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1. Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene

Author

Luyckx, I, Kumar, AA, Reyniers, E, Dekeyser, E, Vanderstraeten, K, Vandeweyer, G, Wunnemann, F, Preuss, C, Mazzella, JM, Goudot, G, Messas, E, Albuisson, J, Jeunemaitre, X, Eriksson, P, Mohamed, SA, Kempers, M, Salemink, S, Duijnhouwer, A, Andelfinger, G, Dietz, HC, Verstraeten, A (Aline), Van Laer, L, Loeys, BL, Zhurayev, R, Zerbino, D, Mital, S, Mertens, L, Franco-Cereceda, A, Verhagen, Judith, De Graaf - van de Laar, Ingrid, Wessels, Marja, Nemcikova, M, Krebsova, A, Clinical Genetics, MIBAVA Leducq Consortium, Goudot, Guillaume, University of Antwerp (UA), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], The Jackson Laboratory [Bar Harbor] (JAX), Centre de Réféfence des Maladies Vasculaires Rares [HEGP, APHP] (CRMVR), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Radboud University Medical Center [Nijmegen], Howard Hughes Medical Institute (HHMI), Johns Hopkins University School of Medicine [Baltimore], and MIBAVA Leducq Consortium: Rustam Zhurayev, Dmytro Zerbino, Seema Mital, Luc Mertens, Anders Franco-Cereceda, Judith M A Verhagen, Ingrid M B H van de Laar, Marja W Wessels, Michaela Nemcikova, Alice Krebsova

Subjects
Adult, Heart Defects, Congenital, Male, Candidate gene, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Population, Heart Valve Diseases, Genome-wide association study, Disease, complex mixtures, Article, 03 medical and health sciences, Aortic aneurysm, All institutes and research themes of the Radboud University Medical Center, Bicuspid aortic valve, Bicuspid Aortic Valve Disease, Databases, Genetic, parasitic diseases, Genetics, medicine, Humans, Copy-number variation, education, Biology, Genetics (clinical), 0303 health sciences, education.field_of_study, Aortic Aneurysm, Thoracic, business.industry, 030305 genetics & heredity, Middle Aged, medicine.disease, Phenotype, digestive system diseases, [SDV] Life Sciences [q-bio], Chemistry, Aortic Valve, Female, Human medicine, T-Box Domain Proteins, business, Genome-Wide Association Study, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

International audience; Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. Based on the presence of overlapping CNVs in patients with cardiovascular phenotypes in the DECIPHER database, the identification of similar CNVs in whole-exome sequencing data of 67 BAV/TAA patients and suggested topological domain involvement from Hi-C data, supportive evidence was obtained for two genes (DGCR6 and TBX20) of the seven initially validated CNVs. A rare variant burden analysis using next-generation sequencing data from 637 BAV/TAA patients was performed for these two candidate genes. This revealed a suggestive genetic role for TBX20 in BAV/TAA aetiology, further reinforced by segregation of a rare TBX20 variant with the phenotype within a BAV/TAA family. To conclude, our results do not confirm a significant contribution for deleterious CNVs in BAV/TAA as only one potentially pathogenic CNV (1.05%) was identified. We cannot exclude the possibility that BAV/TAA is occasionally attributed to causal CNVs though, or that certain CNVs act as genetic risk factors by creating a sensitised background for BAV/TAA. Finally, accumulative evidence for TBX20 involvement in BAV/TAA aetiology underlines the importance of this transcription factor in cardiovascular disease.

Published
2019
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2. Loss of ADAMTS19 causes progressive non-syndromic heart valve disease

Author

Wunnemann, F., Ta-Shma, Asaf, Preuss, C., Leclerc, Severine, Vliet, Patrick Piet van, Oneglia, Andrea, Loeys, B.L., Franco-Cereceda, Anders, Mital, S., Wunnemann, F., Ta-Shma, Asaf, Preuss, C., Leclerc, Severine, Vliet, Patrick Piet van, Oneglia, Andrea, Loeys, B.L., Franco-Cereceda, Anders, and Mital, S.

Abstract

Contains fulltext : 216665.pdf (publisher's version ) (Closed access)

Published
2020

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

Author

Gillis, E., Kumar, A.A., Luyckx, I., Preuss, C., Cannaerts, E., Beek, G. van de, Wieschendorf, B., Alaerts, M., Bolar, N., Vandeweyer, G., Meester, J. de, Wunnemann, F., Gould, R.A., Zhurayev, R., Zerbino, D., Mohamed, S.A., Mital, S., Mertens, L., Bjorck, H.M., Franco-Cereceda, A., McCallion, A.S., Laer, L. Van, Verhagen, J.M.A., Laar, I. van de, Wessels, M.W., Messas, E., Goudot, G., Nemcikova, M., Krebsova, A., Kempers, M.J.E., Salemink, S., Duijnhouwer, T., Jeunemaitre, X., Albuisson, J., Eriksson, P., Andelfinger, G., Dietz, H.C., Verstraeten, A., Loeys, B.L., Gillis, E., Kumar, A.A., Luyckx, I., Preuss, C., Cannaerts, E., Beek, G. van de, Wieschendorf, B., Alaerts, M., Bolar, N., Vandeweyer, G., Meester, J. de, Wunnemann, F., Gould, R.A., Zhurayev, R., Zerbino, D., Mohamed, S.A., Mital, S., Mertens, L., Bjorck, H.M., Franco-Cereceda, A., McCallion, A.S., Laer, L. Van, Verhagen, J.M.A., Laar, I. van de, Wessels, M.W., Messas, E., Goudot, G., Nemcikova, M., Krebsova, A., Kempers, M.J.E., Salemink, S., Duijnhouwer, T., Jeunemaitre, X., Albuisson, J., Eriksson, P., Andelfinger, G., Dietz, H.C., Verstraeten, A., and Loeys, B.L.

Abstract

Contains fulltext : 176973.pdf (publisher's version ) (Open Access), 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.

Published
2017

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

Author

Gillis, E, Kumar, AA, Luyckx, I, Preuss, C, Cannaerts, E, van de Beek, G, Wieschendorf, B, Alaerts, M, Bolar, N, Vandeweyer, G, Meester, J, Wunnemann, F, Gould, RA, Zhurayev, R, Zerbino, D, Mohamed, SA, Mital, S, Mertens, L, Bjorck, HM, Franco-Cereceda, A, McCallion, AS, Van Laer, L, Verhagen, Judith, De Graaf - van de Laar, Ingrid, Wessels, Marja, 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 (Aline), Loeys, BL, Gillis, E, Kumar, AA, Luyckx, I, Preuss, C, Cannaerts, E, van de Beek, G, Wieschendorf, B, Alaerts, M, Bolar, N, Vandeweyer, G, Meester, J, Wunnemann, F, Gould, RA, Zhurayev, R, Zerbino, D, Mohamed, SA, Mital, S, Mertens, L, Bjorck, HM, Franco-Cereceda, A, McCallion, AS, Van Laer, L, Verhagen, Judith, De Graaf - van de Laar, Ingrid, Wessels, Marja, 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 (Aline), and Loeys, BL

Published
2017

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