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Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene.
Luyckx, Ilse; Kumar, Ajay A; Reyniers, Edwin; Dekeyser, Emily; Vanderstraeten, Kathleen; Vandeweyer, Geert; Wünnemann, Florian; Preuss, Christoph; Mazzella, Jean-Michaël; Goudot, Guillaume; Messas, Emmanuel; Albuisson, Juliette; Jeunemaitre, Xavier; Eriksson, Per; Mohamed, Salah A; Kempers, Marlies; Salemink, Simone; Duijnhouwer, Anthonie; Andelfinger, Gregor; Dietz, Harry C; Verstraeten, Aline; Van Laer, Lut; Loeys, Bart L.
Afiliación
  • Luyckx I; Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
  • Kumar AA; Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
  • Reyniers E; Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
  • Dekeyser E; Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
  • Vanderstraeten K; Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
  • Vandeweyer G; Centre of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
  • Wünnemann F; Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Saint-Justine Research Centre, Université de Montréal, Montreal, QC, Canada.
  • Preuss C; Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Saint-Justine Research Centre, Université de Montréal, Montreal, QC, Canada.
  • Mazzella JM; The Jackson Laboratory, Bar Harbor, ME, USA.
  • Goudot G; Centre de réféfence des maladies vasculaires rares, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, France, Paris, France.
  • Messas E; Centre de réféfence des maladies vasculaires rares, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, France, Paris, France.
  • Albuisson J; Centre de réféfence des maladies vasculaires rares, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, France, Paris, France.
  • Jeunemaitre X; Centre de réféfence des maladies vasculaires rares, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, France, Paris, France.
  • Eriksson P; Centre de réféfence des maladies vasculaires rares, Hôpital Européen Georges Pompidou, APHP, Université Paris Descartes, France, Paris, France.
  • Mohamed SA; Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  • Kempers M; Department of Cardiac and Thoracic Vascular Surgery, University Clinic of Schleswig-Holstein, Luebeck, Germany.
  • Salemink S; Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
  • Duijnhouwer A; Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
  • Andelfinger G; Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
  • Dietz HC; Cardiovascular Genetics, Department of Pediatrics, Centre Hospitalier Universitaire Saint-Justine Research Centre, Université de Montréal, Montreal, QC, Canada.
  • Verstraeten A; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Van Laer L; Howard Hughes Medical Institute, Baltimore, MD, USA.
  • Loeys BL; Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Eur J Hum Genet ; 27(7): 1033-1043, 2019 07.
Article en En | MEDLINE | ID: mdl-30820038
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Válvula Aórtica / Aneurisma de la Aorta Torácica / Proteínas de Dominio T Box / Bases de Datos Genéticas / Variaciones en el Número de Copia de ADN / Cardiopatías Congénitas / Enfermedades de las Válvulas Cardíacas Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Eur J Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2019 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Válvula Aórtica / Aneurisma de la Aorta Torácica / Proteínas de Dominio T Box / Bases de Datos Genéticas / Variaciones en el Número de Copia de ADN / Cardiopatías Congénitas / Enfermedades de las Válvulas Cardíacas Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies Límite: Adult / Female / Humans / Male / Middle aged Idioma: En Revista: Eur J Hum Genet Asunto de la revista: GENETICA MEDICA Año: 2019 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Reino Unido