Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort: SMAD6 as an important contributor

MIBAVA Leducq consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number400
JournalFrontiers in Physiology
Volume8
Issue numberJUN
DOIs
StatePublished - Jun 13 2017

Fingerprint

Thoracic Aortic Aneurysm
Genes
Bicuspid Aortic Valve
Exome
Frameshift Mutation
Congenital Heart Defects
Missense Mutation
Knockout Mice

Keywords

  • Bicuspid aortic valve
  • SMAD6
  • Targeted gene panel
  • Thoracic aortic aneurysm
  • Variant burden test

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Candidate gene resequencing in a large bicuspid aortic valve-associated thoracic aortic aneurysm cohort : SMAD6 as an important contributor. / MIBAVA Leducq consortium.

In: Frontiers in Physiology, Vol. 8, No. JUN, 400, 13.06.2017.

Research output: Contribution to journalArticle

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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 = "Bicuspid aortic valve, SMAD6, Targeted gene panel, Thoracic aortic aneurysm, Variant burden test",
author = "{MIBAVA Leducq consortium} and Elisabeth Gillis and Kumar, {Ajay A.} and Ilse Luyckx and Christoph Preuss and Elyssa Cannaerts and Beek, {Gerarda van de} and Bj{\"o}rn Wieschendorf and Maaike Alaerts and Nikhita Bolar and Geert Vandeweyer and Josephina Meester and Florian W{\"u}nnemann and Gould, {Russell A.} and Rustam Zhurayev and Dmytro Zerbino and Mohamed, {Salah A.} and Seema Mital and Luc Mertens and Bj{\"o}rck, {Hanna M.} and Anders Franco-Cereceda and McCallion, {Andrew S} and {Van Laer}, Lut and Verhagen, {Judith M.A.} and {van de Laar}, {Ingrid M.B.H.} and Wessels, {Marja W.} and Emmanuel Messas and Guillaume Goudot and Michaela Nemcikova and Alice Krebsova and Marlies Kempers and Simone Salemink and Toon Duijnhouwer and Xavier Jeunemaitre and Juliette Albuisson and Per Eriksson and Gregor Andelfinger and Dietz, {Harry C} and Aline Verstraeten and Loeys, {Bart L.}",
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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.

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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.

KW - Bicuspid aortic valve

KW - SMAD6

KW - Targeted gene panel

KW - Thoracic aortic aneurysm

KW - Variant burden test

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