart L.
N1 - Publisher Copyright:
© 2017 Gillis, Kumar, Luyckx, Preuss, Cannaerts, van de Beek, et al.
PY - 2017/6/13
Y1 - 2017/6/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85020773719&partnerID=8YFLogxK
U2 - 10.3389/fphys.2017.00400
DO - 10.3389/fphys.2017.00400
M3 - Journal articles
AN - SCOPUS:85020773719
SN - 1664-042X
VL - 8
JO - Frontiers in Physiology
JF - Frontiers in Physiology
IS - JUN
M1 - 400
ER -