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WES/WGS Reporting of Mutations from Cardiovascular "Actionable" Genes in Clinical Practice: A Key Role for UMD Knowledgebases in the Era of Big Databases.

  • Pinard, Amélie1
  • Salgado, David1
  • Desvignes, Jean-Pierre1
  • Rai, Ghadi1
  • Hanna, Nadine2, 3, 4
  • Arnaud, Pauline2, 3, 4
  • Guien, Céline1
  • Martinez, Maria5
  • Faivre, Laurence6, 7, 8
  • Jondeau, Guillaume4, 9, 10
  • Boileau, Catherine3, 4, 10
  • Zaffran, Stéphane1
  • Béroud, Christophe1, 11
  • Collod-Béroud, Gwenaëlle1
  • 1 Aix Marseille Univ, INSERM, GMGF, Marseille, France. , (France)
  • 2 Département de Génétique, Hôpital Bichat AP-HP, Paris, France. , (France)
  • 3 Inserm U1148 LVTS, Equipe 2 Maladies Structurelles Cardiovasculaires, Hôpital Bichat, Université Paris Diderot, Sorbonne Paris Cité.
  • 4 Centre National de Référence Maladies Rares, Syndrome de Marfan et pathologies apparentées, Hôpital Bichat, AP-HP, Paris, France. , (France)
  • 5 IRSD, INSERM, INRA, ENVT, UPS, Université de Toulouse, Toulouse, France. , (France)
  • 6 Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, Dijon, France. , (France)
  • 7 Centre de Génétique et Centre de Référence, Anomalies du Développement et Syndromes Malformatifs de l'Inter-région Est, Centre Hospitalier Universitaire Dijon, Dijon, France. , (France)
  • 8 EA 4271 GAD, Université de Bourgogne Franche-Comté, Dijon, France. , (France)
  • 9 Service de Cardiologie, AP-HP, Hôpital Bichat, Paris, France. , (France)
  • 10 AP-HP, Centre de référence pour les syndromes de Marfan et apparentés, Service de Cardiologie, Hôpital Bichat, Paris, France. , (France)
  • 11 AP-HM, Département de Génétique Médicale, Hôpital Timone Enfants, Marseille, France. , (France)
Published Article
Human Mutation
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2016
DOI: 10.1002/humu.23119
PMID: 27647783


High-throughput next-generation sequencing such as whole-exome and whole-genome sequencing are being rapidly integrated into clinical practice. The use of these techniques leads to the identification of secondary variants for which decisions about the reporting or not to the patient need to be made. The American College of Medical Genetics and Genomics recently published recommendations for the reporting of these variants in clinical practice for 56 "actionable" genes. Among these, seven are involved in Marfan Syndrome And Related Disorders (MSARD) resulting from mutations of the FBN1, TGFBR1 and 2, ACTA2, SMAD3, MYH11 and MYLK genes. Here, we show that mutations collected in UMD databases for MSARD genes (UMD-MSARD) are rarely reported, including the most frequent ones, in global scale initiatives for variant annotation such as the NHLBI GO Exome Sequencing Project (ESP), the Exome Aggregation Consortium (ExAC), and ClinVar. The predicted pathogenic mutations reported in global scale initiatives but absent in locus-specific databases (LSDBs) mainly correspond to rare events. UMD-MSARD databases are therefore the only resources providing access to the full spectrum of known pathogenic mutations. They are the most comprehensive resources for clinicians and geneticists to interpret MSARD-related variations not only primary variants but also secondary variants.

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