Actionable Genes, Core Databases, and Locus-Specific Databases.
Adoption of next-generation sequencing (NGS) in a diagnostic context raises numerous questions with regard to identification and reports of secondary variants (SVs) in actionable genes. To better understand the whys and wherefores of these questioning, it is necessary to understand how they are selected during the filtering process and how their proportion can be estimated. It is likely that SVs are underestimated and that our capacity to label all true SVs can be improved. In this context, Locus-specific databases (LSDBs) can be key by providing a wealth of information and enabling classifying variants. We illustrate this issue by analyzing 318 SVs in 23 actionable genes involved in cancer susceptibility syndromes identified through sequencing of 572 participants selected for a range of atherosclerosis phenotypes. Among these 318 SVs, only 43.4% are reported in Human Gene Mutation Database (HGMD) Professional versus 71.4% in LSDB. In addition, 23.9% of HGMD Professional variants are reported as pathogenic versus 4.8% for LSDB. These data underline the benefits of LSDBs to annotate SVs and minimize overinterpretation of mutations thanks to their efficient curation process and collection of unpublished data.
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Amélie
A
Pinard
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Morgane
M
Miltgen
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Arnaud
A
Blanchard
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Hélène
H
Mathieu
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Jean-Pierre
JP
Desvignes
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
David
D
Salgado
Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Hôpital Timone Enfants, Laboratoire de Génétique Moléculaire, Marseille, 13385, France.
Aurélie
A
Fabre
AP-HP, Hôpital Bichat, Centre National de Référence pour le syndrome de Marfan et apparentés, Paris, France.|UFR de Médecine, Diderot Paris Université Paris 7, Paris, France.|Inserm, U1148, Paris, France.
Pauline
P
Arnaud
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Laura
L
Barré
Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Hôpital Timone Enfants, Laboratoire de Génétique Moléculaire, Marseille, 13385, France.
Martin
M
Krahn
Aix Marseille Univ, INSERM, GMGF, Marseille, France.|AP-HM, Hôpital de la Timone, Gastroentérologie, Marseille, France.
Philippe
P
Grandval
Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Hôpital Timone Enfants, Laboratoire de Génétique Moléculaire, Marseille, 13385, France.|Hôpital Clairval, Ramsay Générale de Santé, Marseille, France.|Hôpital Européen, Fondation Ambroise Paré, Marseille, France.
Sylviane
S
Olschwang
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Stéphane
S
Zaffran
AP-HP, Hôpital Bichat, Centre National de Référence pour le syndrome de Marfan et apparentés, Paris, France.|UFR de Médecine, Diderot Paris Université Paris 7, Paris, France.|Inserm, U1148, Paris, France.
Catherine
C
Boileau
Aix Marseille Univ, INSERM, GMGF, Marseille, France.|APHM, Hôpital Timone Enfants, Laboratoire de Génétique Moléculaire, Marseille, 13385, France.
Christophe
C
Béroud
Aix Marseille Univ, INSERM, GMGF, Marseille, France.
Gwenaëlle
G
Collod-Béroud
D050197:Atherosclerosis / Q000235:genetics*; D019295:Computational Biology; D030541:Databases, Genetic; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D058977:Molecular Sequence Annotation; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012984:Software
LSDB; NGS; actionable genes; databases; secondary variant