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

Fiche publication

Date publication

juin 2017

Journal

Frontiers in physiology

Auteurs

Membres identifiés du Cancéropôle Est :
Dr ALBUISSON Juliette

Tous les auteurs :
Gillis E, Kumar AA, Luyckx I, Preuss C, Cannaerts E, van de Beek G, Wieschendorf B, Alaerts M, Bolar N, Vandeweyer G, Meester J, Wünnemann F, Gould RA, Zhurayev R, Zerbino D, Mohamed SA, Mital S, Mertens L, Björck HM, Franco-Cereceda A, McCallion AS, Van Laer L, Verhagen JMA, van de Laar IMBH, Wessels MW, Messas E, Goudot G, Nemcikova M, Krebsova A, Kempers M, Salemink S, Duijnhouwer T, Jeunemaitre X, Albuisson J, Eriksson P, Andelfinger G, Dietz HC, Verstraeten A, Loeys BL,

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/28659821

Résumé

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 , and . 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., ) or in syndromic (e.g., ) or non-syndromic (e.g., ) 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 ( = 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 ( = 183). After additional burden analysis against the Exome Aggregation Consortium database, the strongest candidate susceptibility gene was ( = 0.002), with 2.5% ( = 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 mutations to the etiology of the BAV/TAA phenotype.